Biopsy is a commonly used method for determining pathological diagnoses by directly using human tissues and cells. Biopsies are widely used to determine disease progression and treatment efficacy. Although organs and tissues are usually obtained by sacrifice during animal experiments, it is theoretically possible to use the same biopsy techniques in humans. In the present study, we examined the feasibility of performing four repeated liver biopsies in a spontaneous metabolic syndrome mouse model. Even though a small number of mice died accidently, most mice were able to undergo four liver biopsies without significant adverse events. We also performed three liver biopsies in mouse liver tumor carcinogen models at 4, 8, and 12 weeks of age. In addition to the sample collected at 16 weeks of age during sacrifice, we successfully collected four liver samples from the same mice at different stages of disease progression. The application of this liver biopsy technique might make it possible for direct evaluation of pathological conditions in the same individual over time, thereby reducing the number of experimental animals.
These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.
Takumi Kakimoto, Masato Hosokawa, Mayuko Shimizu, Hirohisa Ogawa, Yuko Miyakami, Satoshi Sumida and Koichi Tsuneyama : Accumulation of α-synuclein in hepatocytes in nonalcoholic steatohepatitis and its usefulness in pathological diagnosis., Pathology, Research and Practice, Vol.247, 154525, 2023.
(Summary)
Nonalcoholic steatohepatitis (NASH) is characterized by fat deposition, inflammation, and hepatocellular damage. The diagnosis of NASH is confirmed pathologically, and hepatocyte ballooning is an important finding for definite diagnosis. Recently, α-synuclein deposition in multiple organs was reported in Parkinson's disease. Since it was reported that α-synuclein is taken up by hepatocytes via connexin 32, the expression of α-synuclein in the liver in NASH is of interest. The accumulation of α-synuclein in the liver in NASH was investigated. Immunostaining for p62, ubiquitin, and α-synuclein was performed, and the usefulness of immunostaining in pathological diagnosis was examined. Liver biopsy tissue specimens from 20 patients were evaluated. Several antibodies against α-synuclein, as well as antibodies against connexin 32, p62, and ubiquitin were used for immunohistochemical analyses. Staining results were evaluated by several pathologists with varying experience, and the diagnostic accuracy of ballooning was compared. Polyclonal α-synuclein antibody, not the monoclonal antibody, reacted with eosinophilic aggregates in ballooning cells. Expression of connexin 32 in degenerating cells was also demonstrated. Antibodies against p62 and ubiquitin also reacted with some of the ballooning cells. In the pathologists' evaluations, the highest interobserver agreement was obtained with hematoxylin and eosin (H&E)-stained slides, followed by slides immunostained for p62 and α-synuclein, and there were cases with different results between H&E staining and immunostaining CONCLUSION: These results indicate the incorporation of degenerated α-synuclein into ballooning cells, suggesting the involvement of α-synuclein in the pathogenesis of NASH. The combination of immunostaining including polyclonal α-synuclein may contribute to improving the diagnosis of NASH.
Yuko Miyakami, Takeo Minamikawa, Hirohisa Ogawa, Mayuko Shimizu and Koichi Tsuneyama : Definitive Confirmation of Erythropoietic Protoporphyria via Re-biopsy Three Years After Initial Liver Biopsy at Age 15., Curēus, Vol.15, No.4, e38017, 2023.
(Summary)
Erythropoietic protoporphyria (EPP) is a rare inherited disorder of porphyrin metabolism that can cause liver damage and cholestatic hepatocellular failure. We report a case of EPP in a teenaged male who underwent liver biopsy for investigation of liver dysfunction of unknown cause. The diagnosis was not made until a re-biopsy approximately three years later, when the patient presented with recurrent skin lesions and elevated blood and urinary protoporphyrin levels. The liver biopsies contained brownish deposits that exhibited birefringence under polarized light and porphyrin fluorescence under fluorescence spectroscopy. EPP should be considered in young patients with unexplained liver dysfunction, skin symptoms, and seasonal changes in symptoms. Fluorescence spectroscopy of liver biopsy tissue can be a useful tool in the diagnosis of EPP.
Minoru Matsumoto, Takuya Ohmura, Yuto Hanibuchi, Mayuko Shimizu, Yasuyo Saijo, Hirohisa Ogawa, Ryuichiro Miyazawa, Junko Morimoto, Koichi Tsuneyama, Mitsuru Matsumoto and Takeshi Oya : AIRE illuminates the feature of medullary thymic epithelial cells in thymic carcinoma., Cancer Medicine, 2023.
(Summary)
Despite the clear distinction between cortical (cTECs) and medullary thymic epithelial cells (mTECs) in physiology, the cell of origin of thymic carcinomas (TCs) and other thymic epithelial tumors remained enigmatic. We addressed this issue by focusing on AIRE, an mTEC-specific transcriptional regulator that is required for immunological self-tolerance. We found that a large proportion of TCs expressed AIRE with typical nuclear dot morphology by immunohistochemistry. AIRE expression in TCs was supported by the RNA-seq data in the TCGA-THYM database. Furthermore, our bioinformatics approach to the recent single-cell RNA-seq data on human thymi has revealed that TCs hold molecular characteristics of multiple mTEC subpopulations. In contrast, TCs lacked the gene signatures for cTECs. We propose that TCs are tumors derived from mTECs.
Satoshi Sumida, Mayuko Shimizu, Yuko Miyakami, Takumi Kakimoto, Tomoko Kobayashi, Yasuyo Saijo, Minoru Matsumoto, Hirohisa Ogawa, Takeshi Oya, Yoshimi Bando, Hisanori Uehara, Shu Taira, Mitsuo Shimada and Koichi Tsuneyama : Histological and immunohistochemical analysis of epithelial cells in epidermoid cysts in intrapancreatic accessory spleen., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 251-259, 2023.
(Summary)
Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.
Kozo Kagawa, Seidai Satou, Kazuya Koyama, Takeshi Imakura, Kojin Murakami, Yuya Yamashita, Nobuhito Naito, Hirohisa Ogawa, Hiroshi Kawano and Yasuhiko Nishioka : The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-β production in regulatory T-cells., PLoS ONE, Vol.17, No.10, e0275987, 2022.
(Summary)
These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.
Wenhua Shao, Orgil Jargalsaikhan, Mayuko Shimizu, Qinyi Cai, Hirohisa Ogawa, Yuko Miyakami, Kengo Atsumi, Mitsuru Tomita, Mitsuko Sutoh, Shunji Toyohara, Ryoji Hokao, Yasusei Kudo, Takeshi Oya and Koichi Tsuneyama : Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice., International Journal of Molecular Sciences, Vol.23, No.19, 2022.
(Summary)
Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard.
Makoto Tobiume, Atsushi Mitsuhashi, Atsuro Saijo, Hirokazu Ogino, Tania Afroj, Hirohisa Ogawa, Hisatsugu Goto, Seidai Satou, Akane Abe, Keiko Haji, Ryohiko Ozaki, Hiromitsu Takizawa and Yasuhiko Nishioka : Analysis of the chemotactic factors for tumor-infiltrating fibrocytes and their prognostic significances in lung cancer., Oncology Letters, Vol.24, No.5, 417, 2022.
(Summary)
Fibrocytes, which are bone marrow-derived collagen-producing cells, have been reported to be involved in pathogenesis of pulmonary fibrosis. Our previous study reported that tumor-infiltrating fibrocytes play a role in tumor progression and drug resistance in lung cancer. The present study therefore examined chemotactic factors for fibrocytes in tissues of non-small cell lung cancer (NSCLC) and their prognostic significance. Surgically resected tumor tissues were examined for the expression of chemotactic factors, including C-X-C motif chemokine 12 (CXCL12), CCL2, platelet-derived growth factor (PDGF)-AA and PDGF-BB, as well as tumor-infiltrating fibrocytes by immunostaining. The chemotactic ability of fibrocytes in response to each factor was evaluated using a migration assay by counting the migrated cells microscopically, and expression of receptors for chemotactic factors were analyzed by flow cytometry. The expression of CXCL12, but not CCL2, PDGF-AA, or PDGF-BB, was associated with the number of tumor-infiltrating fibrocytes in lung adenocarcinoma (LUAD), but not lung squamous cell carcinoma (LUSQ). In addition, patients with an increased expression of CXCL12 in LUAD but not LUSQ showed a significantly poorer prognosis compared with those with a decreased expression. However, the expression of CCL2, PDGF-AA and PDGF-BB was not correlated with the prognosis of patients with NSCLC. The number of fibrocytes was associated with a poor prognosis in LUAD. Fibrocytes derived from the peripheral blood of healthy subjects as well as patients with lung cancer expressed higher levels of CXCR4 compared with CCR2, PDGF and receptor-α and receptor-β. Overall, these results suggested that targeting tumor-infiltrating fibrocytes via the CXCL12/CXCR4 axis may be a useful strategy for controlling the progression of NSCLC, particularly LUAD.
Hirohisa Ogawa, Masahiko Azuma, Aya Umeno, Mayuko Shimizu, Kazutoshi Murotomi, Yasukazu Yoshida, Yasuhiko Nishioka and Koichi Tsuneyama : Singlet oxygen -derived nerve growth factor exacerbates airway hyperresponsiveness in a mouse model of asthma with mixed inflammation., Allergology International, Vol.71, No.3, 395-404, 2022.
(Summary)
Our findings suggest that neutrophil MPO-derived singlet oxygen induces increased NGF production, leading to AHR and 10- and 12-(Z,E)-HODEs production. These findings may help to develop new therapies targeting this mechanism and to establish a new biomarker for non-type 2 and refractory asthma.
Mayuko Shimizu, Yosuke Tsuchiyama, Yuki Morimoto, Minoru Matsumoto, Tomoko Kobayashi, Satoshi Sumida, Takumi Kakimoto, Takeshi Oya, Hirohisa Ogawa, Michiko Yamashita, Satoru Matsuda, Katsuhisa Omagari, Shu Taira and Koichi Tsuneyama : A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages, The American Journal of Pathology, Vol.192, No.1, 31-42, 2022.
(Summary)
Various cells, such as macrophages and hepatic stellate cells, interact in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), but the mechanism remains unclear. We employed a high-fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis and investigate the pathogenesis of fibrosis. Two mouse strains differing in susceptibility to obesity, the susceptible strain C57BL/6J and the relatively resistant strain A/J, developed hepatic histologic features of NASH, including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis, after 9 weeks of HFCC diet feeding. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in C57BL/6J mice. A/J mice fed the HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light visualized the Maltese cross (namely, cholesterol crystals within the aggregated macrophages). Moreover, fibrosis developed in a ring shape from the periphery of the aggregated macrophages (ie, the starting point of fibrosis could be visualized histologically). Furthermore, matrix-assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine [P-18:1 (11Z)/18:0] and phosphatidylethanolamine [18:0/20:2 (11Z, 14Z)], in aggregated macrophages adjacent to the fibrotic lesions. In conclusion, the present HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.
Mayuko Shimizu, Takeshi Kageyama, Takeshi Oya, Hirohisa Ogawa, Minoru Matsumoto, Satoshi Sumida, Takumi Kakimoto, Yuko Miyakami, Ryosuke Nagatomo, Koichi Inoue, Chunmei Cheng and Koichi Tsuneyama : Verification of the Impact of Blood Glucose Level on Liver Carcinogenesis and the Efficacy of a Dietary Intervention in a Spontaneous Metabolic Syndrome Model, International Journal of Molecular Sciences, Vol.22, No.23, 12844, 2021.
(Summary)
Metabolic syndrome (MS) is a risk factor for type 2 diabetes mellitus, vascular inflammation, atherosclerosis, and renal, liver, and heart diseases. Non-alcoholic steatohepatitis (NASH) is a progressive representative liver disease and may lead to the irreversible calamities of cirrhosis and hepatocellular carcinoma. Metabolic disorders such as hyperglycemia have been broadly reported to be related to hepatocarcinogenesis in NASH; however, direct evidence of a link between hyperglycemia and carcinogenesis is still lacking. Tsumura Suzuki Obese Diabetic (TSOD) mice spontaneously develop metabolic syndrome, including obesity, insulin resistance, and NASH-like liver phenotype, and eventually develop hepatocellular carcinomas. TSOD mice provide a spontaneous human MS-like model, even with significant individual variations. In this study, we monitored mice in terms of their changes in blood glucose levels, body weights, and pancreatic and liver lesions over time. As a result, liver carcinogenesis was delayed in non-hyperglycemic TSOD mice compared to hyperglycemic mice. Moreover, at the termination point of 40 weeks, liver tumors appeared in 18 of 24 (75%) hyperglycemic TSOD mice; in contrast, they only appeared in 5 of 24 (20.8%) non-hyperglycemic mice. Next, we investigated three kinds of oligosaccharide that could lower blood glucose levels in hyperglycemic TSOD mice. We monitored the levels of blood and urinary glucose and assessed pancreatic lesions among the experimental groups. As expected, significantly lower levels of blood and urinary glucose and smaller deletions of Langerhans cells were found in TSOD mice fed with milk-derived oligosaccharides (galactooligosaccharides and lactosucrose). At the age of 24 weeks, mild steatohepatitis was found in the liver but there was no evidence of liver carcinogenesis. Steatosis in the liver was alleviated in the milk-derived oligosaccharide-administered group. Taken together, suppressing the increase in blood glucose level from a young age prevented susceptible individuals from diabetes and the onset of NAFLD/NASH, as well as carcinogenesis. Milk-derived oligosaccharides showed a lowering effect on blood glucose levels, which may be expected to prevent liver carcinogenesis.
Toshifumi Tezuka, Masahiko Azuma, Hirohisa Ogawa, Mayo Kondou, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi and Yasuhiko Nishioka : A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells., Experimental Lung Research, Vol.47, No.9, 451-463, 2021.
(Summary)
The RAS signal pathway plays a crucial role in allergen-induced airway remodeling associated with ILC2s. XRP44X may have therapeutic potential for refractory asthma.
Tomoko Kobayashi, Mayuko Shimizu, Takeshi Oya, Hirohisa Ogawa, Minoru Matsumoto, Yuki Morimoto, Satoshi Sumida, Takumi Kakimoto, Michiko Yamashita, Mitsuko Sutoh, Shunji Toyohara, Ryoji Hokao, Chunmei Cheng and Koichi Tsuneyama : Neonatal streptozotocin treatment rapidly causes different subtype of hepatocellular carcinoma without persistent hyperglycemia in 4CS mice fed on a normal diet., Pathology, Research and Practice, Vol.225, No.153559, 2021.
(Summary)
Although diabetes mellitus (DM) is a well-known risk factor for hepatocellular carcinoma (HCC), the underlying mechanisms have not yet to be defined. We previously reported that DIAR mice fed with standard murine diet developed type 1 diabetes and HCC at age of 16 weeks old with a neonatal streptozotocin treatment (n-STZ). Because DIAR mice did not manifest obesity nor develop steatohepatitis, hyperglycemia with streptozotocin trigger or streptozotocin alone might turn on the hepato-carcinogenesis. An insulin-recruitment to DIAR-nSTZ mice showed an increased frequency of HCC during the first 12 weeks of age, although the diabetic indications notably improved. To elucidate the role of hyperglycemia in hepato-carcinogenesis, we performed a head-to-head comparative study by using 4CS mice and DIAR mice with n-STZ treatment. Newborn 4CS mice and DIAR mice were divided into STZ treated group and control group. The blood glucose levels of DIAR-nSTZ mice increased at age of eight weeks, while that of 4CS-nSTZ mice were maintained in the normal range. At eight weeks old, three out of five DIAR-nSTZ mice (60%) and one out of ten 4CS-nSTZ mice (10%) developed multiple liver tumors. At age of 12 weeks old, all eight of DIAR-nSTZ mice (100%) and two of 10 4CS-nSTZ mice (20%) developed multiple liver tumors. At 16 weeks old, all animals of DIAR-nSTZ and 4CS-nSTZ mice occurred liver tumors. DIAR-nSTZ showed hyperglycemia and HCC, and 4CS-nSTZ developed HCC without hyperglycemia. These results were interpreted that the onset of HCC maybe not related to the presence or absence of hyperglycemia but nSTZ treatment. On the other hand, since the carcinogenesis of 4CS-nSTZ is delayed compared to DIAR-nSTZ, hyperglycemia may play a role in the progression of carcinogenesis. Histologically, the liver tumor appeared irregularly trabecular arrangements of hepatocytes with various degrees of nuclear atypia. By immunohistochemical analyses, all liver tumors showed positive staining of glutamine synthetase (GS), an established human HCC marker. The expression pattern of GS was divided into a strong diffuse pattern and weak patchy pattern, respectively. The liver tumor showing the weak GS-patchy pattern expressed biliary/stem markers, EpCAM, and SALL4, partially. Because 4CS-nSTZ mice did not show any metabolic complications such as gaining body weight or high blood glucose level, it is a unique animal model with a simple condition to investigate hepatic carcinogenesis by excluding other factors.
Mitsuteru Yoshida, Masao Yuasa, Hirohisa Ogawa, Naoki Miyamoto, Yukikiyo Kawakami, Kazuya Kondo and Akira Tangoku : Can Computed Tomography Differentiate Adenocarcinoma In Situ from Minimally Invasive Adenocarcinoma?, Thoracic Cancer, Vol.12, No.7, 1023-1032, 2021.
(Summary)
Given the subtle pathological signs of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), effective differentiation between the two entities is crucial. However, it is difficult to predict these conditions using preoperative computed tomography (CT) imaging. In this study, we investigated whether histological diagnosis of AIS and MIA using quantitative three-dimensional CT imaging analysis could be predicted. We retrospectively analyzed the images and histopathological findings of patients with lung cancer who were diagnosed with AIS or MIA between January 2017 and June 2018. We used Synapse Vincent (v. 4.3) (Fujifilm) software to analyze the CT attenuation values and performed a histogram analysis. There were 22 patients with AIS and 22 with MIA. The ground-glass nodule (GGN) rate was significantly higher in patients with AIS (p < 0.001), whereas the solid volume (p < 0.001) and solid rate (p = 0.001) were significantly higher in those with MIA. The mean (p = 0.002) and maximum (p = 0.025) CT values were significantly higher in patients with MIA. The 25th, 50th, 75th, and 97.5th percentiles (all p < 0.05) for the CT values were significantly higher in patients with MIA. We demonstrated that quantitative analysis of 3D-CT imaging data using software can help distinguish AIS from MIA. These analyses are useful for guiding decision-making in the surgical management of early lung cancer, as well as subsequent follow-up.
(Keyword)
Adenocarcinoma / Adenocarcinoma in Situ / Aged / Female / Humans / Male / Retrospective Studies / Tomography, X-Ray Computed
Shun Morizumi, Seidai Satou, Kazuya Koyama, Hiroyasu Okazaki, Yajuan Chen, Hisatsugu Goto, Kozo Kagawa, Hirohisa Ogawa, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis., American Journal of Respiratory Cell and Molecular Biology, Vol.63, No.3, 317-326, 2020.
(Summary)
H]thymidine incorporation assays. The expression of FGFR was analyzed using IB or flow cytometry. We also investigated the effect of BGJ398 on pulmonary fibrosis induced by bleomycin in mice. Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality resulting from alveolar injury and inhibition of AEC regeneration. These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused.
高松 直子, Yusuke Osaki, Hiroki Yamazaki, Kazutaka Kuroda, Hirohisa Ogawa, Hisanori Uehara, Koichi Tsuneyama, Hiroyuki Nodera and Yuishin Izumi : A case of led to diagnosis of malignancy by brachial plexus ultrasonography, Neurosonology, Vol.33, No.2, 36-40, 2020.
(Summary)
A 72-year-old man admitted to our hospital due to severe pain and drop hand in the left arm. MRI and CT of the head and neck at an outside hospital showed no abnormality. Neurological findings revealed distal weakness in the left upper extremity, vague pain between the radial aspect of the left hand and the middle of the digits 1-3, as well as brisk reflexes in the left extremities. Small masses were palpable in the posterior neck, the lower jaw, and the left neck. Clinically, left radial neuropathy and cervical radiculopathy were suspected. We performed ultrasound of the nerve roots, brachial plexus, and the radial nerve. There was a mass compressing the left brachial plexus from the caudolateral direction. Additionally, nerve swelling in the left arm was identified. Skin biopsy over the mass suggested metastatic adenocarcinoma. Chest CT scan showed a mass in the upper right lobe suggestive of a lung cancer. We concluded that the pain was due to radial neuropathy and upper and middle trunk disturbance of the left brachial plexopathy, of which neuromuscular ultrasound was useful in diagnosis.
Mayo Kondou, Toshifumi Tezuka, Hirohisa Ogawa, Kazuya Koyama, Hiroki Bando, Masahiko Azuma and Yasuhiko Nishioka : Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation., International Archives of Allergy and Immunology, Vol.182, No.1, 1-13, 2020.
(Summary)
These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.
These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.
Kazuya Koyama, Hisatsugu Goto, Shun Morizumi, Kozo Kagawa, Haruka Nishimura, Seidai Satou, Hiroshi Kawano, Yuko Toyoda, Hirohisa Ogawa, Sakae Homma and Yasuhiko Nishioka : The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice., American Journal of Respiratory Cell and Molecular Biology, Vol.60, No.4, 478-487, 2019.
(Summary)
The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.
Masami Kishi, Yoshinori Aono, Seidai Satou, Kazuya Koyama, Momoyo Azuma, Shuichi Abe, Hiroshi Kawano, Jun Kishi, Yuko Toyoda, Hiroyasu Okazaki, Hirohisa Ogawa, Hisanori Uehara and Yasuhiko Nishioka : Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice., PLoS ONE, Vol.13, No.12, 2018.
(Summary)
Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of pulmonary fibrosis. Nintedanib, a multi-kinase inhibitor that targets several tyrosine kinases, including PDGF receptor (PDGFR), was recently approved as an anti-fibrotic agent to reduce the deterioration of FVC in patients with idiopathic pulmonary fibrosis (IPF). However, the effects of PDGFR-α or -β on pulmonary fibrosis remain unclear. In an attempt to clarify their effects, we herein used blocking antibodies specific for PDGFR-α (APA5) and -β (APB5) in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. The effects of these treatments on the growth of lung fibroblasts were examined using the 3H-thymidine incorporation assay in vitro. The anti-fibrotic effects of these antibodies were investigated with the Ashcroft score and collagen content of lungs treated with BLM. Their effects on inflammatory cells in the lungs were also analyzed using bronchoalveolar lavage fluid. We investigated damage to epithelial cells and the proliferation of fibroblasts in the lungs. APA5 and APB5 inhibited the phosphorylation of PDGFR-α and -β as well as the proliferation of lung fibroblasts induced by PDGF-AA and BB. The administration of APB5, but not APA5 effectively inhibited BLM-induced pulmonary fibrosis in mice. Apoptosis and the proliferation of epithelial cells and fibroblasts were significantly decreased by the treatment with APB5, but not by APA5. The late treatment with APB5 also ameliorated fibrosis in lungs treated with BLM. These results suggest that PDGFR-α and -β exert different effects on BLM-induced pulmonary fibrosis in mice. A specific approach using the blocking antibody for PDGFR-β may be useful for the treatment of pulmonary fibrosis.
Yuishin Izumi, Ryosuke Miyamoto, Koji Fujita, Yuki Yamamoto, Hirotsugu Yamada, Tomoyasu Matsubara, Yuki Unai, Ai Tsukamoto, Naoko Takamatsu, Hiroyuki Nodera, Shinya Hayashi, Masaya Oda, Atsuko Mori, Yoshihiko Nishida, Shunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara, Shigeo Murayama, Masataka Sata and Ryuji Kaji : Distinct Incidence of Takotsubo Syndrome Between Amyotrophic Lateral Sclerosis and Synucleinopathies: A Cohort Study., Frontiers in Neurology, Vol.9, 1099, 2018.
(Summary)
Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by regional left ventricular dysfunction with a peculiar circumferential pattern, which typically results in apical ballooning. Evidence indicates a pivotal role of catecholamines in TTS, and researchers have discussed multiple hypotheses on the etiology, including multivessel coronary spasm, myocardial stunning, excessive transient ventricular afterload, and cardiac sympathetic overactivity with local noradrenaline spillover. Although central nervous system disorders, such as stroke and epilepsy, are known to trigger TTS, the incidence and clinical features of TTS in neurodegenerative disorders are poorly understood. Here, we retrospectively examined TTS cases in a single-center cohort composed of 250 patients with amyotrophic lateral sclerosis (ALS) and 870 patients with synucleinopathies [582 patients with Parkinson's disease (PD), 125 patients with dementia with Lewy bodies (DLB), and 163 patients with multiple system atrophy (MSA)] and identified 4 (1.6%, including 2 women) cases with ALS and no cases with synucleinopathies. Two ALS patients underwent autopsy and the pathological findings were compatible with the chronological changes identified in catecholamine-induced cardiomyopathy. A literature review identified 16 TTS cases with ALS, 1 case each with PD and DLB, and no cases with MSA. When current and previous TTS cases with ALS were concatenated: 55% (11/20) were female; 35% (7/20) had a bulbar-onset and 45% (9/20) had a limb-onset; the mean age of TTS onset was 63.3 ± 9.0 years and the mean interval time from ALS onset to TTS development was 4.9 ± 3.0 years; no (0/16) patients developed TTS within 12 months after ALS onset; 50% (10/20) underwent artificial ventilations; the mortality was 17% (3/18); and most cases had precipitating factors, and TTS development was associated with gastrostomy, tracheostomy, or infections in 45% (9/20) of the patients. This study demonstrated that ALS is a considerable predisposing factor of TTS and that synucleinopathies rarely cause TTS. The distinct TTS incidence between ALS and synucleinopathies may be due to cardiac sympathetic overactivity in ALS and may also be affected by cardiac sympathetic denervation in synucleinopathies. Moreover, the etiology of TTS in ALS may be reasonably explained by the two-hit theory.
Kazuchika Nishitsuji, Syunsuke Watanabe, Jinzhong Xiao, Ryosuke Nagatomo, Hirohisa Ogawa, Takaaki Tsunematsu, Hitomi Umemoto, Yuki Morimoto, Hiroyasu Akatsu, Koichi Inoue and Koichi Tsuneyama : Effect of coffee or coffee components on gut microbiome and short-chain fatty acids in a mouse model of metabolic syndrome., Scientific Reports, Vol.8, No.1, 2018.
(Summary)
We previously showed that male Tsumura Suzuki obese diabetes (TSOD) mice, a spontaneous mouse model of metabolic syndrome, manifested gut dysbiosis and subsequent disruption of the type and quantity of plasma short-chain fatty acids (SCFAs), and daily coffee intake prevented nonalcoholic steatohepatitis in this mouse model. Here, we present a preliminary study on whether coffee and its major components, caffeine and chlorogenic acid, would affect the gut dysbiosis and the disrupted plasma SCFA profile of TSOD mice, which could lead to improvement in the liver pathology of these mice. Three mice per group were used. Daily intake of coffee or its components for 16 wk prevented liver lobular inflammation without improving obesity in TSOD mice. Coffee and its components did not repair the altered levels of Gram-positive and Gram-negative bacteria and an increased abundance of Firmicutes in TSOD mice but rather caused additional changes in bacteria in six genera. However, caffeine and chlorogenic acid partially improved the disrupted plasma SCFA profile in TSOD mice, although coffee had no effects. Whether these alterations in the gut microbiome and the plasma SCFA profile might affect the liver pathology of TSOD mice may deserve further investigation.
Hirohisa Ogawa, Masahiko Azuma, Takaaki Tsunematsu, Yuuki Morimoto, Mayo Kondo, Toshifumi Tezuka, Yasuhiko Nishioka and Koichi Tsuneyama : Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation., Clinical and Experimental Allergy, Vol.48, No.12, 1715-1725, 2018.
(Summary)
The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.
Mayo Kondo, Hirokazu Ogino, Hirohisa Ogawa, Tania Afroj, Yuko Toyoda, Satoshi Sakaguchi, Miki Tsuboi, Yoshimi Bando, Hisatsugu Goto, Koichi Tsuneyama and Yasuhiko Nishioka : A case of pulmonary pleomorphic carcinoma with malignant phenotypes induced by ZEB1-associated epithelial-mesenchymal transition., Respiratory Medicine Case Reports, Vol.25, 119-121, 2018.
(Summary)
A 60-year-old man was admitted to our hospital with non-small cell lung cancer (NSCLC). Imaging and pathological studies revealed NSCLC, not otherwise specified (NOS), at clinical stage T3N1M0 stage IIIA. We started radiotherapy alone because of obstructive pneumonia and end-stage renal disease, but the tumors progressed rapidly and resulted in death due to air obstruction by pharyngeal metastasis. The cancer was diagnosed as pleomorphic carcinoma in an autopsy. Viable lung tumor cells, which were resistant to radiotherapy, and the pharyngeal metastasis had mesenchymal phenotypes and expressed ZEB1 but not SNAI1. These observations indicated that ZEB1-associated epithelial-mesenchymal transition has malignant features including resistance to radiotherapy and aggressive metastatic potential. ZEB1-associated EMT may be an important mechanism to understand the pathophysiology of pleomorphic carcinoma.
Atsuro Saijo, Hisatsugu Goto, Nakano Mayuri, Mitsuhashi Atsushi, Yoshinori Aono, Masaki Hanibuchi, Hirohisa Ogawa, Hisanori Uehara, Kazuya Kondo and Yasuhiko Nishioka : Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells., Cancer Letters, Vol.421, 17-27, 2018.
(Summary)
Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches.
Metabolic syndrome (MS) is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases affecting the entire body. The hepatic manifestations of MS include nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH). NASH is known to progress to liver cirrhosis and hepatocellular carcinoma (HCC). Excellent animal models for determining the mechanism of pathogenesis and establishing therapeutic treatment of NASH/HCC are strongly required worldwide. We recently reported that two previously established mouse models of obesity and diabetes mellitus, namely, Tsumura-Suzuki Obese Diabetes (TSOD) mice and MSG mice, developed MS-associated NASH and that their clinical course and pathological characteristics closely mimicked those of human MS-NASH patients. Interestingly, most of the mice developed HCC with advancing age, and the pathological and functional characteristics of this condition were identical to those of human HCC. We further established a novel mouse model of HCC based on type 1 diabetes (DIAR-nSTZ mice) and reported its histopathological features. By comparing various aspects of these mouse models, specific and useful characteristics in a suitable model of MS-associated liver diseases, including hepato-carcinogenesis, can be highlighted.
Seidai Satou, Shinohara Shintaro, Hayashi Shinya, Morizumi Shun, Abe Shuichi, Okazaki Hiroyasu, Chen Yanjuan, Hisatsugu Goto, Yoshinori Aono, Hirohisa Ogawa, Koyama Kazuya, Nishimura Haruka, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity., Respiratory Research, Vol.18, No.1, 172, 2017.
(Summary)
Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.
(Keyword)
Animals / Cell Movement / Cells, Cultured / Dose-Response Relationship, Drug / Fibroblasts / Humans / Indoles / Male / Mice / Mice, Inbred C57BL / Pulmonary Fibrosis / Treatment Outcome / Vascular Endothelial Growth Factor A
Koichi Tsuneyama, Hayato Baba, Yuki Morimoto, Takaaki Tsunematsu and Hirohisa Ogawa : Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms., The Journal of Medical Investigation : JMI, Vol.64, No.1.2, 7-13, 2017.
(Summary)
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease that predominantly affects middle-aged women and is characterized by the chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and, ultimately, fibrosis. The serological hallmark of PBC is the presence of anti-mitochondrial autoantibodies (AMA). Several mechanisms have been proposed for immune-mediated bile duct damage in PBC, including the roles of T cells, B cells, other cell phenotypes, and AMA. A sign of fragility of biliary epithelial cells caused by apoptosis, senescence, and autophagy has also been noted. Several complex steps and mechanisms appear to be involved in the induction and progression of cholangitis and biliary degeneration in patients with PBC. J. Med. Invest. 64: 7-13, February, 2017.
Tetsuyuki Takahashi, Takeshi Nishida, Hayato Baba, Hideki Hatta, Johji Imura, Mitsuko Sutoh, Syunji Toyohara, Ryoji Hokao, Syunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara and Koichi Tsuneyama : Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)., Molecular and Clinical Oncology, Vol.5, No.2, 267-270, 2016.
(Summary)
We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of -catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.
Akira Takashima, Shusuke Yagi, Koji Yamaguchi, Eri Takagi, Tamotsu Kanbara, Hirohisa Ogawa, Takayuki Ise, Kenya Kusunose, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Tetsuya Kitagawa and Masataka Sata : Vegetation in the coronary sinus that concealed the presence of a coronary arteriovenous fistula in a patient with infectious endocarditis., International Journal of Cardiology, Vol.207, 266-268, 2016.
Ryosuke Oki, Akiko Uchino, Yuishin Izumi, Hirohisa Ogawa, Shigeo Murayama and Ryuji Kaji : An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome, Clinical Neurology, Vol.56, No.1, 12-16, 2016.
(Summary)
We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness.
Toshifumi Tezuka, Hirohisa Ogawa, Masahiko Azuma, Hisatsugu Goto, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi, Yamaguchi Yoichi, Fujikawa Tomoyuki, Itai Akiko and Yasuhiko Nishioka : IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators, PLoS ONE, Vol.10, No.3, e0121615, 2015.
(Summary)
Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
Hirohisa Ogawa, G Julie Ledford, Sambuddho Mukherjee, Yoshinori Aono, Yasuhiko Nishioka, J James Lee, Keisuke Izumi and W John Hollingsworth : Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β., Respiratory Research, Vol.15, 143, 2014.
(Summary)
Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.
Hisanori Uehara, Tetsuyuki Takahashi, Mina Oha, Hirohisa Ogawa and Keisuke Izumi : Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression., International Journal of Cancer, Vol.135, No.11, 2558-2568, 2014.
(Summary)
Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum-induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three-dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase-3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor-treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity-prostate cancer progression link.
Hideki Makino, Yoshinori Aono, Momoyo Azuma, Masami Kishi, Yuki Yokota, Katsuhiro Kinoshita, Akio Takezaki, Jun Kishi, Hiroshi Kawano, Hirohisa Ogawa, Hisanori Uehara, Keisuke Izumi, Saburo Sone and Yasuhiko Nishioka : Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice., The Journal of Medical Investigation : JMI, Vol.60, No.1-2, 127-137, 2013.
(Summary)
Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.
Seidai Satou, Masaki Hanibuchi, Takuya Kuramoto, Nodoka Yamamori, Hisatsugu Goto, Hirohisa Ogawa, Atsushi Mitsuhashi, The Trung Van, Souji Kakiuchi, Shin-ichi Akiyama, Yasuhiko Nishioka and Saburo Sone : Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment., Clinical & Experimental Metastasis, Vol.30, No.3, 333-344, 2012.
(Summary)
The organ microenvironment significantly affects the processes of cancer metastasis. Elucidating the molecular mechanisms of interaction between tumor cells and the organ microenvironment is crucial for the development of effective therapeutic strategies to eradicate cancer metastases. Macrophage stimulating protein (MSP), an activator of macrophages, regulates a pleiotropic array of effects, including proliferation, cellular motility, invasiveness, angiogenesis, and resistance to anoikis. However, the role of MSP in cancer metastasis is still largely unknown. In this study, the action of MSP on the production of metastases was determined in a multiple-organ metastasis model. The murine MSP gene was transfected into two human SCLC cell lines, SBC-5 and H1048, to establish transfectants secreting biologically active MSP. MSP gene transduction did not affect cell proliferation and motility in vitro. Intravenously inoculated MSP transfectants produced significantly larger numbers of liver metastases than parental cells or vector control clones, while there were no significant differences in bone or lung metastases among them. Immunohistochemical analyses of liver metastases revealed that tumor-associated microvessel density and tumor-infiltrating macrophages were significantly increased in lesions produced by MSP transfectants. MSP could stimulate the migration of murine macrophages and endothelial cells in vitro. Consequently, MSP may be one of the major determinants that affects the properties of tumor stroma and that produces a permissive microenvironment to promote cancer metastasis.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Atsuro Saijo, Souji Kakiuchi, Yoichi Maekawa, Koji Yasutomo, Masaki Hanibuchi, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-Notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, Molecular Cancer Therapeutics, Vol.11, No.12, 2578-2587, 2012.
(Summary)
Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-κB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-κB signaling.
(Keyword)
Animals / apoptosis / Cell Growth Processes / Cell Movement / Down-Regulation / Humans / Liver Neoplasms, Experimental / Lung Neoplasms / Male / Mice / Mice, SCID / NF-kappa B / Receptors, Notch / Recombinant Fusion Proteins / signal transduction / Small Cell Lung Carcinoma / Transfection / Xenograft Model Antitumor Assays
Adel Gomaa Mohammed Gabr, Hisatsugu Goto, Masaki Hanibuchi, Hirohisa Ogawa, Takuya Kuramoto, Minako Suzuki, Atsuro Saijo, Souji Kakiuchi, Van The Trung, Satoshi Sakaguchi, Yoichiro Moriya, Saburo Sone and Yasuhiko Nishioka : Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression, Clinical & Experimental Metastasis, Vol.29, No.3, 207-216, 2012.
(Summary)
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show dramatic antitumor activity in a subset of patients with non-small cell lung cancer who have an active mutation in the epidermal growth factor receptor (EGFR) gene. On the other hand, some lung cancer patients with wild type EGFR also respond to EGFR-TKIs, suggesting that EGFR-TKIs have an effect on host cells as well as tumor cells. However, the effect of EGFR-TKIs on host microenvironments is largely unknown. A multiple organ metastasis model was previously established in natural killer cell-depleted severe combined immunodeficient mice using human lung cancer cells. This model was used to investigate the therapeutic efficacy of erlotinib, an EGFR-TKI, on multiple organ metastases induced by human small cell lung cancer cells (SBC-5 cells) that did not express EGFR. Although erlotinib did not have any effect on the proliferation of SBC-5 cells in vitro, it significantly suppressed bone and lung metastases in vivo, but not liver metastases. An immunohistochemical analysis revealed that, erlotinib significantly suppressed the number of osteoclasts in bone metastases, whereas no difference was seen in microvessel density. Moreover, erlotinib inhibited EGF-induced receptor activator of nuclear factor kappa-B expression in an osteoblastic cell line (MC3T3-E1 cells). These results strongly suggested that erlotinib prevented bone metastases by affecting host microenvironments irrespective of its direct effect on tumor cells.
Yoshinori Aono, Julie G. Ledford, Sambuddho Mukherjee, Hirohisa Ogawa, Yasuhiko Nishioka, Saburo Sone, Michael F. Beers, Paul W. Noble and Jo Rae Wright : Surfactant protein-D regulates effector cell function and fibrotic lung remodeling in response to bleomycin injury., American Journal of Respiratory and Critical Care Medicine, Vol.185, No.5, 525-536, 2012.
(Summary)
Surfactant protein (SP)-D and SP-A have been implicated in immunomodulation in the lung. It has been reported that patients with idiopathic pulmonary fibrosis (IPF) often have elevated serum levels of SP-A and SP-D, although their role in the disease is not known. The goal of this study was to test the hypothesis that SP-D plays an important role in lung fibrosis using a mouse model of fibrosis induced by bleomycin (BLM). Triple transgenic inducible SP-D mice (iSP-D mice), in which rat SP-D is expressed in response to doxycycline (Dox) treatment, were administered BLM (100 U/kg) or saline subcutaneously using miniosmotic pumps. BLM-treated iSP-D mice off Dox (SP-D off) had increased lung fibrosis compared with mice on Dox (SP-D on). SP-D deficiency also increased macrophage-dominant cell infiltration and the expression of profibrotic cytokines (transforming growth factor [TGF]-1, platelet-derived growth factor-AA). Alveolar macrophages isolated from BLM-treated iSP-D mice off Dox (SP-D off) secreted more TGF-1. Fibrocytes, which are bone marrow-derived mesenchymal progenitor cells, were increased to a greater extent in the lungs of the BLM-treated iSP-D mice off Dox (SP-D off). Fibrocytes isolated from BLM-treated iSP-D mice off Dox (SP-D off) expressed more of the profibrotic cytokine TGF-1 and more CXCR4, a chemokine receptor that is important in fibrocyte migration into the lungs. Exogenous SP-D administered intratracheally attenuated BLM-induced lung fibrosis in SP-D(-/-) mice. These data suggest that alveolar SP-D regulates numbers of macrophages and fibrocytes in the lungs, profibrotic cytokine expression, and fibrotic lung remodeling in response to BLM injury.
Hirohisa Ogawa, Masahiko Azuma, Hisanori Uehara, Tetsuyuki Takahashi, Yasuhiko Nishioka, Saburo Sone and Keisuke Izumi : Nerve growth factor derived from bronchial epithelium afer chronic mite antigen exposure contributes to airway hyperresponsiveness by inducing hyperinnervaiton, and is inhibited by in vivo siRNA., Clinical and Experimental Allergy, Vol.42, No.3, 460-470, 2012.
(Summary)
Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain. In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation. We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined. NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis. These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.
Ezar Hafez, Tetsuyuki Takahashi, Tokiko Nakai, Hirohisa Ogawa, Makoto Sato, Chie Takasu, Hisanori Uehara and Keisuke Izumi : High susceptibility to zymbal gland and intestinal carcinogenesis in diabetic Otsuka Long-Evans Tokushima Fatty rats., Journal of Toxicologic Pathology, Vol.24, No.4, 187-193, 2011.
(Summary)
Diabetes mellitus (DM) and obesity are believed to be risk factors for colorectal cancer in humans. In experiment 1, male nondiabetic Long-Evans Tokushima Otsuka (LETO) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model animal of type 2 DM, were whole-body X-irradiated (4 Gy) at 6 and 8 weeks of age and euthanized at 78 weeks of age (n=15, respectively). The incidences of small intestine adenocarcinoma in LETO and OLETF rats were 0% and 30%, respectively. In experiment 2, male LETO and OLETF rats (n=24, respectively) were given s.c. injections of 15 mg/kg azoxymethane (AOM) once weekly for 3 weeks and euthanized at 36 weeks of age. The incidences of Zymbal gland tumors in LETO and OLETF rats were 0% and 67%, respectively (P<0.001), whereas those of small intestine adenocarcinoma were 0% and 43% (P<0.001) and those of cecum/colon adenocarcinoma were 46% and 79% (P<0.05), respectively. Fatty change of hepatocytes was common in OLETF rats (63%) but not in LETO rats. Serum triglyceride and free fatty acid levels in OLETF rats were significantly higher than in LETO rats at sacrifice, whereas serum insulin levels in OLETF rats were very diverse. These data suggest that hyperlipidemia plays a significant role in high susceptibility to lower intestinal tract carcinogenesis in OLETF rats; this strain is susceptible to AOM-induced Zymbal gland carcinogenesis.
Tetsuyuki Takahashi, Hirohisa Ogawa, Keisuke Izumi and Hisanori Uehara : The solubla EP2 receptor FuEP2/Ex2 suppresses endometrial cancer cell growth in an orthotopic xenograft model in nude mice, Cancer Letters, Vol.306, No.1, 67-75, 2011.
(Summary)
Endometrial cancer is one of the most common gynecologic malignancies and many factors influence in its growth and development. As in many other types of cancer, prostaglandin E(2) (PGE(2)) is thought to be an accelerator of cell proliferation and endometrial cancer progression. In this study, we examined the effect of FuEP2/Ex2, a soluble decoy receptor for PGE(2) on growth of endometrial cancer cells. A stable transfectant expressing FuEP2/Ex2 was established from human endometrial cancer Ishikawa cells (Ish-FuEP2/Ex2). Ish-FuEP2/Ex2 cells expressed FuEP2/Ex2 mRNA and protein. Expression levels of E-prostanoid receptor 1 (EP1), EP2, EP3, EP4, and F-prostanoid receptor (FP) were almost the same in Ish-FuEP2/Ex2 and vector control cells. Growth rates of Ish-FuEP2/Ex2 under normal culture conditions were also similar to vector control cells, although PGE(2)-induced growth stimulation was completely inhibited in Ish-FuEP2/Ex2 or by Ish-FuEP2/Ex2 culture medium. Moreover, phosphorylation of extracellular signal-regulated kinase (ERK) and induction of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), cyclin D1, and c-fos mRNA by PGE(2) were not observed in Ish-FuEP2/Ex2 and Ish-FuEP2/Ex2 culture medium-treated vector control cells, although they were found when treated with prostaglandin F(2α). An orthotopic xenograft model in athymic nude mice revealed that Ish-FuEP2/Ex2-injected mice had significantly decreased mean tumor area. The proportion of Ki-67-positive cells in the tumor lesion was also significantly lower in Ish-FuEP2/Ex2-injected mice. These findings suggest that an EP-targeting strategy using FuEP2/Ex2 may be of use in the treatment of endometrial cancer.
Avirmed Shiirevnyamba, Tetsuyuki Takahashi, Hongchao Shan, Hirohisa Ogawa, Seiji Yano, Hiro-omi Kanayama, Keisuke Izumi and Hisanori Uehara : Enhancement of osteoclastogenic activity in osteolytic prostate cancer cells by physical contact with osteoblasts, British Journal of Cancer, Vol.104, No.3, 505-513, 2011.
(Summary)
The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood. Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay. When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA. Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.
Hirohisa Ogawa, Masahiko Azuma, S Muto, Yasuhiko Nishioka, A Honjo, T Tezuka, Hisanori Uehara, Keisuke Izumi, A Itai and Saburo Sone : IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma, Clinical and Experimental Allergy, Vol.41, No.1, 104-115, 2010.
(Summary)
Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ-NF-κB pathway may be an ideal strategy for the management of airway remodelling. We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-β, via inhibition of IKKβ. IMD-0354 inhibited IL-13 and IL-1β production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.
Tsuchigauchi Takeshi, Tetsuyuki Takahashi, Ohnishi Takamasa, Hirohisa Ogawa, Yoshimi Bando, Hisanori Uehara, Takizawa Tamatsu, Kaneda Shinya, Nakai Tokiko, Hiroshi Shiota and Keisuke Izumi : Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats, The Journal of Medical Investigation : JMI, Vol.56, No.3-4, 93-98, 2009.
(Summary)
The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats.
Akemi Sugita, Hirohisa Ogawa, Masahiko Azuma, Susumu Muto, Akifumi Honjo, Hiroaki Yanagawa, Yasuhiko Nishioka, Kenji Tani, Akiko Itai and Saburo Sone : Antiallergic and anti-inflammatory effects of a novel IκB kinase β inhibitor, IMD-0354, in a mouse model of allergic inflammation., International Archives of Allergy and Immunology, Vol.148, No.3, 186-198, 2008.
(Summary)
BACKGROUND: Nuclear factor (NF)-kappaB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappaB kinase beta (IKK beta), which is responsible for activation of the NF-kappaB pathway, may be an ideal molecular target to inhibit this process. IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] is an attractive novel IKK beta inhibitor that prevents the production of inflammatory cytokines in various diseases, although it is not known if IMD-0354 is effective against allergic inflammation. This study aimed to elucidate the antiallergic effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a mouse model of allergic inflammation. METHODS: We generated ovalbumin (OVA)-sensitized mice which were then challenged with OVA. IMD-0354 was administered intraperitoneally to therapeutic groups. Lung histopathology and the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and supernatants of lung homogenates were determined. RESULTS: Administration of IMD-0354 ameliorated airway hyperresponsiveness and reduced the numbers of bronchial eosinophils and mucus-producing cells in OVA-sensitized mice. The total numbers of cells and eosinophils in BALF were also reduced by treatment with IMD-0354. Treatment with IMD-0354 inhibited the production of Th2 cytokines such as interleukin (IL)-5 and IL-13 and eotaxin in the airways and/or lungs of OVA-sensitized mice, but it did not affect the restoration of Th1 cytokines such as IL-12 and interferon-gamma under the same experimental conditions. IgE production was also inhibited by IMD-0354. CONCLUSION: A specific IKK beta inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.
Hirohisa Ogawa, Shizuka Inoue, Fumitaka Ogushi, Hideo Ogura and Yoichi Nakamura : Toluene diisocyanate (TDI) induces production of inflammatory cytokines and chemokines by bronchial epithelial cells via the epidermal growth factor receptor and p38 mitogen-activated protein kinase pathways., Experimental Lung Research, Vol.32, No.6, 245-262, 2006.
(Summary)
Toluene diisocyanate (TDI) is known as one of causes of occupational asthma and hypersensitivity pneumonitis. To investigate the stimulatory effect on bronchial epithelial cells in response to TDI, the authors examined production of cytokines by the bronchial epithelial cell line BEAS-2B and intercellular signal transduction stimulated by TDI-human serum albumin (HSA) conjugate. The production of interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and regulated on activation normal T cell expressed and secreted (RANTES) from the bronchial epithelial cells were augmented by the TDI-HSA conjugate. Extracellular signal-regulated kinase (Erk) 1/2 and p38 mitogen-activated protein kinase (MAPK) were phosphorylated by the TDI-HSA conjugate. AG1478, SB203580, and dexamethasone prevented augmentation of these cytokine production. TDI-HSA conjugate did not augment release of epidermal growth factor (EGF) ligands from BEAS-2B. These results suggest that TDI directly induces production of proinflammatory cytokines and chemokines through p38 MAPK and EGF receptor (EGFR)-Erk pathway without an autocrine mechanism. Thus, TDI was shown to have a stimulatory effect on bronchial epithelial cells, suggesting the potent role of bronchial epithelial cells in TDI-induced asthma.
(Keyword)
Allergens / Bronchi / Cell Line / Chemokines / Dexamethasone / Dose-Response Relationship, Drug / Drug Antagonism / Enzyme Inhibitors / Humans / Imidazoles / Phosphorylation / Pyridines / Quinazolines / Receptor, Epidermal Growth Factor / Respiratory Mucosa / Serum Albumin / Signal Transduction / Toluene 2,4-Diisocyanate / Tyrphostins / p38 Mitogen-Activated Protein Kinases
Takanori Kanematsu, 大串 文隆, Hirohisa Ogawa, Yasuhiko Nishioka, Tsutomu Shinohara, Hiroaki Yanagawa and Saburo Sone : 嚢胞状変化を呈した肺サルコイドーシスの1例, The journal of the Japanese Respiratory Society, Vol.39, No.2, 117-121, 2001.
Academic Paper (Unrefereed Paper):
1.
Chie Takasu, Katsuki Miyazaki, Kouzou Yoshikawa, Masaaki Nishi, Takuya Tokunaga, Hideya Kashihara, Toshiaki Yoshimoto, Hirohisa Ogawa, Yuji Morine and Mitsuo Shimada : Effect of TU-100 on Peyer's patches in a bacterial translocation rat model., Annals of Gastroenterological Surgery, Vol.5, No.5, 683-691, 2021.
(Summary)
Daikenchuto (TU-100), a Japanese herbal medicine, is widely used for various gastrointestinal diseases. We have previously reported that TU-100 suppresses CPT-11-induced bacterial translocation (BT) by maintaining the diversity of the microbiome. In this study we show that TU-100 modulates the immune response during BT by inducing PD-1 expression in Peyer's patches. Eighteen male Wistar rats were divided into four groups: a control group; a control + TU-100 group, given TU-100 1000 mg/kg orally for 5 d; a BT group, given CPT-11 250 mg/kg intra-peritoneal for 2 d; and a TU-100 group, given TU-100 1000 mg/kg orally for 5 d with CPT-11 250 mg/kg intra-peritoneal on days 4 and 5. The size of Peyer's patch was significantly bigger in the BT group compared to the control group (9.0 104 m vs 29.4 104 m, < .05), but improved in the TU-100 group (15.4 104 m, < .005). TU-100 significantly induced PD-1 expression in Peyer's patch compared to the control group and the BT group (control vs BT vs TU-100 = 4.3 4.9 vs 5.1 10.3 vs 17.9 17.8). The CD4 cells were increased in the BT group ( < .05) compared to the control group but decreased in the TU-100 group. The Foxp3 cells were increased in the BT group compared to the control group ( < .05), and further increased in the TU-100 group compared to the BT group. CPT-11 significantly increased TLR4, NF- , TNF- mRNA expressions in the BT group. TU-100 cotreatment significantly reversed these mRNA expressions. TU-100 may have a protective effect against BT through PD-1 expression in Peyer's patch.
Yoichiro Kawashita, Yuji Morine, Tetsuya Ikemoto, Yu Saitou, Shuichi Iwahashi, Shin-ichiro Yamada, Jun Higashijima, Satoru Imura, Hirohisa Ogawa, Toshiyuki Yagi and Mitsuo Shimada : Loss of Fbxw7 expression is a predictor of recurrence in colorectal liver metastasis., Journal of Hepato-Biliary-Pancreatic Sciences, Vol.24, No.10, 576-583, Oct. 2017.
(Summary)
Fbxw7 is a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of Fbxw7 is frequently observed in various human cancers. In this study, we examined the role of Fbxw7 expression in colorectal liver metastasis (CRLM) and its mechanism. Fifty-six patients with CRLM who undergo curative resection were enrolled. Fbxw7 in tumor tissue was determined by immunohistochemistry. Patients were divided into two groups, the Fbxw7 high and low groups. Clinicopathological factors including miR-223 expression were compared between the high (n = 32) and low Fbxw7 groups (n = 24). Fbxw7 expression in tumor tissues was significantly lower than that in normal tissues. The disease-free survival in the low Fbxw7 group was significantly worse than that in the high Fbxw7 group, and 3 years disease-free survival of the low and high Fbxw7 groups were 12.5% and 47.0%, respectively (P = 0.023). On multivariate analysis, loss of Fbxw7 was detected as one of the independent risk factors for recurrence of CRLM (hazard ratio: 2.390, P = 0.017). Likewise, Fbxw7 expression inversely correlated to miR-223 expression (P = 0.017). Loss of Fbxw7 in tumor tissues could be a reliable predictor of recurrence after hepatectomy in patients with CRLM, and miR-223 might be a possible regulator of Fbxw7.
Seidai Satou, Kazuya Koyama, Hirohisa Ogawa, Murakami Kojin, Yuya Yamashita, Danzan NandinErdene, Bando Hiroki, Keiko Haji, Nobuhito Naito, Hiroshi Kawano, Eiji Hara and Yasuhiko Nishioka : A novel senolytic drug, ARV-825, ameliorates experimental lung fibrosis, ERS International Congress 2023, Milano, Sep. 2023.
2.
Hiroki Bando, Seidai Satou, Hirohisa Ogawa, Kazuya Koyama, Murakami Kojin, Yuya Yamashita, Danzan Nandin-Erdene, Keiko Haji, Nobuhito Naito, Hiroshi Kawano and Yasuhiko Nishioka : Anamorelin, a ghrelin receptor agonist, inhibited the allergic airway inflammation in mice, ERS International Congress 2023, Milano, Sep. 2023.
3.
Kazuya Koyama, Seidai Satou, Hiroshi Kawano, Hiroshi Kawano, Atsushi Mitsuhashi, Murakami Kojin, Yuya Yamashita, Keiko Haji, Kozo Kagawa, Hirohisa Ogawa and Yasuhiko Nishioka : Evaluation of fibrocytes in silica-induced and bleomycin-induced pulmonary fibrosis model in mice by single cell RNA-seq analysis, APSR 2022, Seoul, Nov. 2022.
4.
Imakura Takeshi, Seidai Satou, Kazuya Koyama, Hirohisa Ogawa, Takahiro Niimura, Murakami Kojin, Yuya Yamashita, Keiko Haji, Nobuhito Naito, Kozo Kagawa, Hiroshi Kawano, Yoshito Zamami, Keisuke Ishizawa and Yasuhiko Nishioka : Computational drug repositioning and wet-lab validation approach identifies polo-like kinase inhibitors as potential therapeutics for pulmonary fibrosis, ERS International Congress 2022, Barcelona, Sep. 2022.
5.
Makoto Funaki, Akiko Hata, Mitsuteru Yoshida, Naoki Miyamoto, Takahisa Ikuta, Yuta Uemura, MINATO AKIZUKI, Akira Tangoku, Hiromichi Yumoto, Hirohisa Ogawa and Takeshi Oya : Quiescence Abrogates Stress-Induced Senescence-Associated Secretion Phenotype in Adipose-Derived Stem Cells and May Enhance Their Therapeutic Effects on Diabetic Complications, Diabetes, Vol.71, No.Suppl_1, 305-OR, New Orleans, Jun. 2022.
6.
Seidai Satou, Kazuya Koyama, Hirohisa Ogawa, Kojin Murakami, Takeshi Imakura, Yuya Yamashita, Keiko Haji, Kozo Kagawa, Hiroshi Kawano, Eiji Hara and Yasuhiko Nishioka : A Novel Senolytic Agent, ARV-825, Ameliorates Bleomycin-InducedPulmonary Fibrosis in Mice, ATS 2022 International Conference, San Francisco, May 2022.
7.
Takeshi Imakura, Seidai Satou, Kazuya Koyama, Hirohisa Ogawa, Takahiro Niimura, Kojin Murakami, Yuya Yamashita, Keiko Haji, Nobuhito Naito, Kozo Kagawa, Hiroshi Kawano, Yoshito Zamami, Keisuke Ishizawa and Yasuhiko Nishioka : Computational Drug Repositioning Approach Identifies Polo-Like KinaseInhibitors as Potential Therapeutics for Pulmonary Fibrosis, ATS 2022 International Conference, San Francisco, May 2022.
8.
Kazuya Koyama, Hiroshi Kawano, Atsushi Mitsuhashi, Kojin Murakami, Takeshi Imakura, Yuya Yamashita, Keiko Haji, Kozo Kagawa, Seidai Satou, Hirohisa Ogawa and Yasuhiko Nishioka : Single Cell RNA-seq Analysis of Fibrocytes in Silica Induced Mouse Pulmonary Fibrosis Model, ATS 2022 International Conference, San Francisco, May 2022.
9.
Masahiko Azuma, Hirohisa Ogawa, Toshifumi Tezuka, Mayo Kondou and Yasuhiko Nishioka : A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells, APSR 2021, Kyoto and online, Nov. 2021.
10.
Hirohisa Ogawa, Masahiko Azuma, Umeno Aya, Shimizu Mayuko, Takaaki Tsunematsu, Mayo Kondou, Murotomi Kazutoshi, Koichi Tsuneyama and Yasuhiko Nishioka : Nerve growth factor exacerbates airway hyperresponsiveness via epithelial damage by neutrophils-derived singlet oxygen in a mouse model of asthma with mixed inflammation, JSA/WAO Joint Congress 2020, WEB, Sep. 2020.
11.
Mayuko Shimizu, Hirohisa Ogawa, Minoru Matsumoto and Koichi Tsuneyama : Establishment of a novel dietary-induced mouse model showing steatohepatitis with severe fibrosis, UEG Week 2019, Barcelona, Oct. 2019.
12.
Koyama Kazuya, Kagawa Kozo, Nishimura Haruka, Hiroshi Kawano, Yuko Toyoda, Hisatsugu Goto, Hirohisa Ogawa, Hisanori Uehara and Yasuhiko Nishioka : Novel Multi-tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Pulmonary Fibrosis In Mice., ATS 2018 International Conference, San Diego, May 2018.
13.
Yuko Toyoda, Morizumi Shun, Seidai Satou, Okazaki Hiroyasu, Chen Yanjuan, Hisatsugu Goto, Hirohisa Ogawa, Nishimura Haruka, Koyama Kazuya, Hiroshi Kawano, Yoshinori Aono, Hisanori Uehara and Yasuhiko Nishioka : Role of Fibroblast Growth Factor/Fibroblast Growth Factor Receptor Signal in Bleomycin-Induced Pulmonary Fibrosis in Mice., ATS 2017 International Conference, Washington, D.C., May 2017.
14.
S Morizumi, S Sato, Shinji Abe, H Okazaki, C Yanjuan, Hisatsugu Goto, Masaki Hanibuchi, Yoshinori Aono, Hirohisa Ogawa, Masaki Hanibuchi, Hisanori Uehara and Yasuhiko Nishioka : Anti-fibrotic efficacy of nintedanib on pulmonary fibrosis via suppression of fibrocyte activity., ERS2016 International Conference, Sep. 2016.
15.
Koichi Tsuneyama, Ryosuke Bessho, Masahiro Miki, Hayato Baba, Tetsuyuki Takahashi, Hirohisa Ogawa and Hisanori Uehara : Hyperinsulinemia, not hyperglycemia accelerates the progression of hepatocellular carcinoma in neonatal streptozotocin induced mouse model, Annual meeting, American Association for the study of the Liver, Nov. 2015.
16.
Hisatsugu Goto, Mitsuhashi Atsushi, Atsuro Saijo, Yoshinori Aono, Hirokazu Ogino, Hirohisa Ogawa, Souji Kakiuchi, Masaki Hanibuchi and Yasuhiko Nishioka : The role of fibrocytes in the resistance to anti-angiogenic therapy in malignant pleural mesothelioma and lung cancer, International Conference of Cancer Immunotherapy and Macrophages 2015, Tokyo, Jul. 2015.
17.
Hisatsugu Goto, Atsushi Mitsuhashi, Atsuro Saijo, Trung The Van, Yoshinori Aono, Hirohisa Ogawa, Soji Kakiuchi, Masaki Hanibuchi, Seiji Yano, Keisuke Izumi and Yasuhiko Nishioka : The role of fibrocytes in the resistance to anti-angiogenic therapy in malignant pleural mesothelioma and lung cancer, ATS 2014 International Conference (Mini-symposium), San Diego, May 2014.
18.
Hirohisa Ogawa, Yoshinori Aono, Yasuhiko Nishioka and Keisuke Izumi : Surfactant Protein D Attenuates Sub-Epithelial Fibrosis In A Model Of Allergic Airways Disease Trough Regulation Of TGF-, San Francisco, May 2013.
19.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Atsuro Saijo, Souji Kakiuchi, Masaki Hanibuchi, Yoichi Maekawa, Koji Yasutomo, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, 14th International Biennial Congress of the Metastasis Research Society, Brisbane, Sep. 2012.
20.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Seidai Sato, Souji Kakiuchi, Masaki Hanibuchi, Yoichi Maekawa, Koji Yasutomo, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, AACR Annual Meeting 2012, Chicago, Apr. 2012.
21.
Hirohisa Ogawa, Naoki Nishimura, Yoichi Nakamura, Yasuhiko Nishioka, Masahiko Azuma, Mari Miki, Fumitaka Ogushi and Saburo Sone : Functionl analysis of human bronchial epithelial cell transduced with IL-12 gene by adenovirus vector, American thoracic society (ATS) 2001 97th International Conference, San Francisco, May 2001.
Natsumi Ohara, Yumiko Yamashita, Ayumi Masumi, Shingen Nakamura, Hirohisa Ogawa, Koichi Tsuneyama and Michiko Yamashita : A case of ascitic plasmacytosis needed to distinguish to the fluid overload large B cell lymphoma FO-LBCL, 第267回徳島医学会学術集会, Aug. 2023.
10.
Makoto Funaki, Akiko Hata, Mitsuteru Yoshida, Naoki Miyamoto, Takahisa Ikuta, Yuta Uemura, Minato Akizuki, Akira Tangoku, Hiromichi Yumoto, Hirohisa Ogawa and Takeshi Oya : 休眠状態の脂肪組織由来間葉系幹細胞による細胞老化随伴分泌現象の解除と糖尿病性合併症治療への応用の可能性, Journal of the The Japan Diabetes Society, Vol.66, No.Suppl.1, S.246, May 2023.
Makoto Funaki, Mitsuteru Yoshida, Naoki Miyamoto, Takahisa Ikuta, Yuta Uemura, MINATO AKIZUKI, Akiko Hata, Akira Tangoku, Hiromichi Yumoto, Hirohisa Ogawa and Takeshi Oya : 休眠状態の導入・維持による脂肪組織由来間葉系幹細 胞の若返りを通じた，糖尿病性合併症治療への応用の可能性, Journal of the The Japan Diabetes Society, Vol.65, No.Suppl.1, S257, May 2022.
16.
Seidai Satou, Kazuya Koyama, Hirohisa Ogawa, Kojin Murakami, Takeshi Imakura, Yuya Yamashita, Hiroshi Kawano, Eiji Hara and Yasuhiko Nishioka : Antifibrotic and senolytic activity of novel BRD4 degrader ARV825 in experimental model of lung fibrosis, The 62nd Annual Meeting of the Japanese Respiratory Society, Apr. 2022.
Honoka Nakahara, Asuka Watanabe, Mayuko Shimizu, Hirohisa Ogawa and Koichi Tsuneyama : Inhibitory effects of berberine on liver fibrosis in NASH model mice, 第111回日本病理学会総会, Apr. 2022.
19.
Soichiroh Ishimaru, Mayuko Shimizu, Hirohisa Ogawa and Koichi Tsuneyama : An Application of Raman Microscopy to Analyzing Dermal Changes in Cutaneously Sensitized Food Allergy Mice, 第111回日本病理学会総会, Apr. 2022.
20.
Minoru Matsumoto, Yasuyo Saijo, Mayuko Shimizu, Hirohisa Ogawa, Koichi Tsuneyama, Mitsuru Matsumoto and Takeshi Oya : 胸腺癌におけるAIRE発現と胸腺髄質上皮細胞との類似性, Proceedings of the Japanese Society of Pathology, Vol.111, No.1, 243, Apr. 2022.
21.
正田 真由美, 大久保 律子, 高橋 雅子, Soichiroh Sasa, Hirohisa Ogawa and Takeshi Oya : Collagenous spherulosisが目立った乳腺病変の1例, 令和3年度徳島臨床細胞学会学術集会(Web開催), Mar. 2022.
22.
柿本 拓海, Mayuko Shimizu, Hirohisa Ogawa, Minoru Matsumoto, Takeshi Oya and Koichi Tsuneyama : Validation of α -synuclein immunohistochemical staining in the diagnosis of non-alcoholic steatohepatitis, The 67th Autumn Annual Meeting of Japanese Society of Pathology, Nov. 2021.
23.
Takumi Kakimoto, Mayuko Shimizu, Hirohisa Ogawa and Koichi Tsuneyama : 非アルコール性脂肪性肝炎の診断におけるα-synuclein免疫組織化学染色の有用性, Proceedings of the Japanese Society of Pathology, Vol.110, No.2, 102, Oct. 2021.
(Keyword)
*免疫組織化学 *Alpha-Synuclein *肝疾患-非アルコール性脂肪性(病理学) ヒト
24.
Hirohisa Ogawa, 立花 尚太郎, Mayuko Shimizu and Koichi Tsuneyama : Lysophosphatidic acid is involved in the formation of airway remodeling in chronic bronchial asthma, Proceedings of the Japanese Society of Pathology, Vol.110, No.2, 98, Oct. 2021.
Mayuko Shimizu, 平 修, Hirohisa Ogawa and Koichi Tsuneyama : Phospholipids Imaging of the Liver and Brain in a Mouse Model of Nonalcoholic Steatohepatitis, 第69回質量分析総合討論会2021, May 2021.
(Keyword)
pathogen lipids / Mass spectrometry imaging
26.
Mayuko Shimizu, 遠藤 亜衣子, 石丸 漱一郎, 小島 拓海, Hirohisa Ogawa and Koichi Tsuneyama : Epicutaneous sensitization conditions for food allergens in animal models, 第110回日本病理学会総会, Apr. 2021.
27.
住田 智志, Mayuko Shimizu, 西條 康代, Minoru Matsumoto, Hirohisa Ogawa, Takeshi Oya, Yoshimi Bando, Hisanori Uehara and Koichi Tsuneyama : Pathological features and pathogenesis of epidermoid cyst in intrapancreatic accessory spleen, 第110回日本病理学会総会, Apr. 2021.
Atsushi Mitsuhashi, Makoto Tobiume, Hirokazu Ogino, Mayo Kondou, Yuko Toyoda, Hisatsugu Goto, Mitsuteru Yoshida, Hirohisa Ogawa, Hiroshi Nokihara and Yasuhiko Nishioka : 肺多形癌における上皮間葉転換 (EMT)の検討, 第120回日本内科学会四国地方会, May 2019.
37.
Mayuko Shimizu, Takeshi Oya, Hirohisa Ogawa, 大曲 勝久 and Koichi Tsuneyama : Cholesterol-loaded macrophage is associated with development of hepatic fibrosis in mice, 第108回日本病理学会総会, May 2019.
Toshifumi Tezuka, Hirohisa Ogawa, Mayo Kondoh, Yuko Toyoda, Seidai Satou, Hisatsugu Goto, Jun Kishi, Masahiko Azuma, Masaki Hanibuchi and Yasuhiko Nishioka : ダニ抗原誘導性のアレルギー性気道炎症および気道リモデリングはPAR-2 antagonistの投与により抑制される, 第57回日本呼吸器学会学術講演会, Apr. 2017.
55.
Ayumi Sugitani, Ryusei Takahashi, Kohki Kai, Mayuko Shimizu, 平 修, 川口 誠, Hirohisa Ogawa, Takaaki Tsunematsu, Koichi Tsuneyama, 野本 一博 and Koichi Tsuneyama : A case of lipid-rich carcinoma of the breast with numerous hyaline globules, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 492-493, Mar. 2017.
56.
Takaaki Tsunematsu, Yasusei Kudo, Akiko Yamada, Rieko Arakaki, Hirohisa Ogawa, Koichi Tsuneyama and Naozumi Ishimaru : 胎児性癌細胞におけるユビキチンプロテアソーム経路による未分化性維持機構, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 356, Mar. 2017.
57.
Koichi Tsuneyama, 渡邊 俊介, 高橋 徹行, 馬場 逸人, 森本 友樹, Takaaki Tsunematsu and Hirohisa Ogawa : 自然発症メタボリックシンドローム-NASHモデル動物を用いた少量のコーヒー摂取による病態抑制効果の検討, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 441, Mar. 2017.
58.
Hirohisa Ogawa, Takaaki Tsunematsu, 森本 友樹 and Koichi Tsuneyama : IL-17/好中球は気道粘膜上皮透過性を増加させFGF-2産生を介した気道平滑筋肥厚を誘導する, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 474, Mar. 2017.
59.
杉谷 鮎美, 高橋 立成, 甲斐 幸樹, Mayuko Shimizu, 平 修, 川口 誠, Hirohisa Ogawa, Takaaki Tsunematsu, Koichi Tsuneyama, 野本 一博 and 常山 幸一 : A case of lipid-rich carcinoma of the breast with numerous hyaline globules(和訳中), Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 492-493, Mar. 2017.
60.
甲斐 幸樹, 常松 貴明, 杉谷 鮎美, 高橋 立成, Hirohisa Ogawa, 森本 友樹 and Koichi Tsuneyama : コーヒーに含まれるクロロゲン酸(5-カフェオイルキナ酸:5-CQA)の抗腫瘍効果の検討, Proceedings of the Japanese Society of Pathology, Vol.106, No.1, 513, Mar. 2017.
Toshifumi Tezuka, Hirohisa Ogawa, Mayo Kondoh, Masahiko Azuma, Yuko Toyoda, Seidai Satou, Hiroyasu Okazaki, Hiroshi Kawano, Jun Kishi, Hisatsugu Goto, Masaki Hanibuchi and Yasuhiko Nishioka : RAS阻害剤 (XRP44X) を用いた喘息モデルマウスにおける検討, 第56回日本呼吸器学会学術講演会, Apr. 2016.
63.
Koichi Tsuneyama, Hirohisa Ogawa, Takaaki Tsunematsu and Hisanori Uehara : 新生児期ストレプトゾトシン投与4CS系マウスは通常食飼育によって持続高血糖なしに肝腫瘍を発症する, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 384, Apr. 2016.
64.
Hirohisa Ogawa, Takaaki Tsunematsu, Hisanori Uehara and Koichi Tsuneyama : ダニ抗原経鼻感作はIL-17/好中球を増加させ平滑筋肥厚を伴う気道リモデリングを誘導する, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 386, Apr. 2016.
65.
Hisanori Uehara, Hirohisa Ogawa, Takaaki Tsunematsu and Koichi Tsuneyama : 前立腺癌細胞の骨内増殖におけるlipolysis stimulated lipoprotein receptorの役割, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 466, Apr. 2016.
66.
Takaaki Tsunematsu, Yasusei Kudo, Akiko Yamada, Rieko Arakaki, Hirohisa Ogawa, Hisanori Uehara, Naozumi Ishimaru and Koichi Tsuneyama : 染色体パッセンジャー複合体タンパク質Borealinのユビキチン分解の意義とその癌化への関与, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 548, Apr. 2016.
67.
良祐 別所, Takaaki Tsunematsu, Hirohisa Ogawa, Hisanori Uehara and Koichi Tsuneyama : 自然発症2型糖尿病モデルマウスにおける膵島の外分泌腺組織への変化がβ細胞の機能不全に果たす役割, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 595, Apr. 2016.
Hirohisa Ogawa and Keisuke Izumi : Surfactant Protein Dはダニ抗原慢性暴露による気道線維化を抑制する, Jun. 2013.
76.
Hirohisa Ogawa, Yoshinori Aono, Toshifumi Tezuka, Hisatsugu Goto and Yasuhiko Nishioka : Surfactant Protein Dはダニ抗原慢性暴露による気道線維化を抑制する, Apr. 2013.
77.
Hirohisa Ogawa, Toshifumi Tezuka and Yasuhiko Nishioka : Surfactant Protein Dはダニ抗原慢性暴露による気道線維化を抑制する, Nov. 2012.
78.
The Trung VAN, Hisatsugu Goto, 倉本 卓哉, Souji Kakiuchi, Seidai Satou, The Trung VAN, Atsuro Saijo, 田畑 祥, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Yasuhiko Nishioka, Rae Jo WRIGHT and Saburo Sone : 肺サーファクタント蛋白SP-Aの肺がん進展における機能解析, Journal of Japanese Medical Society for Lung Surfactant and Biological Interface, Vol.43, 32, Oct. 2012.
Atsuhi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Wright Jo Rae, Saburo Sone and Yasuhiko Nishioka : 肺surfactant protein A(SP-A)の肺癌進展における機能解析, 第21回日本がん転移学会学術集会・総会, Jul. 2012.
80.
Atsushi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Syo Tabata, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Jo Rae Wright, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses progression of human lung adenocarcinoma in nude mice via modulating host immune response., 第52回日本呼吸器学会学術講演会, Apr. 2012.