Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Ono Takamasa Last modified date:2019.12.28

Assistant Professor / internal medicine / Department of Hepatology and Pancreatology / Kyushu University Hospital


Papers
1. Masami Miki, Nao Fujimori, takamasa ono, Ken Kawabe, Akihisa Ohno, Kazuhide Matsumoto, Katsuhito Teramatsu, Yuichi Tachibana, Yoshihiro Ogawa, Relapse patterns and predictors of IgG4-related diseases involved with autoimmune pancreatitis
A single-center retrospective study of 115 patients, Journal of Digestive Diseases, 10.1111/1751-2980.12708, 20, 3, 152-158, 2019.03, Objective: Autoimmune pancreatitis is an autoimmune disorder accompanied by clinicopathological manifestations that have been established as immunoglobulin (IgG)4-related diseases (IgG4-RD). Other IgG4-RD are often involved with autoimmune pancreatitis. They sometimes relapse despite a favorable response to steroid therapy. This study aimed to clarify the patterns and risk factors for extrapancreatic relapse. Methods: We reviewed the data of 115 patients diagnosed with definite autoimmune pancreatitis type 1 and followed up for > 1 year. We analyzed two items: the timing and pattern of extrapancreatic relapse, and risk factors for relapse with three common manifestations: IgG4-related sclerosing cholangitis (SC), IgG4-related dacryoadenitis and sialadenitis (DS), and IgG4-related retroperitoneal fibrosis (RF). Results: Remission was achieved in all patients, except one. The extrapancreatic relapse rates were 11.0%, 19.7%, and 40% within 3, 5, and 10 years, respectively. Of 26 patients with extrapancreatic relapse, nine (34.6%) relapsed with a new IgG4-RD. Based on multivariate analysis, the interval between symptom onset and steroid initiation, and the presence of RF at onset were significant risk factors for relapse with SC and RF, respectively. Conclusions: Our results indicate that they may be various extrapancreatic relapse patterns especially in autoimmune pancreatitis with other organ involvement. Patients with a delayed initiation of steroids or RF at onset should be carefully followed up as high-risk groups for SC and RF relapse..
2. Yusuke Niina, Tetsuhide Ito, takamasa ono, Taichi Nakamura, Nao Fujimori, Hisato Igarashi, Yoshiki Sakai, Ryoichi Takayanagi, A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats, Pancreatology, 10.1016/j.pan.2014.02.009, 14, 3, 201-210, 2014.01, Background: ONO-1301, a novel sustained-release prostacyclin agonist, has an anti-fibrotic effect on the lungs, heart, and kidneys that is partly associated with the induction of hepatocyte growth factor (HGF). This study examined the anti-fibrotic effect of ONO-1301 on chronic pancreatitis (CP) progression. Methods: CP was induced in rats in vivo by dibutyltin dichloride (DBTC). Seven days after DBTC injection (day 7), a slow-release form of ONO-1301 (10 mg/kg; ONO-1301etreated group) or vehicle (DBTC-treated group) was injected. On days 14 and 28, we evaluated the histopathological CP score and mRNA expressions of HGF, cytokines, and collagen in the pancreas by real-time RT-PCR. In vitro, monocytes and pancreatic stellate cells (PSCs) were isolated from normal rat spleen and pancreas, respectively. The cytokine and collagen expressions of monocytes and PSCs were detected by real-time RT-PCR, and PSCs proliferation was examined by BrdU assay. Results: Histopathological CP scores in vivo improved in the ONO-1301etreated group compared to the DBTC-treated group, particularly inflammatory cell infiltration on day 14 and interstitial fibrosis on day 28. HGF mRNA increased significantly after ONO-1301 administration, whereas IL-1b, TNF-α, TGF-β, MCP-1, and collagen mRNA decreased significantly. Cytokine expression in monocytes was suppressed in vitro not only by HGF, but also ONO-1301 alone. However, neither ONO-1301 nor HGF affected the proliferation, or cytokine or collagen expression of PSCs. Conclusions: ONO-1301 suppresses pancreatic fibrosis in the DBTC-induced CP model by inhibiting monocyte activity not only with induction of HGF but also by ONO-1301 itself..
3. Masahiko Uchida, Tetsuhide Ito, Taichi Nakamura, Masayuki Hijioka, Hisato Igarashi, takamasa ono, Masaki Kato, Kazuhiko Nakamura, Koichi Suzuki, Ryoichi Takayanagi, Robert T. Jensen, Pancreatic stellate cells and CX3CR1
Occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist, Pancreas, 10.1097/MPA.0000000000000109, 43, 5, 708-719, 2014.01, OBJECTIVES: Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs. METHODS: CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting. RESULTS: In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation. CONCLUSIONS: CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated..
4. Akira Aso, Hiroaki Kubo, Kazuhiko Nakamura, Yuzo Shimokawa, takamasa ono, Eikichi Ihara, Hisato Igarashi, Tetsuhide Ito, Ayako Goto, Yoshinao Oda, Masao Tanaka, Ryoichi Takayanagi, Diagnosis of acinar cell carcinoma using endoscopic ultrasound-guided fine needle aspiration
A case report, Gastroenterological Endoscopy, 55, 4, 1494-1501, 2013.04, In February 2010, a 50-year-old man was admitted to a clinic complaining of back pain. Enhanced computed tomography (CT) images showed that there was a unilocular cyst, approximately 40 mm in size, in the pancreatic head of his abdomen. He was diagnosed as having a pancreatic pseudocyst caused by pancreatitis. After treatment, the patient's symptoms disappeared. However, in July 2010, he was referred to our medical center because back pain had reappeared along with obstructive jaundice. CT imaging showed growth of the cystic lesion and a low-density area of newly appeared cysts. The combination of clinical course and ¡results suggested malignancy, but it was difficult to confirm the diagnosis. Specimens sampled with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed acinar cell carcinoma (ACC). This case showed atypical images for ACC as cystic lesions were dominant These results are notable in that ACC may reveal atypical findings and that EUS-FNA can be useful in the diagnosis of such cases..
5. Akira Aso, Eikichi Ihara, Hiroaki Kubo, Takashi Osoegawa, takamasa ono, Kazuhiko Nakamura, Tetsuhide Ito, Yoshihiro Kakeji, Osada Mikako, Hidetaka Yamamoto, Tatsuhiro Oishi, Yayoi Oishi, Yoichi Hachitanda, Ryoichi Takayanagi, Gastric gastrointestinal stromal tumor smaller than 20 mm with liver metastasis, Clinical Journal of Gastroenterology, 10.1007/s12328-012-0351-0, 6, 1, 29-32, 2013.02, There have been no reports of gastric gastrointestinal stromal tumors (GISTs) <20 mm with distant metastasis. We report a case of a 15-mm gastric GIST with liver metastasis 1 year after surgical resection of the primary lesion. A 35-year-old man underwent routine esophagogastroduodenoscopy in July 2009. A submucosal tumor (SMT) <20 mm was incidentally detected at the posterior wall of the gastric body. Endoscopic ultrasound (EUS) indicated that it was a gastrointestinal mesenchymal tumor, including GIST, leiomyoma or schwannoma. He did not accept regular follow-up for this gastric SMT, therefore local laparoscopic excision was carried out in October 2009. The final pathological diagnosis after surgery was GIST, 15 mm in size, and a mitotic rate of 7/50 high-power fields, which did not indicate a high metastatic risk. The patient was followed up regularly without adjuvant chemotherapy. At 1 year after surgery, a space-occupying lesion ~15 mm was detected in the left lobe of the liver by abdominal ultrasound, where no mass lesion had been observed before surgery. To make a definite diagnosis of the hepatic mass lesion, EUS-guided fine-needle aspiration was performed, which demonstrated a metastatic liver tumor from a gastric GIST. Although this was a rare case, we should keep in mind that gastric GISTs do have a chance of malignant behavior, even if <20 mm..
6. Nao Fujimori, Tetsuhide Ito, Hisato Igarashi, takamasa ono, Taichi Nakamura, Yusuke Niina, Masayuki Hijioka, Lingaku Lee, Masahiko Uchida, Ryoichi Takayanagi, Retroperitoneal fibrosis associated with immunoglobulin G4-related disease, World Journal of Gastroenterology, 10.3748/wjg.v19.i1.35, 19, 1, 35-41, 2013.02, Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs. Retroperitoneal fibrosis can be of 2 types: idiopathic and secondary. The recently advocated concept and diagnostic criteria of immunoglobulin G4 (IgG4)-related disease, derived from research on autoimmune pancreatitis (AIP), has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease. We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease; however, the actual prevalence is unclear. Conversely, some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease. Because retroperitoneal fibrosis has no specific symptoms, diagnosis is primarily based on diagnostic imaging (computed tomography and magnetic resonance imaging), which is also useful in evaluating the effect of therapy. Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP. Thus, the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis. High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease. The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause. For patients with concurrent AIP, i.e., IgG4-related retroperitoneal fibrosis, the starting dose of steroid is usually 30-40 mg/d. The response to steroid therapy is generally favorable. In most cases, the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment. However, the epidemiology, treatment for recurring retroperitoneal fibrosis, and long-term prognosis are still largely unknown. Further analysis of such cases and research are necessary..
7. Masahiko Uchida, Tetsuhide Ito, Taichi Nakamura, Hisato Igarashi, takamasa ono, Nao Fujimori, Ken Kawabe, Koichi Suzuki, Robert T. Jensen, Ryoichi Takayanagi, ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells, Laboratory Investigation, 10.1038/labinvest.2012.156, 93, 1, 41-53, 2013.01, The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP..
8. Taichi Nakamura, Tetsuhide Ito, Hisato Igarashi, Masahiko Uchida, Masayuki Hijioka, takamasa ono, Nao Fujimori, Yusuke Niina, Koichi Suzuki, Robert T. Jensen, Ryoichi Takayanagi, Cytosolic double-stranded DNA as a damage-associated molecular pattern induces the inflammatory response in rat pancreatic stellate cells
A plausible mechanism for tissue injury-associated pancreatitis, International Journal of Inflammation, 10.1155/2012/504128, 2012, 2012.11, Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes..
9. Hisato Igarashi, Tetsuhide Ito, takamasa ono, Taichi Nakamura, Nao Fujimori, Yusuke Niina, Masayuki Hijioka, Masahiko Uchida, Ringaku Lee, Risa Iwao, Kazuhiko Nakamura, Kazuhiro Kotoh, Ryoichi Takayanagi, Relationship between pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels in IgG4-related diseases, Journal of Digestive Diseases, 10.1111/j.1751-2980.2012.00583.x, 13, 5, 274-279, 2012.05, Objective: We aimed to investigate the relationship between the number of involved organs or regions and serum immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) levels. Methods: The number of pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels were examined by groups in 46 patients with IgG4-related diseases at diagnosis prior to the initiation of steroid treatment: group A (one region involved, n=7), group B (two regions involved, n=11), group C (three regions involved, n=12), group D (four regions involved, n=9) and group E (five to seven regions involved, n=7). Results: Both serum IgG and IgG4 levels increased with the number of inflamed regions. Mean serum IgG levels were 15.11, 18.65, 20.92, 23.29 and 30.98g/L while the mean IgG4 levels were 3.99, 4.70, 4.70, 9.86 and 16.49g/L in group A, B, C, D and E, respectively. Regression analysis also suggested that IgG4 was positively correlated with the number of regions involved. Additionally, serum IgG4 was higher in patients with multiple lesions when accompanied by sclerosing sialadenitis. Conclusion: Patients having IgG4-related disease with high serum IgG and IgG4 levels should be systematically examined for involved lesions..
10. Tetsuhide Ito, Makoto Otsuki, Hisato Igarashi, Yasuyuki Kihara, Ken Kawabe, Taichi Nakamura, Nao Fujimori, takamasa ono, Ryoichi Takayanagi, Tooru Shimosegawa, Epidemiological study of pancreatic diabetes in japan in 2005
A nationwide study, Pancreas, 10.1097/MPA.0b013e3181ca3da4, 39, 6, 829-835, 2010.08, Objectives: There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan. Methods: We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes). Results: A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers. Conclusion: We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation..
11. Mikihiko Yasuda, Tetsuhide Ito, takamasa ono, Ken Kawabe, Toyoma Kaku, Hisato Igarashi, Taichi Nakamura, Ryoichi Takayanagi, Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans, World Journal of Gastroenterology, 10.3748/wjg.14.6488, 14, 42, 6488-6495, 2008.11, Aim: To clarify whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of chronic pancreatitis (CP). This study aimed at clarifying whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of CP. Methods: Serum monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta-1 (TGF-β1), and soluble type fractalkine (s-fractalkine) concentrations were examined in patients with CP (n = 109) and healthy controls (n = 116). Severity of disease was classified in patients with CP by a staging system. Relationships between stage-specific various clinical factors and serum MCP-1, TGF-β1, and s-fractalkine levels were investigated. Furthermore, 57 patients with non-alcoholic CP were similarly evaluated in order to exclude influence of alcohol intake. Results: Patients with CP showed significant higher levels of serum TGF-β1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-β1 in the severe stage and s-fractalkine in the mild and the severe stage of CP significantly increased compared to those of controls. However, it was observed that both TGF-β1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-β1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed significant increase in the early stage of CP. Conclusion: It is suggested that the measurement of serum F-fractalkine is useful to diagnose early-stage CP. Moreover, the combined determination of both, s-fractalkine and TGF-β1, in human sera may be helpful in evaluating the severity status of CP..
12. Yoshifumi Ino, Yoshiyuki Arita, Tetsuro Akashi, Toshinari Kimura, Hisato Igarashi, takamasa ono, Masayuki Furukawa, Ken Kawabe, Keiichiro Ogoshi, Jiro Oochi, Toshihiko Miyahara, Ryoichi Takayanagi, Tetsuhide Ito, Continuous regional arterial infusion therapy with gabexate mesilate for severe acute pancreatitis, World Journal of Gastroenterology, 10.3748/wjg.14.6382, 14, 41, 6382-6387, 2008.11, Aim: To evaluate the efficacy of continuous regional arterial infusion therapy (CRAI) with gabexate mesilate and antibiotics for severe acute pancreatitis (SAP). Methods: We conducted a prospective study on patients who developed SAP with or without CRAI. Out of 18 patients fulfilled clinical diagnostic criteria for SAP in Japan, 9 patients underwent CRAI, while 9 patients underwent conventional systemic protease inhibitor and antibiotics therapy (non-CRAI). CRAI was initiated within 72 h of the onset of pancreatitis. Gabexate mesilate (2400 mg/d) was continuously administered for 3 to 5 d. The clinical outcome including serum inflammation-related parameters were examined. Results: The duration of abdominal pain in the CRAI group was 1.9 ± 0.26 d, whereas that in the non-CRAI group was 4.3 ± 0.50. The duration of SIRS in the CRAI group was 2.2 ± 0.22 d, whereas that in the non-CRAI group was 3.2 ± 0.28. Abdominal pain and SIRS disappeared significantly in a short period of time after the initiation of CRAI using gabexate mesilate. The average length of hospitalization significantly differed between the CRAI and non-CRAI groups, 53.3 ± 7.9 d and 87.4 ± 13.9 d, respectively. During the first two weeks, levels of serum CRP and the IL6/IL10 ratio in the CRAI group tended to have a rapid decrease compared to those in the non-CRAI group. Conclusion: The present results suggest that CRAI using gabexate mesilate was effective against SAP..
13. H. F. Zhao, Tetsuhide Ito, J. Gibo, Ken Kawabe, takamasa ono, T. Kaku, Y. Arita, Q. W. Zhao, M. Usui, Kensuke Egashira, H. Nawata, Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats, Gut, 10.1136/gut.2004.049403, 54, 12, 1759-1767, 2005.12, Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibulyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 μg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, α-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions: Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis..
14. Junya Gibo, Tetsuhide Ito, Ken Kawabe, Terumasa Hisano, Masanobu Inoue, Nao Fujimori, takamasa ono, Yoshiyuki Arita, Hajime Nawata, Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity, Laboratory Investigation, 10.1038/labinvest.3700203, 85, 1, 75-89, 2005.01, Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC + CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen α1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-α production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen α1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity..
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