Role of leucine-rich repeat kinase 2 in severe acute pancreatitis

IntroductionIntrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in Lrrk2 is a risk factor for Parkinson’s disease and Crohn’s disease, both of which are driven by innate immune responses to gut organisms.DiscussionIn this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis

Pancreatic colonization of fungi in the development of severe acute pancreatitis

Acute pancreatitis is a common emergent disorder, a significant population of which develops the life-threatening condition, called severe acute pancreatitis (SAP). It is generally accepted that bacterial infection is associated with the development and persistence of SAP. In addition to bacterial infection, recent clinical studies disclosed a high incidence of fungal infection in patients with SAP. Moreover, SAP patients with fungal infection exhibit a higher mortality rate than those without infection. Although these clinical studies support pathogenic roles played by fungal infection in SAP, beneficial effects of prophylactic anti-fungal therapy on SAP have not been proved. Here we summarize recent clinical findings as to the relationship between fungal infection and the development of SAP. In addition, we discuss molecular mechanisms accounting for the development of SAP in the presence of fungal infection

Bispectral index-guided propofol sedation during endoscopic ultrasonography

Background/Aims Bispectral index (BIS) monitors process and display electroencephalographic data are used to assess the depth of anesthesia. This study retrospectively evaluated the usefulness of BIS monitoring during endoscopic ultrasonography (EUS). Methods This study included 725 consecutive patients who underwent EUS under sedation with propofol. BIS monitoring was used in 364 patients and was not used in 361. The following parameters were evaluated: (1) median dose of propofol; (2) respiratory and circulatory depression; (3) occurrence of body movements; (4) awakening score >8 at the time; and (5) awakening score 2 hours after leaving the endoscopy room. Results The BIS group received a significantly lower median dose of propofol than the non-BIS group (159.2 mg vs. 167.5 mg; p=0.015) in all age groups. For patients aged ≥75 years, the reduction in heart rate was significantly lower in the BIS group than in the non-BIS group (1.2% vs. 9.1%; p=0.023). Moreover, the occurrence of body movements was markedly lower in the BIS group than in the non-BIS group (8.5% vs. 39.4%; p<0.001). Conclusions During EUS examination, BIS monitoring is useful for maintaining a constant depth of anesthesia, especially in patients 75 years of age or older

生活習慣に起因する腸管バリア機能の破綻が自己免疫性膵炎の発症に果たす役割の解明

本研究では高脂肪食による肥満が自己免疫性膵炎(AIP)の発症に及ぼす効果を検討した。MRL/MpJマウスに普通食または高脂肪食を摂取させた後、poly (I:C) を腹腔内注射しAIPを誘導した。病理学的検討から、高脂肪食摂取による肥満はAIPを悪化させ、膵臓における形質細胞様樹状細胞(pDC)を活性化し、I型IFNの発現を増加させた。I型IFN経路の中和により高脂肪食摂取によるAIPの悪化は抑制された。高脂肪食による腸管TJPの発現に有意な変化は認めなかった。以上の結果から、高脂肪食摂取が膵臓におけるpDCの活性化を誘導しI型IFNの産生を亢進することによりAIPを悪化させることが判明した。Although autoimmune pancreatitis (AIP) predominantly occurs in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of AIP are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.研究分野：消化器内科

The role of lifestyle-induced intestinal barrier dysfunction in the pathogenesis of autoimmune pancreatitis

本研究では高脂肪食による肥満が自己免疫性膵炎(AIP)の発症に及ぼす効果を検討した。MRL/MpJマウスに普通食または高脂肪食を摂取させた後、poly (I:C) を腹腔内注射しAIPを誘導した。病理学的検討から、高脂肪食摂取による肥満はAIPを悪化させ、膵臓における形質細胞様樹状細胞(pDC)を活性化し、I型IFNの発現を増加させた。I型IFN経路の中和により高脂肪食摂取によるAIPの悪化は抑制された。高脂肪食による腸管TJPの発現に有意な変化は認めなかった。以上の結果から、高脂肪食摂取が膵臓におけるpDCの活性化を誘導しI型IFNの産生を亢進することによりAIPを悪化させることが判明した。Although autoimmune pancreatitis (AIP) predominantly occurs in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of AIP are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.研究分野：消化器内科