- 作者列表："Nozu T","Miyagishi S","Nozu R","Takakusaki K","Okumura T
BACKGROUND:Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes. METHODS:The threshold of visceromotor response (VMR), that is, abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 minutes spectrophotometrically. KEY RESULTS:Lipopolysaccharide (1 mg kg-1 ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5-25 mg kg-1 s.c.) for 3 days inhibited these changes in a dose-dependent manner. Moreover, repeated WAS (1 hour daily for 3 days) or intraperitoneal injection of CRF (50 µg kg-1 ) induced the similar visceral changes as LPS, which were also eliminated by losartan. These effects by losartan in LPS model were reversed by GW9662 (a peroxisome proliferator-activated receptor-γ [PPAR-γ] antagonist), NG -nitro-L-arginine methyl ester (a nitric oxide [NO] synthesis inhibitor), or naloxone (an opioid receptor antagonist). Moreover, it also inhibited by sulpiride (a dopamine D2 receptor antagonist) or domperidone (a peripheral dopamine D2 antagonist). CONCLUSION & INFERENCES:Losartan prevented visceral allodynia and colonic hyperpermeability in rat IBS models. These actions may be PPAR-γ-dependent and also mediated by the NO, opioid, and dopamine D2 pathways. Losartan may be useful for IBS treatment.
背景: 脂多糖 (LPS) 或反复回避水应激 (WAS) 通过促肾上腺皮质激素释放因子 (CRF) 和促炎细胞因子诱导内脏异常性疼痛和结肠高通透性, 被认为是大鼠肠易激综合征 (IBS) 模型。由于已知氯沙坦能抑制促炎细胞因子的释放，我们假设它能改善这些内脏变化。 方法: 测定大鼠内脏运动反应 (VMR) 的阈值，即结肠球囊扩张引起的腹部肌肉收缩。通过分光光度法定量结肠组织中吸收的伊文思蓝 15 min，在体内测定结肠通透性。 关键结果: 脂多糖 (1 mg · kg-1) 皮下 (s.c.) 降低 VMR 阈值，增加结肠通透性。氯沙坦 (5-25 mg kg-1 s.c.) 3 天，以剂量依赖性方式抑制这些变化。此外，重复给药 (每日 1 小时，共 3 天) 或腹腔注射 CRF (50 µ g · kg-1) 诱导的内脏变化与 LPS 相似，氯沙坦也消除了这些变化。在 LPS 模型中氯沙坦的这些作用被 GW9662 (一种过氧化物酶体增殖物激活受体-γ [PPAR-γ] 拮抗剂) 逆转, NG-硝基-L-精氨酸甲酯 (一氧化氮 [NO] 合成抑制剂)，或纳洛酮 (阿片受体拮抗剂)。此外，舒必利 (多巴胺 D2 受体拮抗剂) 或多潘立酮 (外周多巴胺 D2 拮抗剂) 也可抑制它。 结论: 氯沙坦可预防 IBS 大鼠模型内脏痛觉异常和结肠高通透性。这些作用可能是 PPAR-γ 依赖性的，也由 NO 、阿片类和多巴胺 D2 通路介导。氯沙坦可能对 IBS 治疗有用。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.