Role of Cathelicidin in Intestinal Inflammation

描述(由申请人提供)：上皮和免疫系统以及肠道微生物区系之间的动态平衡对于控制机体对炎症刺激的反应非常重要。长春花素是一种具有抗微生物功能的内源性多肽。它构成了整个先天免疫反应的一部分，以保护宿主免受感染。最近的证据表明，放线菌素(人类的IL-37和小鼠的mCRAMP)可能调节炎症、细胞凋亡和血管生成的反应。然而，很少有信息支持放线菌素在肠道炎症中的作用。我们的初步研究结果表明，在IBD患者和小鼠结肠炎模型的结肠中，放线菌素及其受体的表达增加，但在肠道炎症过程中分泌放线菌素的特定细胞尚不清楚。此外，短期给药可从多方面缓解三硝基苯磺酸诱导的小鼠结肠炎。因此，我们假设发炎的结肠释放分子，刺激上皮细胞和/或免疫细胞表达泻药，但肠道中这些适度增加的泻药素水平可能不足以抵消严重炎症。因此，外源性长春花碱给药可能是必要的，以对抗结肠炎。在目标1中，我们将对IBD患者和几种急、慢性结肠炎小鼠模型的结肠细胞中的长春花素表达谱进行表征，并将探讨在体内应用丁酸钠来增加内源性长春花素水平以减少结肠炎的可能性。目的2研究在小鼠急性和慢性结肠炎模型中短期和长期给予长春新碱的体内治疗效果。目标3中的实验将确定长春花素在培养的人肠道微血管内皮细胞和成纤维细胞中的抗血管生成和抗纤维化作用。综上所述，我们提出的实验将对肠道炎症和IBD的病理生理学中的作用以及肠道炎症调节结肠炎的机制提供重要的见解。 公共卫生相关性：我们的研究计划将检查一个重要的和病理生理学相关的研究主题，即肠道炎症中肠道毒素的作用。我们的研究结果将为炎症性肠病的病理生理学提供深入的认识，并评估放线菌素在肠道炎症中的治疗潜力。

DESCRIPTION (provided by applicant): Homeostasis between epithelial and immune systems and intestinal microbiota is important in controlling the organism's responses to inflammatory stimuli. Cathelicidin is an endogenous peptide that possesses anti- microbial functions. It constitutes a part of the overall innate immune response to protect the host against infection. Recent evidence suggests that cathelicidins (LL-37 in humans and mCRAMP in mice) may modulate responses in inflammation, apoptosis and angiogenesis. However, very little information is available to support a role of cathelicidin in intestinal inflammation. Results from our preliminary studies indicate that cathelicidins and expression of their receptors are increased in the colon of IBD patients and mouse models of colitis, but the particular cells secreting cathelicidin during intestinal inflammation are not known yet. Moreover, short-term administration of mouse cathelicidin (mCRAMP) relieves many aspects of trinitrobenzene sulphonic acid- induced colitis in mice. Therefore, we hypothesize that the inflamed colon releases molecules that stimulate cathelicidin expression from epithelial cells and/or immune cells but these moderately increased cathelicidin levels in the intestine may not be sufficient to counteract severe inflammation. Thus exogenous cathelicidin administration may be necessary to counteract colonic inflammation. In aim 1, we will characterize the cellular cathelicidin expression profile in colons of IBD patients and several mouse models of acute and chronic colitis and we will examine the possibility to administer sodium butyrate to increase endogenous cathelicidin levels to reduce colitis in vivo. Aim 2 will examine the in vivo therapeutic effects of short- and long-term administration of cathelicidin in mouse models of acute and chronic colonic inflammation. Experiments in aim 3 will determine the anti-angiogenic and anti-fibrogenic role of cathelicidin in cultured human intestinal microvascular endothelial cells and fibroblasts. In summary, our proposed experiments will provide important insights into the role of cathelicidins in the pathophysiology of intestinal inflammation and IBD and the mechanisms by which cathelicidins modulate colonic inflammation. PUBLIC HEALTH RELEVANCE: Our research proposal will examine an important and pathophysiologically relevant research topic, namely the role of cathelicidins in intestinal inflammation. Results from our studies will provide insights of the pathophysiology of inflammatory bowel disease and evaluate the therapeutic potential of cathelicidins in intestinal inflammation.