Role of Cathelicidin in Intestinal Inflammation

描述（由申请人提供）：上皮系统和免疫系统以及肠道微生物群之间的稳态在控制机体对炎症刺激的反应中很重要。抗菌肽是一种具有抗菌功能的内源性肽。它构成了保护宿主免受感染的整体先天免疫反应的一部分。最近的证据表明，cathelicidins（人类的LL-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，很少有信息支持抗菌肽在肠道炎症中的作用。我们的初步研究结果表明，在IBD患者和结肠炎小鼠模型的结肠中，cathelicidins及其受体的表达增加，但肠道炎症期间分泌cathelicidin的特定细胞尚不清楚。此外，短期给予小鼠抗菌肽（mCRAMP）可减轻三硝基苯磺酸引起的小鼠结肠炎的许多方面。因此，我们假设发炎的结肠释放刺激上皮细胞和/或免疫细胞表达抗菌肽的分子，但肠道中适度增加的抗菌肽水平可能不足以抵消严重的炎症。因此，外源性抗菌肽的施用可能是必要的，以抵消结肠炎症。在目的1中，我们将描述IBD患者和几种急性和慢性结肠炎小鼠模型结肠中抗菌肽的细胞表达谱，我们将研究给药丁酸钠增加内源性抗菌肽水平以减少体内结肠炎的可能性。目的2将在小鼠急性和慢性结肠炎症模型中研究短期和长期给药抗菌肽的体内治疗效果。目的3的实验将确定抗菌肽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生成作用。总之，我们提出的实验将为抗菌肽在肠道炎症和IBD的病理生理中的作用以及抗菌肽调节结肠炎症的机制提供重要的见解。

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.