Role of Cathelicidin in Intestinal Inflammation

描述（由申请人提供）：上皮和免疫系统与肠道微生物群之间的稳态在控制生物体对炎症刺激的反应中很重要。Cathelicidin是一种具有抗菌功能的内源性多肽.它构成了整体先天免疫应答的一部分，以保护宿主免受感染。最近的证据表明，cathelicidins（人类中的LL-37和小鼠中的mCRAMP）可以调节炎症、细胞凋亡和血管生成的反应。然而，很少有信息支持cathelicidin在肠道炎症中的作用。我们的初步研究结果表明，cathelicidin及其受体的表达在IBD患者和结肠炎小鼠模型的结肠中增加，但在肠道炎症期间分泌cathelicidin的特定细胞尚不清楚。此外，短期施用小鼠凯萨林菌素（mCRAMP）缓解了小鼠中三硝基苯磺酸诱导的结肠炎的许多方面。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cathelicidin的分子，但肠道中这些适度增加的cathelicidin水平可能不足以抵消严重的炎症。因此，外源性凯萨林菌素管理可能是必要的，以抵消结肠炎症。在目标1中，我们将表征IBD患者和几种急性和慢性结肠炎小鼠模型的结肠中的细胞凯萨林菌素表达谱，并且我们将检查施用丁酸钠以增加内源性凯萨林菌素水平以减少体内结肠炎的可能性。目的2将检查在急性和慢性结肠炎症的小鼠模型中短期和长期施用凯萨林菌素的体内治疗效果。目的3中的实验将确定凯萨林菌素在培养的人肠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，我们提出的实验将提供重要的见解cathelicidins在肠道炎症和IBD的病理生理学的作用和cathelicidins调节结肠炎症的机制。

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.