Intestinal Barrier Function: Protective Effects of Curcumin

描述（由申请人提供）：肠上皮单层不仅在调节跨细胞和细胞旁营养吸收方面发挥关键作用，而且还通过提供针对病原菌和寄生菌以及微生物和饮食抗原的先天屏障发挥关键作用。这种保护屏障的破坏与急性疾病的发病机制有关，例如细菌移位导致败血症和多器官系统衰竭。它还与几种起源于婴儿期的慢性疾病有关，这些疾病在以后的生活中表现出来。这些包括特应性疾病，如湿疹、食物过敏、乳糜泻、1型糖尿病、哮喘和炎症性肠病。肠屏障功能障碍的重要诱导剂包括促炎细胞因子（IFN-？作为典型的屏障破坏细胞因子）和浸润和易位嗜中性粒细胞及其酶产物。慢性和严重的中性粒细胞浸润，跨上皮迁移和上皮和细胞外基质的酶和氧化损伤，显着有助于上皮屏障的损害。在许多炎症性人类疾病中，包括缺血性肠损伤、坏死性小肠结肠炎和特发性炎症性肠病，强烈的中性粒细胞跨上皮迁移是一种普遍特征，并与疾病病理生理学相关。在这个建议中，我们假设姜黄素通过抑制IFN-？在CEC中的信号传导，抑制中性粒细胞募集和顶端滞留，以及彻底抑制中性粒细胞在迁移过程中对屏障功能的不利影响。这些作用可能是姜黄素在肠道炎症中表现出的保护作用的基础，如结肠炎动物模型和溃疡性结肠炎患者的临床试验所示。我们建议解决这些新归因的功能姜黄素在三个特定的目标量身定制（1）确定姜黄素对IFN-γ抑制作用的分子机制？结肠细胞中的信号传导;（2）确定姜黄素对中性粒细胞化学运动和趋化性的抑制作用的分子机制;和（3）表征姜黄素对嗜中性粒细胞诱导的上皮功能障碍的保护作用的分子机制。综上所述，该项目将为姜黄素改善肠道屏障功能的机制和分子靶点提供新的信息。 公共卫生相关性：该建议集中于由肠上皮屏障功能障碍或失效引发或加重的许多肠和肠外疾病的临床相关方面。营养干预，例如使用所述天然化合物姜黄素，有望作为有效的补充疗法，其可以改善症状，降低慢性炎性病症的复发率，并且总体上提供了改善患有复发性肠道炎性病症的患者的生活质量的容易耐受且廉价的手段。

DESCRIPTION (provided by applicant): The intestinal epithelial monolayer pays a crucial role not only in regulating transcellular and paracellular nutrient absorption, but also by providing an innate barrier against pathogenic and commensal bacteria and microbial and dietary antigens. Breakdown of this protective barrier has been implicated in the pathogenesis of acute illnesses such as bacterial translocation leading to sepsis and multiple organ system failure. It also has been implicated in several chronic diseases having their origins during infancy that manifest in later life. These include atopic disease such eczema, food allergies, celiac enteropathy, type 1 diabetes, asthma, and inflammatory bowel disease. Important inducers of intestinal barrier dysfunctions include proinflammatory cytokines (with IFN-? as a prototypical barrier-damaging cytokine) and infiltrating and translocating neutrophils and their enzymatic products. Chronic and severe neutrophil infiltration, transepithelial migration and enzymatic and oxidative damages of the epithelium and the extracellular matrix, significantly contribute to the impairment of the epithelial barrier. In a number of inflammatory human diseases, including ischemic bowel injury, necrotizing enterocolitis, and idiopathic inflammatory bowel disease, intense neutrophil transepithelial migration is a prevalent feature and correlates with disease pathophysiology. In this proposal, we hypothesize that curcumin improves intestinal barrier through inhibition of IFN-? signaling in the CEC, inhibition of neutrophil recruitment and apical retention, and thorough inhibition of the detrimental effects of neutrophils on the barrier function during transmigration. These effects likely underlie the demonstrated protective effects of curcumin in intestinal inflammation, as demonstrated in animal models of colitis and in the clinical trial with ulcerative colitis patients. We propose to address these newly attributed functions of curcumin in three specific aims tailored to (1) identify the molecular mechanism of the inhibitory effects of curcumin on IFN-? signaling in the colonocytes; (2) identify the molecular mechanisms of inhibitory effects of curcumin on neutrophil chemokinesis and chemotaxis; and (3) to characterize the molecular mechanisms of the protective effects of curcumin on neutrophil-induced epithelial dysfunction. In summary, the proposed project will provide novel information about the mechanisms and molecular targets of curcumin in improving the intestinal barrier function. PUBLIC HEALTH RELEVANCE: This proposal is focused on a clinically relevant aspect of numerous intestinal and extraintestinal disorders initiated or exacerbated by a dysfunction or failure of the intestinal epithelial barrier. Nutritional interventions, such as with the described natural compound, curcumin, hold promise as effective supplemental therapy which may lead to improvement of symptoms, decreased relapse rate in chronic inflammatory conditions, and overall provide easily tolerated and inexpensive means of improving life quality in patients with recurring inflammatory conditions of the bowel.