Intestinal Barrier Function: Protective Effects of Curcumin

描述(申请人提供)：肠上皮单分子层不仅在调节跨细胞和细胞旁营养吸收方面发挥着关键作用，而且还通过提供一种天然屏障来对抗病原菌和共生菌以及微生物和饮食抗原。这种保护屏障的破坏与急性疾病的发病机制有关，如细菌易位导致败血症和多器官系统衰竭。它还与几种慢性疾病有关，这些疾病起源于婴儿时期，并在以后的生活中表现出来。这些疾病包括特应性疾病，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因包括促炎细胞因子(与干扰素？作为一种典型的屏障破坏细胞因子)，并渗透和转移中性粒细胞及其酶产物。慢性严重的中性粒细胞浸润、跨上皮细胞迁移以及上皮细胞和细胞外基质的酶和氧化损伤是导致上皮屏障受损的重要原因。在许多人类炎症性疾病中，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皮细胞迁移是一种普遍的特征，并与疾病的病理生理相关。在这项提议中，我们假设姜黄素通过抑制干扰素？？来改善肠道屏障。在CEC中传递信号，抑制中性粒细胞募集和心尖滞留，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炎中所表现出的保护作用的基础，正如在结肠炎的动物模型和溃疡性结肠炎患者的临床试验中所证明的那样。我们建议从以下三个方面探讨姜黄素的这些新功能：(1)确定姜黄素抑制干扰素的分子机制。(2)明确姜黄素抑制中性粒细胞趋化和趋化作用的分子机制；(3)研究姜黄素保护中性粒细胞诱导的上皮功能障碍的分子机制。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：这项建议侧重于许多肠道和肠外疾病的临床相关方面，这些疾病是由肠道上皮屏障功能障碍或衰竭引发或加剧的。营养干预，例如使用所描述的天然化合物姜黄素，有望成为有效的补充治疗，可能导致症状改善，降低慢性炎症条件下的复发率，并总体上提供易于耐受的廉价手段，改善反复出现的肠道炎症条件的患者的生活质量。

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.