Mechanisms of intestinal failure in post-surgical inflammatory bowel disease

描述（由申请人提供）：克罗恩病是肠切除术的主要原因。复发性炎症、纤维狭窄性疾病和小肠梗阻经常导致重复手术，增加了肠衰竭或短肠综合征的风险。目前的疗法不能有效预防术后炎症或纤维化。本研究的一个主要目标是开发回盲肠切除术（ICR）后手术后炎症和纤维化的新动物模型，ICR是CD中的一种常见手术干预。在常规（CONV）或无菌（GF）条件下给予ICR或假横切的白细胞介素-10（IL-10）无效小鼠将用于检验以下假设：手术期间组织损伤释放的细菌非依赖性因子可在易感宿主中引发术后纤维化和炎症，但维持慢性术后疾病需要肠道微生物群。残余小肠或结肠的适应性生长可防止肠切除术后的肠衰竭，但对细菌或活动性IBD对肠道适应的影响知之甚少。拟议的研究将检验肠道微生物菌群或活动性IBD对早期ICR诱导的干细胞扩增或肠道长期适应性生长的影响的假设。具体目标如下：目标一：将分析ICR或假横切后CONV IL-10缺失或WT小鼠的术后炎症和纤维化，并确定IL-10缺失小鼠的术后小肠疾病是否进展为狭窄、梗阻或肠衰竭。这些研究还将测试组织损伤相关模式信号（DAMPS）或晚期糖基化终产物受体（DAMPS）是否与术后炎症或纤维化的发生或持续相关。目的#2将分析无菌（GF）IL-10缺失和WT小鼠对ICR的反应，以确定细菌非依赖性因子是否可以在易感的IL-10缺失小鼠中引发或维持手术后炎症或纤维化，以及这是否与DAMPS或DAMPS的上调相关。目标#3将分析ICR后GF和CONV WT或IL-10缺失小鼠肠道中的隐窝干细胞和长期适应性生长，以确定肠道微生物区系或活动性IBD在肠切除适应性生长反应中的作用。 动物模型和来自这些探索性研究的信息将为更广泛的未来实验提供基础，以确定CD手术后复发性炎症和纤维化的新机制或致病因素，并测试旨在降低肠衰竭风险的新预防或治疗干预措施。克罗恩病的多次手术可导致肠衰竭和短肠综合征的破坏性状况，导致暂时或长期需要静脉内喂养。纤维狭窄性疾病和梗阻是肠衰竭的常见原因，但没有预防这些并发症的治疗方法。这项研究将开发新的动物模型，使人们能够更好地了解导致肠道衰竭的机制，并测试新的治疗方法，这些方法可能会预防损害生活质量并造成医疗保健费用的重大负担的疾病。

DESCRIPTION (provided by applicant): Crohn's disease is a major cause of bowel resection. Recurrent inflammation, fibrostenotic disease and obstruction in small intestine frequently lead to repeat surgeries, increasing the risk of intestinal failure or short bowel syndrome. Current therapies do not effectively prevent post-surgical inflammation or fibrosis. A major goal of this research is to develop a new animal model of post- surgical inflammation and fibrosis after ileo-cecal resection (ICR), a common surgical intervention in CD. Interleukin-10 (IL-10) null mice given ICR or sham transection under conventional (CONV) or germ free (GF) conditions will be used to test a hypothesis that bacteria independent factors released by tissue damage during surgery can initiate post-surgical fibrosis and inflammation in susceptible hosts, but commensal microflora are required to sustain chronic post-surgical disease. Adaptive growth of remnant small intestine or colon protects against intestinal failure after bowel resection, but little is known about the effects of bacteria or active IBD on intestinal adaptation. Proposed studies will test the hypothesis that commensal microflora or active IBD impact on early ICR-induced expansion of stem cells or long-term adaptive growth of intestine. Specific aims are as follows: Aim #1: will analyze post-surgical inflammation and fibrosis in CONV IL-10 null or WT mice after ICR or sham transection, and establish if post-surgical small bowel disease in IL-10 null mice progresses to stenosis, obstruction or intestinal failure. These studies will also test if tissue damage associated pattern signals (DAMPS) or receptor for advanced glycosylation end products (RAGE) correlate with initiation or perpetuation of post-surgical inflammation or fibrosis. Aim #2 will analyze responses to ICR in germ free (GF) IL-10 null and WT mice to define if bacteria-independent factors can initiate or sustain post-surgical inflammation or fibrosis in susceptible IL-10 null mice, and if this correlates with up-regulation of DAMPS or RAGE. Aim#3 will analyze crypt stem cells and long-term adaptive growth in the intestine of GF and CONV WT or IL-10 null mice after ICR, to define the role of commensal microflora or active IBD in adaptive growth responses to bowel resection. Animal models and information derived from these exploratory studies will provide the basis for more extensive future experiments to define new mechanisms or causative factors underlying recurrent inflammation and fibrosis after surgery for CD, and test new preventative or therapeutic interventions aimed at reducing the risk of intestinal failure.Multiple surgeries for Crohn's disease can cause intestinal failure and the devastating condition of short bowel syndrome, leading to temporary or long-term requirement for intravenous feeding. Fibrostenosing disease and obstruction are common causes of intestinal failure yet there are no therapies to prevent these complications. This research will develop new animal models that will permit better understanding of mechanisms that lead to intestinal failure, and testing of new therapies that may prevent a condition that compromises quality of life and poses a major burden in health care costs.