Mechanisms mediating severity of acute pancreatitis in the aged

摘要 本项目的目的是了解导致重症急性冠脉综合征发生的机制。 胰腺炎(SAP)是一种以胰腺坏死为特征的高死亡率的危及生命的疾病，严重 全身炎症、凝血、多器官功能障碍综合征(MODS)。AP是一个特别严重的 老年人的疾病，因为发病率和进展为SAP的可能性都显著增加 随着年龄的增长。尽管认识到这一临床问题，但对其潜在的原因知之甚少。 这种疾病的生物学机制，或者为什么进展为SAP在老年患者中更常见。我们 最近开发了一种老年AP小鼠模型，在该模型中只有老年小鼠表现出与临床相似的SAP 观察包括持续的全身炎症、凝血、多器官功能障碍综合征和死亡率。我们的观察 在这种小鼠模型中，组织损伤和细胞因子基因随着年龄的增长而急剧增加 内脏脂肪组织中的表达，腹水中游离脂肪酸水平的升高。集体地 这些发现表明，内脏脂肪组织是促进AP向SAP进展的关键介质 在老年人中。该项目的中心假设是，老年动物更容易患上SAP，原因是 胰源性消化酶渗漏引起的内脏脂肪组织炎症 从受损的胰腺进入腹膜。AP诱导的脂肪组织炎症导致释放 游离脂肪酸、炎性细胞因子和促血栓形成因子，都能促进MODS。我们的假设将 在以下三个具体目标中进行测试：确定内脏脂肪组织炎症的特征 老年SAP动物(目标1)；证明内脏脂肪组织炎症增加促进 老年急性胰腺炎向重症急性胰腺炎的进展(目标2)；并制定预防急性胰腺炎进展的策略 通过抑制脂肪组织炎症对老年动物SAP的作用(目标3)。

ABSTRACT The objective of this project is to understand the mechanisms leading to the development of severe acute pancreatitis (sAP), a life-threatening illness with high mortality characterized by necrotizing pancreas, severe systemic inflammation, coagulation, multiple organ dysfunction syndrome (MODS). AP is a particularly serious disease among the elderly as both incidence and the likelihood for progression to sAP increases dramatically with advancing age. Despite recognition of this clinical problem, little is known regarding the underlying biological mechanisms of this disease or why progression to sAP is more common among elderly patients. We recently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinical observations including prolonged systemic inflammation, coagulation, MODS, and fatality. Our observations with this mouse model include a dramatic age-dependent increase in tissue damage and cytokine gene expression within visceral adipose tissue, and elevated levels of free fatty acids in the ascitic fluid. Collectively these findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAP in the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due to pronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymes into the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release of free fatty acids, inflammatory cytokines, and pro-thrombotic factors, all promoting MODS. Our hypothesis will be tested in the following three specific aims: To determine features of visceral adipose tissue inflammation in aged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotes the progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of AP to sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).