Mechanisms mediating severity of acute pancreatitis in the aged

介导老年人急性胰腺炎严重程度的机制

• 批准号: 9389830
• 负责人: Hiroshi Saito
• 金额: $ 31.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389830
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Agonist; Animal Model; Animals; Antibodies; Area; Biological; Blood Circulation; Cells; Cessation of life; Characteristics; Clinical; Coagulation Process; Creatinine; Cytokine Gene; Development; Diagnostic; Disease; Elderly; Enzymes; Excision; Exhibits; Extravasation; Fatty acid glycerol esters; Foundations; Gene Expression; Immune; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-6; Intraperitoneal Injections; Kidney; Life; Link; Lipase; Lipolysis; Lung; Mediating; Mediator of activation protein; Modeling; Multiple Organ Failure; Mus; Mutant Strains Mice; Necrosis; Nonesterified Fatty Acids; Organ; PPAR alpha; Pancreas; Pathologic; Peritoneal; Peritoneal Fluid; Peritoneum; Phase; Plasminogen Activator Inhibitor 1; Prevention strategy; Production; Public Health; Research; Risk; Severities; Source; Testing; Therapeutic; Thrombosis; Tissues; Visceral; acute pancreatitis; age related; aged; cytokine; effective therapy; experimental study; inhibitor/antagonist; mortality; mouse model; older patient; prevent; release factor; therapeutic development; treatment strategy

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).

抽象的 该项目的目的是了解导致重症急性发作的机制 胰腺炎（sAP），一种危及生命的高死亡率疾病，其特征是胰腺坏死，严重 全身炎症、凝血、多器官功能障碍综合征（MODS）。 AP是特别严重的 老年人中的疾病，发病率和进展为 SAP 的可能性都急剧增加 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小鼠 AP 模型，其中只有老年小鼠表现出与临床相似的 sAP 观察结果包括长期全身炎症、凝血、MODS 和死亡。我们的观察 该小鼠模型包括组织损伤和细胞因子基因随年龄的急剧增加 内脏脂肪组织中的表达，以及腹水中游离脂肪酸的水平升高。集体 这些发现表明内脏脂肪组织是促进 AP 进展为 SAP 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，因为 由胰腺来源的消化酶渗漏引起的明显内脏脂肪组织炎症 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、炎症细胞因子和促血栓形成因子，均会促进 MODS。我们的假设将 进行以下三个具体目标的测试： 确定内脏脂肪组织炎症的特征 患有 SAP 的老年动物（目标 1）；证明内脏脂肪组织炎症增加会促进 老年人中 AP 进展为 sAP（目标 2）；制定预防 AP 进展的策略 通过抑制脂肪组织炎症来治疗老年动物的 sAP（目标 3）。