Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury

创伤后急性肺损伤的巨噬细胞焦亡机制

基本信息

批准号：
9593050
负责人：
Jie Fan
金额：
$ 39.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9593050
关键词：
Acute Lung Injury Alveolar Alveolar Macrophages Apoptosis CASP1 gene Cell Culture Techniques Cell Death Cell Death Process Cell Differentiation process Cells Cytolysis Development Dynamin Early Intervention Endocytosis Event Goals HMGB1 Protein Hemorrhagic Shock Human In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Injury Intervention Kupffer Cells Liver Lung Inflammation Modeling Molecular Multiple Organ Failure Mus Organ failure Pathogenesis Pattern Peripheral Peritoneal Phagocytosis Preventive Intervention Process Regulation Reporting Role Signal Transduction Sterility Systemic Inflammatory Response Syndrome Testing Therapeutic Intervention Trauma Trauma patient base effective therapy extracellular human disease in vivo insight macrophage monocyte mortality mouse model new therapeutic target novel preclinical study prevent prophylactic uptake

项目摘要

Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury ABSTRACT Trauma is a major cause of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), in which acute lung injury (ALI) is an important component. The underlying mechanism of how trauma leads to SIRS, MODS, and ALI has yet to be fully determined, but understanding these mechanisms is of prime importance as early interventional treatment of trauma patients may prevent organ failure and damage that usually occurs days later. Our long-term goal is to determine the mechanism by which trauma promotes ALI, thereby, potentially identifying novel targets for prophylactic intervention. We have reported a novel mechanism by which damage-associated molecular pattern (DAMP) molecules induce macrophage (Mφ) pyroptosis, a caspase-1-dependent programmed cell death. The ultimate osmotic lysis of pyroptotic cells releases intracellular contents and causes inflammation. Our following preliminary studies further show that: 1) HMGB1 induces human peripheral monocyte pyroptosis; 2) circulating monocyte pyroptosis does occur in trauma patients, and intracellular inflammasome components are released and can be detected in sera of trauma patients about four days after trauma; 3) Mφ phagocytosis of extracellular Nlrp3 inflammasome components activates inflammatory responses in the Mφ; 4) in a mouse model of HS/trauma, alveolar macrophage (AMφ) pyroptosis is induced in a HMGB1- RAGE-dependent manner; and 5) AMφ pyroptosis is associated with augmented lung inflammation. Based on the above findings, we hypothesize that: 1) HMGB1-RAGE signaling serves as a novel mechanism that induces Mφ pyroptosis following trauma; and 2) Mφ pyroptosis promotes the development of ALI after trauma by influencing inflammatory processes; and 3) inflammasome components that are released from pyroptotic Mφ serve as novel secondary danger signals to induce amplified inflammation. In order to test these hypotheses, we propose the following two specific aims: Specific Aim 1: To determine the molecular mechanism through which trauma induces Mφ pyroptosis. Specific Aim 2: To determine the role of Mφ pyroptosis in the development of ALI following trauma.