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 (M?) 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) M? phagocytosis of extracellular Nlrp3 inflammasome components activates inflammatory responses in the M?; 4) in a mouse model of HS/trauma, alveolar macrophage (AM?) pyroptosis is induced in a HMGB1- RAGE-dependent manner; and 5) AM? 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 M? pyroptosis following trauma; and 2) M? pyroptosis promotes the development of ALI after trauma by influencing inflammatory processes; and 3) inflammasome components that are released from pyroptotic M? 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 M? pyroptosis.
Specific Aim 2 : To determine the role of M? pyroptosis in the development of ALI following trauma.
Acute lung injury (ALI) is a major component of post-hemorrhagic shock (HS)/ trauma (T) systemic inflammatory response syndrome (SIRS); however, few specific targets have yet been identified that predispose to SIRS and ALI, rendering mortality rates high and effective treatment lacking. Gaining insight into the HS/T regulation of macrophage (M?) pyroptosis, a form of cell death that induces inflammation, will provide us with novel targets for preventive and therapeutic interventions in post-HS/T SIRS and ALI. Furthermore, in a broader sense, the proposed studies will contribute to a greater understanding of the pathogenesis of a number of human diseases in which M? is involved in the inflammatory process.
