Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS.

Xiao Song,Peng Zhang,Yuehua Li,Yong Yang,Gening Jiang,Junjie Zhu,Jie Yang,Jie Fan,Yanfeng Zhao,Yang Yang

doi:10.1038/cddis.2016.274

Abstract

Hemorrhagic shock (HS) often renders patients more susceptible to lung injury by priming for an exaggerated response to a second infectious stimulus. Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome following HS and regularly serves as a major cause of patient mortality. The lung vascular endothelium is an active organ that has a central role in the development of ALI through synthesizing and releasing of a number of inflammatory mediators. Cell pyroptosis is a caspase-1-dependent regulated cell death, which features rapid plasma membrane rupture and release of proinflammatory intracellular contents. In this study, we demonstrated an important role of HS in priming for LPS-induced lung endothelial cell (EC) pyroptosis. We showed that LPS through TLR4 activates Nlrp3 (NACHT, LRR, and PYD domains containing protein 3) inflammasome in mouse lung vascular EC, and subsequently induces caspase-1 activation. However, HS induced release of high-mobility group box 1 (HMGB1), which acting through the receptor for advanced glycation end products initiates EC endocytosis of HMGB1, and subsequently triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. These HS-induced events enhance LPS-induced EC pyroptosis. We further showed that lung vascular EC pyroptosis significantly exaggerates lung inflammation and injury. The present study explores a novel mechanism underlying HS-primed ALI and thus presents a potential therapeutic target for post-HS ALI.

Highlights

Hemorrhagic shock (HS) often renders patients more susceptible to a secondary stimulus resulting in the development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) by activating and priming the inflammatory process
Pulmonary endothelial cell (EC) are the first cells of the lung to be altered in Acute lung injury (ALI)/ ARDS triggered by sepsis, trauma, and shock, and activated lung EC play an important role in the development of ALI.[4]
HS induced release of highmobility group box 1 (HMGB1) through receptor for advanced glycation end products (RAGE) signaling initiates EC endocytosis of HMGB1, which in turn triggers cathepsin B (CatB) release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation

Summary

Introduction

Hemorrhagic shock (HS) often renders patients more susceptible to a secondary stimulus (e.g., infection) resulting in the development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) by activating and priming the inflammatory process. Low level of activation of caspase-1 might be necessary for cell survival in response to external stimulations.[15] over-activation of caspase-1 may serve as a premise for cell pyroptosis.[5,6] The platform for caspase-1 activation includes inflammasome and pyroptosome. The former comprises of NOD-like receptors (NLRs) or AIM2 receptor, caspase-1, and apoptosis-associated speck-like protein containing a CARD domain (ASC); and the latter is composed of oligomerized ASC dimers.[16] We have previously reported that. We showed that LPS through TLR4 activates Nlrp[3] inflammasome in mouse lung vascular EC (MLVEC), and subsequently induces

Methods

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Conclusion