Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS.
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.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Jie
J
Yang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Yanfeng
Y
Zhao
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Peng
P
Zhang
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Yuehua
Y
Li
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Yong
Y
Yang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Yang
Y
Yang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Junjie
J
Zhu
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Xiao
X
Song
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Gening
G
Jiang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Jie
J
Fan
D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D002401:Cathepsin B / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000276:immunology / Q000473:pathology; D008247:Lysosomes / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D000069292:Pyroptosis / Q000276:immunology*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D020170:Caspase 1