Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men

TLDR

Hemorrhagic shock triggers systemic inflammation and acute lung injury by activating innate immunity, with IL‑1β from lung endothelial cells via inflammasome playing a key role. The study investigates the mechanism by which hemorrhagic shock activates the inflammasome in lung endothelial cells. High‑mobility group box‑1 signals through TLR4, TLR2, and RAGE to activate NAD(P)H oxidase in endothelial cells, generating ROS that link TXNIP to NLRP3 and trigger inflammasome assembly and IL‑1β release, while neutrophil‑derived ROS further amplifies this pathway. The results reveal a novel pathway for hemorrhagic‑shock‑induced inflammasome activation in endothelial cells, suggesting a therapeutic target for SIRS and acute lung injury.

Abstract

Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS), including acute lung injury (ALI), through activating and exaggerating the innate immune response. IL-1β is a crucial proinflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1β, and the production of active IL-1β is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 acting through TLR4, and a synergistic collaboration with TLR2 and receptor for advanced glycation end products signaling, mediates HS-induced activation of EC NAD(P)H oxidase. In turn, reactive oxygen species derived from NAD(P)H oxidase promote the association of thioredoxin-interacting protein with the nucleotide-binding oligomerization domain-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1β secretion from the EC. We also show that neutrophil-derived reactive oxygen species play a role in enhancing EC NAD(P)H oxidase activation and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and thus presents a potential therapeutic target for SIRS and ALI induced after HS.