Abstract
The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.
Highlights
Acute lung injury (ALI) following severe burns remains a prominent source of morbidity and mortality among critically ill patients
We analyzed the production of IL-1β and IL-18 in rat serum and lung tissue samples
The Enzyme-Linked Immunosorbent Assay (ELISA) and qRT-polymerase chain reaction (PCR) results demonstrated that the levels of IL-1β (Figures 1(a) and 1(c)) and IL-18 (Figures 1(b) and 1(d)) were significantly increased compared with the sham group (0 h) over time; the expression levels of IL-1β and IL-18 peaked at either 24 h or 48 h
Summary
Acute lung injury (ALI) following severe burns remains a prominent source of morbidity and mortality among critically ill patients. Severe burn injury, consisting of several damage factors like trauma stress, thermal attack, and tissue hypoperfusion, triggers an abundance of detrimental secondary effects, including inflammation, oxidative stress, and apoptosis, which results in either ALI or acute respiratory distress syndrome (ARDS) [1,2,3]. The primary pathological mechanisms underlying ALI are vascular endothelial and alveolar epithelial cell damage, which result in the destruction of blood-alveolar barrier. This destruction yields pulmonary edema, intrapulmonary hemorrhage, and severely impaired gas exchange [4]. The precise mechanisms underlying the development of ALI following severe burn injury remain unclear, inflammatory response accounts for major reasons. Literatures suggest that inflammatory responses following burn insult are associated with robust release of proinflammatory cytokines and activation of sympathetic inflammatory signaling pathways [5, 6]
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