Abstract
Lung ischemia reperfusion injury (LIRI) is a complex pathophysiological process with high morbidity and mortality. An important pathophysiological characteristic of LIRI is endothelial barrier dysfunction, although the mechanism involved in this process remains unclear. VX765, a specific caspase-1 inhibitor, has been shown to have a protective effect against several diseases including sepsis, atherosclerosis, and glial inflammatory disease. The objective of this study was to determine whether VX765 had a protective effect in LIRI. The results showed that lung ischemia/reperfusion (I/R) and oxygen/glucose deprivation and reoxygenation (OGD/R) induced endothelial pyroptosis and barrier dysfunction characterized by an inflammatory response. Treatment with VX765 successfully alleviated I/R- and OGD/R-induced endothelial pyroptosis and barrier dysfunction by inhibiting caspase-1 in vivo and in vitro. In conclusion, these findings showed that VX765 provided effective protection against lung I/R-induced endothelial pyroptosis and barrier dysfunction.
Highlights
Lung ischemia reperfusion injury (LIRI) leads to lung tissue damage during blood supply after a period of ischemia [1]
Recent studies demonstrated that pyroptosis plays a key role in I/R injury [8,9,10], it remains unclear whether pyroptosis is related to LIRI-induced endothelial barrier dysfunction
The canonical pyroptosis pathway is dependent on caspase-1 and cleaved gasdermin D (GSDMD) forming cell membrane pores that allow the exchange of ions [12, 13]
Summary
Lung ischemia reperfusion injury (LIRI) leads to lung tissue damage during blood supply after a period of ischemia [1]. Studies have indicated that endothelial barrier dysfunction is a key factor in ischemia/reperfusion (I/R) injury [6]. The findings of our previous study were consistent with these other studies as we showed that lung I/R released large amounts of inflammatory factors and induced endothelial barrier dysfunction [7]. Recent studies demonstrated that pyroptosis plays a key role in I/R injury [8,9,10], it remains unclear whether pyroptosis is related to LIRI-induced endothelial barrier dysfunction. During the process of pyroptosis, several cellular events occur following activation by caspases such as caspase-1/4/ 5/11 and include cleaving of GSDMD and secretion of inflammatory factors, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6) [14,15,16].
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