NOX2 is involved in CB2-mediated protection against lung ischemia-reperfusion injury in mice

Lung ischemia-reperfusion injury (LIRI) can occur in many clinical scenarios. Activation of the cannabinoid 2 (CB2) receptor limits tissue injury in some ischemia-reperfusion (I/R) models. However, whether and how CB2 receptor activation alleviates lung injury induced by I/R remain unclear. In this study, we sought to determine whether JWH133, a selective CB2 receptor agonist, could alleviate lung injury induced by I/R and to examine the role of NOX2 in this process. Here, an I/R model was established using male C57BL/6 mice, by blocking the left pulmonary hilum for 1 h, followed by reperfusion for 2 h. Results showed that pretreatment with JWH133 significantly attenuated I/R-induced lung injury (decreased lung injury scores and wet-to-dry weight ratio and increased oxygenation index), alleviated oxidative stress (increased superoxide dismutase (SOD), and decreased Malondialdehyde (MDA) levels). It also significantly increased CB2 receptor mRNA expression and protein levels and significantly reduced NOX2 mRNA and protein expression. Further, the CB2 receptor antagonist AM630 eliminated these effects mediated by JWH133. Pretreatment with the NOX2 inhibitor, gp91 ds-tat, reduced NOX2 expression, but did not affect CB2 receptor expression and failed to alleviate lung injury and oxidative stress after additional JWH133 treatment. Our study suggests that CB2 receptor activation alleviates LIRI by inhibiting oxidative stress and that NOX2 is involved in CB2-mediated protection against LIRI in mice.