Activation of cannabinoid receptor type 2 reduces lung ischemia reperfusion injury through PI3K/Akt pathway

Cannabinoid receptor-2 activation plays a protective role against ischemic reperfusion injury (IRI) in various organs, and exerts a protective effect against paraquat-induced acute lung injury, while the role of CB₂ in lung IRI remains unclear. Hence, the present study was designed to explore the role of CB₂ in lung IRI, and whether the PI3K pathway was involved. C57BL/6 mice were subjected to lung ischemia by clamping the left hilum for 1 hour, followed by 2 hours' reperfusion. Mice were pretreated with vehicle, CB₂ agonist JWH133, or antagonist AM630 followed by JWH133. Arterial blood and left lung tissues were collected to detect the PaO₂/FiO₂ ratio, lung wet-to-dry weight ratio, lung pathologic scoring, pro-inflammatory cytokines, MDA, and SOD. Secondly, mice were pretreated with vehicle, JWH133, or both PI3K-inhibitor LY294002 and JWH133. Arterial blood and left lung tissues were collected for the above studies and protein expression of CB₂ receptor, p-AKT, and AKT. After mice were pretreated with JWH133, IR-induced lung edema and lung histopathologic changes were significantly attenuated. Pretreatment with JWH133 improved PaO₂/FiO₂ ratio, decreased lung TNF-α, IL-6, MDA levels and MPO activities, and increased SOD activity. By contrast, the protective effect of JWH133 was blocked by pretreatment with CB₂ antagonist AM630. Similarly, pretreatment with PI3K-inhibitor weakened the protection induced by JWH133, and downregulated the expression of p-AKT without altering CB₂ expression. The study suggested that activation of CB₂ receptor plays a protective role against IR-induced lung injury through reducing inflammation in mice. The PI3K/Akt pathway might be involved in the protective effect of CB₂ receptors in lung IRI.