κ-opioid receptor agonist U50488H alleviates acute lung injury induced by cardiopulmonary bypass rats by regulating macrophage polarization

Objective To investigate whether κ-opioid receptor (KOR) agonist U50488H alleviates acute lung injury (ALI) induced by cardiopulmonary bypass (CPB) in rats by regulating macrophage polarization.

Methods Twenty-four adult male clean grade SD rats (weight of 50 to 450 g) were randomly divided into Sham group (sham surgery), CPB group (CPB), and U50488H group (KOR agonist+CPB), with 8 rats in each group. The U50488H group was intravenously injected with 1.5 mg/kg of U50488H 30 minutes before CPB. Arterial blood gas analysis was performed at 0, 1 hour and 2 hours after CPB to calculate the alveolar-arterial oxygen gradient (A-aDO₂) and respiratory index (RI). Rats of all three groups were euthanized 2 hours after CPB cessation, and the entire right lower lobe of the lung was excised. The extravascular lung water (EVLW) was measured using the gravimetric method, and lung tissue morphology changes were observed through hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of plasma lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-4 (IL-4). Immunofluorescence was used to measure the levels of iNOS and CD206 in the lung tissue of rats.

Results Compared to the Sham group, the CPB group of rats showed significant increases in extravascular lung water (EVLW) and levels of TNF-α, plasma IL-6 and lung tissue iNOS expression, as well as significant decreases in plasma IL-4 levels and lung tissue CD206 expression (P < 0.05). At 0, 1 hour and 2 hours after CPB, A-aDO₂, RI and LPS in the CPB group weresignificantly higher than those in the Sham group, and A-aDO₂, RI and LPS in the U50488H group were significantly lower than those in the CPB group (P < 0.05). The rats in the CPB group showed severe lung injury with alveolar congestion/bleeding and extensive infiltration of inflammatory cells, while lung injury was significantly reduced in the U50488H group.

Conclusion The KOR agonist U50488H can promote M2 polarization of lung macrophages in rats after CPB, reduce inflammatory response, increase anti-inflammatory factor release, and thereby reducing the occurrence of ALI after CPB.