α2A‐AR antagonism by BRL‐44408 maleate attenuates acute lung injury in rats with downregulation of ERK1/2, p38MAPK, and p65 pathway

Acute respiratory distress syndrome (ARDS), characterized by acute hypoxic respiratory dysfunction or failure, is a manifestation of multiple organ failure in the lung, and the most common risk factor is sepsis. We previously showed that blocking α2‐adrenoceptor (α2‐AR) could attenuate lung injury induced by endotoxin in rats. α2A‐adrenoceptor (α2A‐AR), a subtype of α2‐AR plays a key role in inflammatory diseases, but the mechanism remains unknown. Here, we explored the effect of BRL‐44408 maleate (BRL), a specific α2A‐AR antagonist, on cecal ligation puncture (CLP)‐induced ARDS in rats and the underlying mechanism. Preadministration of BRL‐44408 maleate significantly alleviated CLP‐induced histological injury, macrophage infiltration, inflammatory response, and wet/dry ratio in lung tissue. However, there was no statistical difference in survival rate between the CLP and CLP+BRL groups. Extracellular regulated protein kinase (ERK1/2), p38MAPK, and p65 were activated in the CLP group, and BRL‐44408 maleate inhibited the activation of these signal molecules, c‐Jun N‐terminal kinase (JNK) and protein kinase A (PKA) showed no changes in activation between these two groups. BRL‐44408 maleate decreased lipopolysaccharide (LPS)‐induced expression of cytokines in NR8383 rat alveolar macrophages and reduced phosphorylation of ERK1/2, p38MAPK, and p65. JNK and PKA were not influenced by LPS. Together, these findings suggest that antagonism of α2A‐AR improves CLP‐induced acute lung injury and involves the downregulation of ERK1/2, p38MAPK, and p65 pathway independent of the activation of JNK and PKA. ARDS animal models were induced by cecal ligation puncture with an intraperitoneal injection of BRL‐44408 maleate after 5 hours, and sacrificed after 6 hours or 24 hours. NR8383 cell line was incubated with BRL‐44408 maleate for 30 min and then treated with or without LPS (10 ng/mL) for 30 min or 12 hours.