Description:
<jats:title>Abstract</jats:title><jats:p>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 α<jats:sub>2</jats:sub>‐adrenoceptor (α<jats:sub>2</jats:sub>‐AR) could attenuate lung injury induced by endotoxin in rats. α<jats:sub>2A</jats:sub>‐adrenoceptor (α<jats:sub>2A</jats:sub>‐AR), a subtype of α<jats:sub>2</jats:sub>‐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 α<jats:sub>2A</jats:sub>‐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 α<jats:sub>2A</jats:sub>‐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.</jats:p>