α_2A‐AR antagonism by BRL‐44408 maleate attenuates acute lung injury in rats with downregulation of ERK1/2, p38MAPK, and p65 pathway

Abstract

Abstract 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 2 ‐adrenoceptor (α 2 ‐AR) could attenuate lung injury induced by endotoxin in rats. α 2A ‐adrenoceptor (α 2A ‐AR), a subtype of α 2 ‐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 2A ‐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 2A ‐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.

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