α1-adrenoceptor stimulation ameliorates lipopolysaccharide-induced lung injury by inhibiting alveolar macrophage inflammatory responses through NF-κB and ERK1/2 pathway in ARDS.

Abstract

Catecholamines such as norepinephrine or epinephrine have been reported to participate in the development of acute respiratory distress syndrome (ARDS) by activating adrenergic receptors (ARs). But the role of α1-AR in this process has yet to be elucidated. In this study, ARDS mouse model was induced by intratracheal instillation of lipopolysaccharide. After treatment with α1-AR agonist phenylephrine or antagonist prazosin, lung pathological injury, alveolar barrier disruption and inflammation, and haemodynamic changes were evaluated. Cytokine levels and cell viability of alveolar macrophages were measured in vitro. Nuclear factor κB (NF-κB), mitogen-activated protein kinase, and Akt signalling pathways were analysed by western blot. It showed that α1-AR activation alleviated lung injuries, including reduced histopathological damage, cytokine expression, and inflammatory cell infiltration, and improved alveolar capillary barrier integrity of ARDS mice without influencing cardiovascular haemodynamics. In vitro experiments suggested that α1-AR stimulation inhibited secretion of TNF-α, IL-6, CXCL2/MIP-2, and promoted IL-10 secretion, but did not affect cell viability. Moreover, α1-AR stimulation inhibited NF-κB and enhanced ERK1/2 activation without significantly influencing p38, JNK, or Akt activation. Our studies reveal that α1-AR stimulation could ameliorate lipopolysaccharide-induced lung injury by inhibiting NF-κB and promoting ERK1/2 to suppress excessiveinflammatoryresponses of alveolar macrophages.