Alpha2A-adrenoceptor deficiency attenuates lipopolysaccharide-induced lung injury by increasing norepinephrine levels and inhibiting alveolar macrophage activation in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality and few interventions. The role of sympathetic stress in the pathogenesis of ARDS has attracted recent research attention. Blockade of alpha-2 or alpha 2A-adrenoceptor (alpha(2A)-AR) has been shown to attenuate lung injury induced by lipopolysaccharide (LPS) in rats. However, the mechanism is unclear. We confirmed the role of alpha(2A)-AR in ARDS using knockout mice and alveolar macrophages following LPS stimulation to assess the underlying mechanisms. We found that alpha(2A)-AR deficiency decreased the permeability of the alveolar capillary barrier in ARDS mice and suppressed lung inflammation by reducing inflammatory cell infiltration and the production of TNF-alpha, interleukin (IL)-6, and CXCL2/MIP-2. LPS stimulation decreased NF-kappa B activation in lung tissues of alpha(2A)-AR deficient mice and increased nore-pinephrine concentrations. In vitro, we found that norepinephrine inhibited the production of TNF-alpha, IL-6, and CXCL2/MIP-2 and promoted the secretion of IL-10 from LPS-stimulated murine alveolar macrophages. Blockade of alpha(2A)-AR by a specific antagonist further inhib-ited the production of TNF-alpha, IL-6, and IL-10. Furthermore, norepinephrine down-regulated NF-kappa B activation in stimulated alveolar macrophages. Altogether, these results suggest that alpha(2A)-AR deficiency ameliorates lung injury by increasing norepinephrine concentrations in lung tissues and inhibiting the activation of alveolar macrophages.