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

Zhukai Cong, Dan Li, Xiangpeng Lv, Cui Yang, Qiang Zhang, Changyi Wu, Zongyu Wang, Xi Zhu
Clinical Science (1979-) 2020 July 9
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 alpha2A-adrenoceptor (α2A-AR) has been shown to attenuate lung injury induced by lipopolysaccharide in rats. However, the mechanism is unclear. We confirmed the role of α2A-AR in ARDS using knockout mice and alveolar macrophages following lipopolysaccharide stimulation to assess the underlying mechanisms. We found that α2A-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-α, IL-6, and CXCL2/MIP-2. Lipopolysaccharide stimulation decreased NF-κB activation in lung tissues of α2A-AR deficient mice and increased norepinephrine concentrations. In vitro, we found that norepinephrine inhibited the production of TNF-α, IL-6, and CXCL2/MIP-2 and promoted the secretion of IL-10 from lipopolysaccharide-stimulated murine alveolar macrophages. Blockade of α2A-AR by a specific antagonist further inhibited the production of TNF-α, IL-6, and IL-10. Furthermore, norepinephrine down-regulated NF-κB activation in stimulated alveolar macrophages. Altogether, these results suggest that α2A-AR deficiency ameliorates lung injury by increasing norepinephrine concentrations in lung tissues and inhibiting the activation of alveolar macrophages.

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