AR-R17779, an agonist of alpha-7 nicotinic acetylcholine receptor, attenuates trauma-induced lung epithelial glycocalyx injury by suppressing macrophage proinflammatory activity.

Abstract

BACKGROUND: Acute lung injury (ALI) after trauma is associated with alveolar dysfunction that causes significant morbidity with limited treatment options. We have shown that AR-R17779, a small molecule agonist of the α7 nicotinic acetylcholine receptor highly expressed on macrophages, prevents lung edema in preclinical models of injury. The mechanism by which AR-R17779 attenuates trauma-induced ALI is unknown. We hypothesized that AR-R17779 decreases trauma-induced ALI by limiting macrophage activation and preventing lung epithelial glycocalyx breakdown. METHODS: C57BL/6 mice underwent a polytrauma model consisting of lung contusion and liver crush injury with cohorts treated with an intraperitoneal dose of AR-R17779 (25 mg/kg) immediately following polytrauma. Lungs were harvested 24 hours postinjury for evaluation of ALI using histology and immunofluorescence of heparan sulfate (HS), a key component of the glycocalyx. In vitro coculture studies were performed to assess the impact of AR-R17779 on the activation of macrophages by lipopolysaccharide (LPS) and its effects on the lung epithelial glycocalyx by immunoblotting, enzyme-linked immunosorbent assay, and HS expression. RESULTS: AR-R17779 attenuated polytrauma-induced histological ALI and loss of HS from the lung epithelial glycocalyx. In vitro, AR-R17779 dose-dependently suppressed signal transducer and activator of transcription 3 phosphorylation and tumor necrosis factor release from LPS-treated macrophages. In coculture studies, treating LPS-stimulated macrophages with AR-R17779 decreased epithelial glycocalyx degradation compared with macrophages treated with LPS alone. CONCLUSION: AR-R17779 attenuated trauma-induced ALI by preventing lung epithelial glycocalyx breakdown, which may result from the suppression of macrophage proinflammatory activity. Future research should test AR-R17779 as an adjunct to resuscitation aimed at limiting dysregulated macrophage activation and ALI after trauma.