Lung‐delivered IL‐10 mitigates Lung inflammation induced by repeated endotoxin exposures in male mice

Abstract Therapies capable of resolving inflammatory lung disease resulting from high‐consequence occupational/environmental hazards are lacking. This study seeks to determine the therapeutic potential of direct lung‐delivered interleukin (IL)‐10 following repeated lipopolysaccharide exposures. C57BL/6 mice were intratracheally instilled with LPS (10 μg) and treated with IL‐10 (1 μg) or vehicle control for 3 days. Lung cell infiltrates were enumerated by flow cytometry. Lung sections were stained for myeloperoxidase (MPO), CCR2, vimentin, and post‐translational protein citrullination (CIT) and malondialdehyde‐acetaldehyde (MAA) modifications. Lung function testing and longitudinal in vivo micro‐CT imaging were performed. Whole lungs were profiled using bulk RNA sequencing. IL‐10 treatment reduced LPS‐induced weight loss, pentraxin‐2, and IL‐6 serum levels. LPS‐induced lung proinflammatory and wound repair mediators (i.e., TNF‐α, IL‐6, CXCL1, CCL2, MMP‐8, MMP‐9, TIMP‐1, fibronectin) were decreased with IL‐10. IL‐10 reduced LPS‐induced influx of lung neutrophils, CD8 + T cells, NK cells, recruited monocyte‐macrophages, monocytes, and tissue expression of CCR2 + monocytes‐macrophages, MPO + neutrophils, vimentin, CIT, and MAA. IL‐10 reduced LPS‐induced airway hyperresponsiveness and improved lung compliance. Micro‐CT imaging confirmed the reduction in LPS‐induced lung density by IL‐10. Lung‐delivered IL‐10 therapy administered after daily repeated endotoxin exposures strikingly reduces lung inflammatory and wound repair processes to decrease lung pathologic changes and mitigate airway dysfunction.