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

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.