CXCL10 and ISG15 are Upregulated in LPS-Induced ALI and Facilitate the Inflammatory State of Alveolar Macrophages

Acute lung injury (ALI) is a common critical illness in clinical practice with high mortality and limited specific treatment options. This study aimed to investigate the molecular mechanisms underlying lipopolysaccharide (LPS)-induced ALI and identify potential therapeutic targets. Through the integration of bulk RNA-seq and single-cell RNA-seq analyses, alveolar macrophages (AMs) were identified as a potentially important inflammatory cell population in LPS-induced ALI. Subsequent functional enrichment and protein-protein interaction (PPI) network analysis Identified CXCL10 and ISG15 as candidate mediators associated with the inflammatory activation of AM. Experiments using primary AMs suggested that LPS upregulates the expression of Cxcl10 and Isg15 by activating the NF-κB signaling pathway, thereby promoting the secretion of pro-inflammatory cytokines TNF-α and IL-6. Moreover, knockdown of Cxcl10 and Isg15 attenuated LPS-induced pro-inflammatory activation of AM, whereas the overexpression enhanced the inflammatory response, and combined manipulation produced an enhanced effect. In vivo studies using an LPS-induced ALI mouse model further demonstrated increased CXCL10 and ISG15 expression in lung injury. Collectively, these findings highlight CXCL10 and ISG15 as potential contributors to AM-mediated inflammation during ALI and suggest that the CXCL10/ISG15 axis may represent a potential therapeutic target for ALI.