Neutrophil-chemoattractant CXCL5 disrupts the lung barrier during acute lung injury

<bold>Background:</bold> Acute lung injury is manifested in various forms, with its severity linked to inflammatory cell recruitment and lung barrier breakdown. Identifying novel treatment pathways is crucial for clinical management. <bold>Aim:</bold> Exploring the effects of epithelial-derived chemokine CXCL5 on the lung barrier in acute lung injury <bold>Methods:</bold> We investigated CXCL5 and related chemokines in severe pneumonia patients and studied its impact on cells exposed to <italic>Streptococcus pneumoniae</italic> or mechanical stress. Additionally, we examined the functional role of CXCL5 using <italic>Cxcl5</italic>-deficient mice and human lung cell models. <bold>Findings:</bold> In both mice and humans, pneumonia and mechanical ventilation gave rise to increased CXCL5 levels. Epithelial cells in the lungs produced CXCL5, which was stored in the alveolar epithelial glycocalyx. In <italic>Cxcl5</italic>-deficient mice, the lung barrier was better maintained during acute lung injury, despite no alteration of neutrophil recruitment. Examining individual cell types revealed that CXCL5 disrupted barrier function in lung epithelial cells but not in vascular endothelial cells. <bold>Conclusion:</bold> Our findings unveil a new role for CXCL5 in acute lung injury, beyond its known function in inflammatory cell recruitment. Targeting CXCL5 alongside antibiotics could potentially mitigate excessive inflammation and stabilize lung function during severe bacterial infections.