Neutrophil-chemoattractant CXCL5 increases lung barrier permeability in acute lung injury

Acute lung injury is a common complication of pneumonia, with disease severity linked to inflammatory cell recruitment and lung barrier dysfunction. In this study, we investigate the role of neutrophil-chemoattractant CXCL5 in lung barrier function and inflammation. We examined CXCL5 in patients with severe pneumonia and in in vitro and in vivo models of acute lung injury. Pneumococcal infection and mechanical ventilation triggered CXCL5 release in both humans and mice. In Cxcl5-deficient mice, the alveolar-epithelial barrier remained intact despite acute lung injury, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial cells of Cxcl5-deficient mice. Consistently, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells. Beyond its known role in neutrophil recruitment, CXCL5 independently increases alveolar-epithelial barrier permeability. Therefore, targeting CXCL5 inhibition as adjunctive therapy with antibiotics in severe bacterial pneumonia may help reduce excessive inflammation and preserve lung barrier function.