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A2962 - CXCL5 Drives Neutrophil Recruitment and Development of Lung Barrier Failure in Acute Lung Injury
Author Block: G. Nouailles1, S. Berger1, S. M. Wienhold1, C. Goekeri1, U. Behrendt1, H. C. Muller-Redetzky1, K. Dietert2, A. D. Gruber2, M. Witzenrath1; 1Department of Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin, Berlin, Germany, 2Institute of Veterinary Pathology, FU Berlin, Berlin, Germany.
RATIONALE: Neutrophils are important components of the innate immune response against bacterial infections in the lungs. However, excessive neutrophil responses might result in life-threatening lung injury. Neutrophil recruitment to sites of inflammation is partly driven by the chemokine receptor CXCR2. Chemokine cognates, which target a shared receptor like the CXCR2 ligands, are generally considered redundant. We postulated that pneumocyte-derived ligand CXCL5/LIX might play a superordinate role in acute lung injury due to its particulate spatial and temporal regulation in inflamed lungs.
METHODS: Using murine models of ventilator-induced lung injury (VILI) and pneumococcal pneumonia in CXCL5-deficient (CXCL5‒/‒) and wild-type (WT) mice, we studied the role of CXCL5 and neutrophil recruitment in ALI.
RESULTS: Following high tidal volume mechanical ventilation, CXCL5 absence reduced alveolar PMN recruitment significantly, which was accompanied with reduced vascular leakage. In line, in response to pulmonary Streptococcus pneumoniae (S. pn.) infection, PMN recruitment into alveolar spaces likewise significantly depended on CXCL5 signaling. Reduced PMN numbers resulted in increased bacterial burden in CXCL5‒/‒ compared to WT mice without affecting overall survival rates. Notably, despite elevated bacterial burden, vascular leakage was reduced in the absence of CXCL5.
CONCLUSIONS: Our results confirm the non-redundancy of CXCR2 ligands in ALI and highlight the importance of CXCL5 in neutrophil recruitment and development of lung barrier failure in ALI. Targeting CXCL5 may possibly provide a therapeutic perspective in pneumonia and mechanical ventilation.