• J. Clin. Invest. · Dec 2002

    Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury.

    • John A Belperio, Michael P Keane, Marie D Burdick, Vedang Londhe, Xue Ying Ying YY, Kewang Li, Roderick J Phillips, and Robert M Strieter.
    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90024-1922, USA.
    • J. Clin. Invest. 2002 Dec 1; 110 (11): 1703-16.

    AbstractMortality related to adult respiratory distress syndrome (ARDS) ranges from 35% to 65%. Lung-protective ventilator strategies can reduce mortality during ARDS. The protective strategies limit tidal volumes and peak pressures while maximizing positive end-expiratory pressure. The efficacy of this approach is due to a reduction of shear-stress of the lung and release of inflammatory mediators. Ventilator-induced lung injury (VILI) is characterized by inflammation. The specific mechanism(s) that recruit leukocytes during VILI have not been elucidated. Because the murine CXC chemokines KC/CXCL1 and MIP-2/CXCL2/3, via CXCR2, are potent neutrophil chemoattractants, we investigated their role in a murine model of VILI. We compared two ventilator strategies in C57BL/6 mice: high peak pressure and high stretch (high peak pressure/stretch) versus low peak pressure/stretch for 6 hours. Lung injury and neutrophil sequestration from the high-peak pressure/stretch group were greater than those from the low-peak pressure/stretch group. In addition, lung expression of KC/CXCL1 and MIP-2/CXCL2/3 paralleled lung injury and neutrophil sequestration. Moreover, in vivo inhibition of CXCR2/CXC chemokine ligand interactions led to a marked reduction in neutrophil sequestration and lung injury. These findings were confirmed using CXCR2(-/-) mice. Together these experiments support the notion that increased expression of KC/CXCL1 and MIP-2/CXCL2/3 and their interaction with CXCR2 are important in the pathogeneses of VILI.

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