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

Abstract

Mortality 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.