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.

• Authors: John A Belperio, Michael P Keane, Marie D Burdick, Vedang Londhe, Ying Ying Xue, Kewang Li, Roderick J Phillips, Robert M Strieter
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 110 Issue 11 Pg. 1703-16 (Dec 2002) ISSN: 0021-9738 [Print] United States
• PMID: 12464676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokines, CXC
• Ligands
• Receptors, Interleukin-8B
• Peroxidase

Topics

• Animals
• Chemokines, CXC (physiology)
• Humans
• Ligands
• Lung (pathology)
• Lung Injury
• Mice
• Models, Animal
• Peroxidase (analysis)
• Phosphorylation
• Receptors, Interleukin-8B (physiology)
• Respiration, Artificial (adverse effects)