title: 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.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: Vedang
authors.initials: V
authors.lastname: Londhe
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Xue
authors.forename: Kewang
authors.initials: K
authors.lastname: Li
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Phillips
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000818:Animals; D019743:Chemokines, CXC / Q000502:physiology; D006801:Humans; D008024:Ligands; D008168:Lung / Q000473:pathology*; D055370:Lung Injury; D051379:Mice; D023421:Models, Animal; D009195:Peroxidase / Q000032:analysis; D010766:Phosphorylation; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D019743:Chemokines, CXC; D008024:Ligands; D023063:Receptors, Interleukin-8B; D009195:Peroxidase