Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury.
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.
Belperio
John A
JA
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.
Keane
Michael P
MP
Burdick
Marie D
MD
Londhe
Vedang
V
Xue
Ying Ying
YY
Li
Kewang
K
Phillips
Roderick J
RJ
Strieter
Robert M
RM
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*
D019743:Chemokines, CXC; D008024:Ligands; D023063:Receptors, Interleukin-8B; D009195:Peroxidase