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PMID: 12464676 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 110 ·No. 11 ·2002-12-00 ·Pages 1703-16

Belperio JA, Keane MP, Burdick MD, Londhe V, Xue YY, Li K, Phillips RJ, Strieter RM

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.

MeSH Terms
Animals Chemokines, CXC/physiology Humans Ligands Lung/pathology Lung Injury Mice Models, Animal Peroxidase/analysis Phosphorylation Receptors, Interleukin-8B/physiology Respiration, Artificial/adverse effects
Chemicals
Chemokines, CXC Ligands Receptors, Interleukin-8B Peroxidase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Belperio John A
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
Burdick Marie D
Londhe Vedang
Xue Ying Ying
Li Kewang
Phillips Roderick J
Strieter Robert M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI15849
Published
2002-12-00
Pages
1703-16
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151632
Subset
IM
Grants
NCI NIH HHS · P50CA90388 · United States
NHLBI NIH HHS · HL66027 · United States
NHLBI NIH HHS · K08 HL004493 · United States
NCI NIH HHS · R01 CA087879 · United States
NHLBI NIH HHS · HL03906 · United States
NHLBI NIH HHS · P01HL67665 · United States
NHLBI NIH HHS · P01 HL067665 · United States
NHLBI NIH HHS · HL04493 · United States
NHLBI NIH HHS · R01 HL066027 · United States
NCI NIH HHS · CA87879 · United States
NHLBI NIH HHS · HL68694 · United States
NCI NIH HHS · P50 CA090388 · United States
Corrections
CommentIn
PMID: 12464663
External Links
PubMed source DOI: 10.1172/JCI15849 PMC Full Text View journal details
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