Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice.

Abstract

BACKGROUND AND PURPOSE:

Acute lung injury (ALI) remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of ALI. The main chemokine receptor on neutrophils is CXCR2, which regulates neutrophil recruitment and vascular permeability, but no small molecule CXCR2 inhibitor has been demonstrated to be effective in ALI or animal models of ALI. To investigate the functional relevance of the CXCR2 inhibitor Reparixin in vivo, we determined its effects in two models of ALI, induced by either lipopolysaccharide (LPS) inhalation or acid instillation.

EXPERIMENTAL APPROACH:

In two ALI models in mice, we measured vascular permeability by Evans blue and evaluated neutrophil recruitment into the lung vasculature, interstitium and airspace by flow cytometry.

KEY RESULTS:

Pharmacological inhibition of CXCR2 by Reparixin reduced CXCL1-induced leukocyte arrest in the microcirculation of the cremaster muscle, but did not influence arrest in response to leukotriene B4 (LTB4) demonstrating specificity. Reparixin (15 microg g(-1)) reduced neutrophil recruitment in the lung by approximately 50% in a model of LPS-induced ALI. A higher dose did not provide additional reduction of neutrophil recruitment. This dose also reduced accumulation of neutrophils in the interstitial compartment and vascular permeability in LPS-induced ALI. Furthermore, both prophylactic and therapeutic application of Reparixin improved gas exchange, and reduced neutrophil recruitment and vascular permeability in a clinically relevant model of acid-induced ALI.

CONCLUSIONS AND IMPLICATIONS:

Reparixin, a non-competitive allosteric CXCR2 inhibitor attenuates ALI by reducing neutrophil recruitment and vascular permeability.

• Authors: A Zarbock, M Allegretti, K Ley
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 155 Issue 3 Pg. 357-64 (Oct 2008) ISSN: 0007-1188 [Print] England
• PMID: 18587419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Receptors, Interleukin-8B
• Sulfonamides
• reparixin

Topics

• Animals
• Capillary Permeability (drug effects)
• Cell Movement (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Lipopolysaccharides
• Mice
• Mice, Inbred C57BL
• Neutrophils (drug effects, metabolism)
• Pulmonary Gas Exchange (drug effects)
• Receptors, Interleukin-8B (antagonists & inhibitors)
• Respiratory Distress Syndrome (drug therapy, physiopathology)
• Sulfonamides (administration & dosage, pharmacology)