CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin

Am J Respir Crit Care Med. 2013 Jan 1;187(1):65-77. doi: 10.1164/rccm.201203-0508OC. Epub 2012 Nov 9.

Abstract

Rationale: Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome-coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation.

Objectives: We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins.

Methods: We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/β receptor 1), or TIR domain-containing adaptor inducing IFN-β (TRIF).

Measurements and main results: We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a unique CXCR3 receptor via TRIF. CXCL10-CXCR3 acts in an autocrine fashion on the oxidative burst and chemotaxis in the inflamed neutrophils, leading to fulminant pulmonary inflammation.

Conclusions: CXCL10-CXCR3 signaling appears to be a critical factor for the exacerbation of the pathology of ARDS. Thus, the CXCL10-CXCR3 axis could represent a prime therapeutic target in the treatment of the acute phase of ARDS of nonviral and viral origins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Chemokine CXCL10 / drug effects
  • Chemokine CXCL10 / physiology*
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Influenza A Virus, H5N1 Subtype
  • Lung Injury / immunology
  • Lung Injury / physiopathology*
  • Lung Injury / virology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Middle Aged
  • Neutrophils / immunology
  • Neutrophils / physiology*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / physiopathology*
  • Protein Array Analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, CXCR3 / drug effects
  • Receptors, CXCR3 / physiology*
  • Respiratory Distress Syndrome, Adult / drug therapy
  • Respiratory Distress Syndrome, Adult / immunology
  • Respiratory Distress Syndrome, Adult / physiopathology*
  • Respiratory Distress Syndrome, Adult / virology

Substances

  • Chemokine CXCL10
  • Receptors, CXCR3