title: CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Morita
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Chida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tezuka
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohteki
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
authors.forename: Claudia C
authors.initials: CC
authors.lastname: dos Santos
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054357:Chemokine CXCL10 / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D055370:Lung Injury / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000503:physiopathology*; D040081:Protein Array Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054367:Receptors, CXCR3 / Q000187:drug effects / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology* / Q000821:virology
chemical_list: D054357:Chemokine CXCL10; D054367:Receptors, CXCR3