title: CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation.
abstract: Oxidative stress from ozone (O(3)) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O(3) oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O(3), or 0.8 ppm O(3) for 6 h. Compared with sham air, 0.8 ppm O(3), but not 0.2 ppm O(3), induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O(3) up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-alpha and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O(3) increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O(3) exposure. As expected, anti-mouse growth-related oncogene-alpha inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.
authors.affiliation: National Institutes of Health Asthma and Allergic Diseases Research Center and Department of Internal Medicine and Department Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Michalec
authors.forename: Barun K
authors.initials: BK
authors.lastname: Choudhury
authors.forename: Edward
authors.initials: E
authors.lastname: Postlethwait
authors.forename: James S
authors.initials: JS
authors.lastname: Wild
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
authors.forename: Michael
authors.initials: M
authors.lastname: Lett-Brown
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D000280:Administration, Inhalation; D000818:Animals; D000918:Antibody Specificity; D054410:Chemokine CCL7; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D016207:Cytokines; D004306:Dose-Response Relationship, Immunologic; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D010126:Ozone / Q000008:administration & dosage; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C515451:Ccl7 protein, mouse; C515351:Ccr3 protein, mouse; D054410:Chemokine CCL7; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D010126:Ozone