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CCL7 and CXCL10 Orchestrate Oxidative Stress-Induced Neutrophilic Lung Inflammation¹

Lidia Michalec^2,*, Barun K. Choudhury^2,*, Edward Postlethwait, James S. Wild^*, Rafeul Alam^*, Michael Lett-Brown^* and Sanjiv Sur^3,*

^* 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

Oxidative stress from ozone (O₃) 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 O₃ 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 O₃, or 0.8 ppm O₃ for 6 h. Compared with sham air, 0.8 ppm O₃, but not 0.2 ppm O₃, induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O₃ up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene- and macrophage-inflammatory protein-2), CXCL10 (IFN--inducible protein-10), CCL3 (macrophage-inflammatory protein-1), 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. O₃ 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 O₃ exposure. As expected, anti-mouse growth-related oncogene- 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.

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