Abstract
Neutrophil influx in lung injury is controlled in part by chemokines acting through the receptor, CXCR2. To avoid adverse effects of steroids typically used to modify inflammation, we evaluated the effects of competitive blockade of CXCR2 in rats on neutrophil function in vitro and on neutrophil influx in vivo in hyperoxia-induced newborn lung injury, a model of bronchopulmonary dysplasia. In vitro, SB-265610 antagonizes rat cytokine-induced neutrophil chemoattractant-1 (CINC-1)-induced calcium mobilization, IC50 = 3.7 nM, and rat neutrophil chemotaxis in a concentration-dependent manner, IC50 = 70 nM. In vivo, newborn rats exposed to 95% O2 for 8 days had increased lung neutrophil content. Injection with 1 to 3 mg/kg SB-265610 on days 3 to 5 reduced hyperoxia-induced neutrophil accumulation in bronchoalveolar lavage and whole lung myeloperoxidase accumulation at the highest doses. To determine whether these effects might be due in part to increased neutrophil apoptosis, peripheral neutrophils were cultured with and without SB-265610. Apoptosis was assessed by morphology, viability, and terminal transferase deoxyuridine triphosphatidyl nucleotide nick-end labeling. Treatment of neutrophils with CINC-1 reduced apoptosis compared with untreated neutrophils. SB-265610 reduced the antiapoptotic effect of CINC-1 to the levels of those untreated with CINC-1. A selective CXCR2 antagonist may be useful in diseases where neutrophil-mediated exacerbation is present.
Footnotes
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Supported by National Institute of Dental and Craniofacial Research Grant DE 13076, National Institute of Allergy and Infectious Diseases Grant AI 3891, and the American Lung Association of North Carolina.
- Abbreviations:
- IL
- interleukin
- GRO
- growth-related oncogene
- CXCR2
- C-X-C chemokine receptor 2
- TUNEL
- terminal transferase deoxyuridine triphosphatidyl nucleotide nick-end labeling
- HBSS
- Hanks' balanced salt solution
- MPO
- myeloperoxidase
- DAPI
- 4′,6 diamidino-2-phenylindole
- BAL
- bronchoalveolar lavage
- PMN
- polymorphonuclear neutrophil
- CINC-1
- cytokine-induced neutrophil chemoattractant-1
- MIP-2
- macrophage inflammatory protein-2
- BPD
- bronchopulmonary dysplasia
- C5a
- human complement 5a
- Received March 1, 2001.
- Accepted June 13, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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