Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats

Citation
Rl. Auten et al., Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats, J PHARM EXP, 299(1), 2001, pp. 90-95
Citations number
33
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
00223565 → ACNP
Volume
299
Issue
1
Year of publication
2001
Pages
90 - 95
Database
ISI
SICI code
0022-3565(200110)299:1<90:NCAPNA>2.0.ZU;2-0
Abstract
Neutrophil influx in lung injury is controlled in part by chemokines acting through the receptor, CXCR2. To avoid adverse effects of steroids typicall y used to modify inflammation, we evaluated the effects of competitive bloc kade of CXCR2 in rats on neutrophil function in vitro and on neutrophil inf lux in vivo in hyperoxia-induced newborn lung injury, a model of bronchopul monary dysplasia. In vitro, SB-265610 antagonizes rat cytokine-induced neut rophil 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% O-2 for 8 days had increased lung neutrophil content. Injection with 1 to 3 mg/kg SB-265610 on days 3 t o 5 reduced hyperoxia-induced neutrophil accumulation in bronchoalveolar la vage and whole lung myeloperoxidase accumulation at the highest doses. To d etermine 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 ne utrophils with CINC-1 reduced apoptosis compared with untreated neutrophils . SB-265610 reduced the antiapoptotic effect of CINC-1 to the levels of tho se untreated with CINC-1. A selective CXCR2 antagonist may be useful in dis eases where neutrophil-mediated exacerbation is present.