Am. J. Respir. Crit. Care Med., Volume 162, Number 6, December 2000, 2316-2323

Lung Inflammation in Hyperoxia Can Be Prevented By Antichemokine Treatment in Newborn Rats

HUI DENG, S. NICHOLAS MASON, and RICHARD L. AUTEN Jr.

Neonatal Perinatal Research Institute, Division of Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina

Hyperoxia may contribute to lung disease in newborns through effects on alveolar neutrophils which predominate in respiratory distress syndrome and other acute lung injuries. Neutrophil chemokines such as interleukin-8 (IL-8) regulate chemoattraction, and are elevated in tracheal aspirates of newborns who develop bronchopulmonary dysplasia (BPD). Blockade of neutrophil chemokines may reduce hyperoxia-induced inflammatory lung injury and BPD. We therefore tested the hypothesis that hyperoxia contributes to elevations of rat neutrophil chemokines, cytokine- induced neutrophil chemoattractant-1 (CINC-1), and macrophage inflammatory protein-2 (MIP-2) in newborn rat lung. Newborn rats were exposed to air or 95% O₂ for 8 d. CINC-1 and MIP-2 were measured in whole lung homogenates by ELISA. Newborn 95% O₂-exposed animals were given anti-CINC-1 or anti-MIP-2, 1, 5, or 10 µg on Days 3 and 4 of 95% O₂ exposure. Bronchoalveolar lavage (BAL) was performed after perfusion on Day 6 to evaluate airway neutrophils, and myeloperoxidase (MPO) was measured in perfused whole lung. Lungs were examined histologically and immunohistochemically for effects of 95% O₂ ± antichemokine. CINC-1 and MIP-2 increased nearly tenfold by Day 8 95% O₂ treatment versus air control. CINC-1 and MIP-2 immunolabeling was increased in alveolar macrophages and alveolar epithelium in 95% O₂. Anti-CINC-1 and anti-MIP-2 treatment at every dose reduced neutrophil number > 90% in BAL. Anti-CINC-1 10 µg reduced tissue MPO by 50%. Antichemokine treatment on Days 3 and 4 prevented alveolar septal thickening and reduced chemokine immunolabeling on Day 6. Hyperoxia-induced neutrophil influx is mediated in part by CINC-1 and MIP-2 in newborn rats and can be partially prevented by treatment with anti-CINC-1 and anti-MIP-2.

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