Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats

Abstract

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% O2 exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% O2, or 95% O2 + anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-microg anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% O2 exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia.

CXCR2 Is Critical to Hyperoxia-Induced Lung Injury

“…This finding was supported by Kaplan-Meier survival analysis and log rank test, and was in contrast to studies using only a strategy of neutralization of CXCL1 for a limited period of time (50,51). Moreover, our findings demonstrate that the interactions between CXCR2 ligands and CXCR2 are paramount to the generation of an inflammatory response characterized by neutrophil sequestration and alveolar-capillary membrane injury in the adult lung.…”

“…Although previous studies have shown that using nonpeptide CXCR2 antagonist or neutralizing CXCL1 or CXCL2/3 Abs can reduced neutrophil infiltration into the lung under hyperoxic conditions (50,51,58), our study is the first to demonstrate that knockout of a single gene, CXCR2, can result in a marked survival advantage of adult mice in hyperoxia. This finding was supported by Kaplan-Meier survival analysis and log rank test, and was in contrast to studies using only a strategy of neutralization of CXCL1 for a limited period of time (50,51).…”

“…In this study, they found a marked reduction of neutrophils in the bronchoalveolar lavage fluid in response to hyperoxia and neutralization of CXCL1 (51). However, the use of the neutralizing anti-CXCL1 Abs did not fully attenuate levels of CXCL1 in the bronchoalveolar lavage fluid, nor did this approach fully protect the lung in hyperoxia-exposed animals (51), suggesting that the effect seen was related to the inability to fully deplete CXCL1 in their system.…”

“…For example, in a study by Auten et al (51), they only used neutralizing Abs to CXCL1 in the same rat newborn model of hyperoxia as Deng et al (50). In this study, they found a marked reduction of neutrophils in the bronchoalveolar lavage fluid in response to hyperoxia and neutralization of CXCL1 (51).…”

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…Following exposure to 80% O 2 for 6 days, CXCR2 −/− mice showed reduced neutrophil sequestration, which is associated with significantly decreased lung vascular permeability, edema and injury [121]. Furthermore, administration of neutralizing antibodies and antagonists of CXCR2 ligand, such as cytokine-induced neutrophil chemoattractant-1 (CINC-1), reduced the neutrophil mediated inflammatory responses and markedly increased survival of adult mice subjected to hyperoxia [118,122,123]. Another CXCR2 antagonist, SB265610, blocked chemokine effects on neutrophil viability and lung apoptosis in new born rats exposed to 95% O 2 for 8 days [122].…”