A Critical Role for the IL-1 Receptor in Lung Injury Induced in Neonatal Rats by 60% O2

Abstract

IL-1 beta, a proinflammatory cytokine, may contribute to the development of the chronic neonatal lung injury, bronchopulmonary dysplasia. Chronic neonatal lung injury was induced in rats, by exposure to 60% O2 for 14 d from birth, to determine whether pulmonary IL-1 expression was up-regulated and, if so, whether a daily s.c. IL-1 receptor antagonist injections would be protective. Exposure to 60% O2 for 14 d caused pulmonary neutrophil and macrophage influx, increased tissue fraction and tyrosine nitration, reduced VEGF-A and angiopoietin-1 expression, and reduced small vessel (20-65 microm) and alveolar numbers. Lung IL-1 alpha and -1 beta contents were increased after a 4-d exposure to 60% O2. IL-1 receptor antagonist treatment attenuated the 60% O2-dependent neutrophil influx, the increased tissue fraction, and the reduced alveolar number. Treatment did not restore VEGF-A or angiopoietin-1 expression and only partially attenuated the reduced vessel number in 60% O2-exposed pups. It also caused a paradoxical increase in macrophage influx and a reduction in small vessels in air-exposed pups. We conclude that antagonism of IL-1-mediated effects can, in major part, protect against lung injury in a rat model of 60% O2-induced chronic neonatal lung injury.

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

“…As expected, tracheal aspirates of infants exposed to hyperoxia had elevated inflammatory mediators primarily secreted by macrophages, notably IL-1b and tumor necrosis factor-a (14,15). In infants with sepsis-induced inflammation, inhibitors against the two cytokines showed little improvement in survival rates; in mouse models treated with inhibitors against these cytokines, only some BPD features improved (16)(17)(18)(19)(20). This suggests that alternative, more broadly functioning or upstream targets are needed to prevent BPD.…”

Chronic lung injury in the neonatal rat: Up-regulation of TGFβ1 and nitration of IGF-R1 by peroxynitrite as likely contributors to impaired alveologenesis

“…14), exposure to 60% O 2 results in an increase in the proinflammatory cytokine, IL-1 [16]. IL-1 is an upstream regulator of the neutrophil chemokine, CINC-1, which regulates neutrophil influx in the 60% O 2 -exposed lung [15].…”

“…Neonatal rats exposed to 60% O 2 develop a BPD-like chronic neonatal lung injury in which there is reduced total lung cell DNA synthesis, secondary crest DNA synthesis, and secondary crest formation with resultant impaired alveolar formation [9,12,[15][16][17]20]. These features are induced by alveolar macrophage-dependent peroxynitrite formation [13], and are reversed by treatment with a peroxynitrite decomposition catalyst [18].…”

“…Pathogen-free timed-pregnant Sprague-Dawley rats (250-275 g) were obtained from Charles River (St-Constant, Senneville, QC, Canada). Rat pups (10-12/litter) were exposed to air or 60% O 2 in paired chambers (Biospherix, Lacona, NY, USA) for up to 14 days, as previously described [9,[12][13][14][15][16][17][18][19]. Pups were delivered inside the chambers.…”

“…Neonatal rats exposed to 60% O 2 from birth for 14 days develop a chronic neonatal lung injury with many of the pathological features observed in human BPD. These include impaired alveologenesis, Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed parenchymal thickening, and evidence of pulmonary hypertension with small vessel pruning [8][9][10][12][13][14][15][16][17][18][19][20]. Marked immunoreactivity of lung tissue for nitrotyrosine is evident following exposure to 60% O 2 [13], which is prevented by concurrent treatment with a peroxynitrite decomposition catalyst [18].…”