Am J Physiol Lung Cell Mol Physiol 2017 02 2;312(2):L208-L216. Epub 2016 Dec 2.
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O until day 14 were recovered in air with or without IH (FI = 0.10 for 10 min every 6 h) until day 28 Animals exposed to 60% O and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10-12 wk. In contrast, 60% O-exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10-12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 14-28], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD.