Intermittent Hypoxia Increases the Severity of Bleomycin‐Induced Lung Injury in Mice

Abstract

Background Severe obstructive sleep apnea (OSA) with chronic intermittent hypoxia (IH) is common in idiopathic pulmonary fibrosis (IPF). Here, we evaluated the impact of IH on bleomycin- (BLM-) induced pulmonary fibrosis in mice. Methods C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO2 nadir: 6%; 8 hours/day) or intermittent air (IA). In the four experimental groups, we evaluated (i) survival; (ii) alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii) lung cell apoptosis; and (iv) pulmonary fibrosis. Results Survival at day 21 was lower in the BLM-IH group (p < 0.05). Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content (p = 0.02) and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, (p < 0.001). Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice (p < 0.05 versus BLM-IA group). At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group. Conclusion These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.

Nocturnal hypoxaemia is associated with adverse outcomes in interstitial lung disease

“…A substantive body of evidence links chronic intermittent hypoxaemia (CIH) during sleep with increased oxidative stress and chronic inflammation . Disruption of oxygen homeostasis is associated with maladaptive cardiorespiratory consequences, including development of pulmonary hypertension (PH) .…”

“…Disruption of oxygen homeostasis is associated with maladaptive cardiorespiratory consequences, including development of pulmonary hypertension (PH) . Furthermore, CIH has been shown to worsen lung fibrosis in animal models, suggesting plausible links between NOD and disease progression and survival …”

“…9,10 A substantive body of evidence links chronic intermittent hypoxaemia (CIH) during sleep with increased oxidative stress and chronic inflammation. 11,12 Disruption of oxygen homeostasis is associated with maladaptive cardiorespiratory consequences, including development of pulmonary hypertension (PH). 11,13 Furthermore, CIH has been shown to worsen lung fibrosis in animal models, suggesting plausible links between NOD and disease progression and survival.…”

“…11,13 Furthermore, CIH has been shown to worsen lung fibrosis in animal models, suggesting plausible links between NOD and disease progression and survival. 12,14 In this study, we aimed to define sleep-breathing patterns and extent of NOD in ILD patients. We sought to define relationships between apnoeas and degree of NOD with markers of disease severity and mortality.…”

Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

“…For example, IH induced epithelial cell proliferation in lungs from a chronic exposure model (19). In a bleomycininduced lung injury model, fibrosis in mouse lung is worsened by IH (68). In our model, shortterm exposure to IH did not result in changes to the parenchyma or vessels.…”