Intermittent hypoxia worsens pulmonary fibrosis induced by bleomycin (BLM) in a mouse model, according to a new study by Chinese researchers published in International Immunopharmacology. This could be via reactive oxygen species (ROS)- and hypoxia-inducible factor1α (HIF-1α)-related oxidative stress and inflammation.

These findings propose a possible mechanism of the worsening effect of episodes of obstructive sleep apnea on patients with idiopathic pulmonary fibrosis (IPF).

Researchers have increasingly recognized obstructive sleep apnea as a risk factor for IPF. Moreover, it is known that the intermittent hypoxia and reoxygenation that occur during obstructive sleep apnea contribute to poor outcomes in patients with the disease. However, the molecular mechanism of how this occurs remains unknown.

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Here, a team of researchers from the Department of Respiratory and Critical Care Medicine at Renmin Hospital of Wuhan University in China used a mouse model of IPF to test the hypothesis that intermittent hypoxia could promote the development of pulmonary fibrosis by increasing ROS/HIF-1α-related oxidative stress and inflammation.

Read more about IPF etiology

To test this hypothesis, the researchers exposed mice with BLM-induced pulmonary fibrosis to alternating cycles of 21% FiO2 for 60 seconds and 10% FiO2 for 30 seconds. These cycles were repeated 40 times per hour for 8 hours each day to mimic obstructive sleep apnea. As controls, the researchers exposed another group of animals to intermittent air for 4, 8, or 21 days. 

They found that pulmonary fibrosis was more severe in animals that were exposed to intermittent hypoxia than those exposed to intermittent air at days 8 and 21 but not at day 4.

Moreover, the expression of ROS and HIF-1α were higher in animals exposed to intermittent hypoxia than in those exposed to intermittent air, and intermittent hypoxia increased these indices from day 4 to day 21.

“Interestingly, a positive linear correlation between the HIF-1α expression and hydroxyproline (HYP) content was observed,” the researchers wrote. They also reported that some inflammatory cells increased significantly from day 4 to day 21 in the bronchoalveolar lavage fluid of the animals and that there was a positive correlation between inflammation and ROS expression.

“Our results demonstrated that [intermittent hypoxia] aggravated BLM-induced pulmonary fibrosis, and ROS/HIF-1α related oxidative stress and inflammation involved,” the researchers concluded.


Xiong M, Zhao Y, Mo H, Yang H, Yue F, Hu K. Intermittent hypoxia increases ROS/HIF-1α ‘related oxidative stress and inflammation and worsens bleomycin-induced pulmonary fibrosis in adult male C57BL/6J mice. Int Immunopharmacol. Published online September 21, 2021. doi:10.1016/j.intimp.2021.108165