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Tuberc Respir Dis > Accepted Articles
DOI:    [Accepted]
Published online October 8, 2020.
The Effects of Chronic Intermittent Hypoxia in Bleomycin-induced lung injury on Pulmonary Fibrosis via Regulating the NF-κB/Nrf2 Signaling Pathway
Hyeon Hui Kang, 1, In Kyoung Kim, 2,3, Chang Dong Yeo, 2, Sei Won Kim, 2, Hea Yon Lee, 2, Jeong Hyeon Im, 2, Hee Young Kwon, 2, Sang Haak Lee, M.D., PhD.2,3
1Division of Pulmonary, Critical care and Sleep Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 044033, Republic of Korea
2Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
3Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
Correspondence:  Sang Haak Lee, Tel: 82-2-2030-4640, Fax: 82-2-2030-4641, 
Received: 15 September 2020   • Revised: 29 September 2020   • Accepted: 8 October 2020
Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis. Chronic intermittent hypoxia (CIH) is considered to be a surrogate of OSA. However, its exact role in pulmonary fibrosis remains uncertain. Therefore, we investigated the mechanism underlying CIH-induced pulmonary fibrosis and the role of the anti-fibrotic agent in bleomycin (BLE) induced lung injury.
Mice were divided into eight groups: the normoxia (NOR), CIH, NOR plus BLE, CIH plus BLE, NOR plus pirfenidone (PF), CIH plus PF, NOR plus BLE and PF, and CIH plus BLE and PF groups. BLE was administered intratracheally on day 14 following CIH or NOR exposure. Subsequently, the mice were exposed to CIH or NOR for an additional 4 weeks. PF was administered orally on day 5 after BLE instillation once daily for 3 weeks.
In the BLE-treated groups, CIH induced collagen deposition in lung tissues than NOR, and significantly increased hydroxyproline and transforming growth factor beta expression. The CIH and BLE-treated group showed increased lung inflammation compared to NOR or CIH. Following CIH with BLE treatment, nuclear factor-kappa B (NF-κB) protein expression significantly increased, whereas nuclear factor-erythroid-related factor 2 (Nrf2) and heme oxygenase-1 protein levels decreased. After PF treatment, NF-κB and Kelch-like ECH-associated protein 1 expression were suppressed, and Nrf2 expression was increased.
CIH accelerated lung fibrosis in BLE-induced lung injury in mice, potentially by regulating the NF-κB/Nrf2 signaling pathway. Our results implicate PF as a potential therapeutic agent for treating pulmonary fibrosis in individuals with OSA and idiopathic pulmonary fibrosis.
Key Words: Obstructive sleep apnea, Pulmonary fibrosis, Bleomycin

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