Consecutive Hyperoxia Exposure Increased Expression of Interferon a and. Receptor Genes IFNAR2 and IFNGR2, the SARS-CoV-2, MERS and Influenza Viral Entry Genes TMPRSS2, DPP4 and ST3GAL4, as Well as the Interferon-Stimulated and Fibrosis-Associated Genes DUOX2, MDK, PI3, S100P, ASS1, OAS1 and MX1 in COPD-Diseased Human Small Airway Epithelial Cells
Authors: T. Yu-Chia, J. Chen, Y. Chang, Y. Hsu, Y. Chen
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: The therapeutic application of both hyperbaric oxygen (HBO) and hyperoxia exposure has been proven to be effective procedures for mitigating the hypoxia situation in the COVID-19 patients with pneumonia. However, given that hyperoxic exposure has been shown to increase reactive oxygen species (ROS) and oxidative stress and cause a variety of cardiovascular and pulmonary side effects including damages to endothelial cells, alveolar hypoplasia, pulmonary congestion and edema, and pulmonary vascular abnormalities, it is of interest to study whether HBO and hyperoxia exposure affect expression and regulation of viral entry genes and innate immune response genes including interferons and interferon receptors in human airway epithelial cells. Methods: The normal (N-SAECs) and COPD-diseased (D-SAECs) human small airway epithelial cells were respectively exposed daily to 100% O2 at 2.5 ATA for 90 min for 3 days in total, or cultured under hyperoxia (85% O2) for consecutively 3 days, followed by cultured under 21% O2 for consecutively another 3 days. Total mRNAs were then extracted from N-SAECs and D-SAECs followed by microarray and qPCR analyses. Results: While HBO exposure did not significantly influence the expression levels of both viral entry/receptor genes and innate immune response genes, we observed concordantly increased expression of the coronaviral entry genes TMPRSS2 and DPP4 and the influenza viral receptor gene ST3GAL4 in D-SAECs cultured under consecutive hyperoxia compared to those cultured under normoxia or under HBO, and concordantly increased expression of the interferon α and γ receptor genes IFNAR2 and IFNGR2 in both N-SAECs and D-SAECs cultured under hyperoxia compared to those cultured under normoxia or under HBO. Concordant with the significantly upregulated expression of interferon receptor genes, we also observed significantly increased expression of various interferon α- and γ-stimulated genes (ISGs) including ASS1, DUOX2, IDO1, MDK, MX1, OAS1, PI3, and S100P in D-SAECs cultured under hyperoxia. Notably, among these ISGs, MDK, MX1 and PI3 also showed significantly increased expression in N-SAECs cultured under hyperoxia. Conclusions: Given that the ISGs DUOX2, MDK, MX1, PI3 and S100P have also been reported to be positively correlated with pulmonary fibrosis, our study demonstrates for the first time that consecutive hyperoxia exposure may increase the probability of intrusion of SARS-CoV-2, MERS and influenza viruses as well as pulmonary fibrosis. It remains to be studied whether inhibition of interferon receptors IFNAR2 and/or IFNGR2 will provide an effective therapeutic intervention for mitigating pulmonary fibrosis in severely ill COVID-19 patients.