4.1.1. Lung injury
Under hypoxic conditions, the body undergoes compensatory adaptive pulmonary vasoconstriction, which reduces blood flow around the hypoxic alveoli and redirects it to the well-ventilated alveoli. However, prolonged hypoxia causes the body to develop a pathological state, resulting in increased pulmonary artery pressure and eventually, pulmonary hypertension. High-altitude pulmonary hypertension (HAPH) is a common chronic disease worldwide.
Researchers have proposed several oxygen-sensing mechanisms, including CYPs, to regulate pulmonary contractile processes under hypoxia. CYP and its metabolically produced epoxide are highly expressed in the lungs and are involved in vasoconstriction and remodelling processes in chronic hypoxia-induced pulmonary hypertension. Initially, the study by Earley et al. found that the epoxide metabolite of CYP, EET, contributes to the endothelium-dependent hyperpolarization of vascular smooth muscle cells after chronic hypoxia, which in turn regulates vasoconstriction under hypoxia (Earley et al., 2003). Pokreisz et al. investigated the acute hypoxic vasoconstrictor response in Swiss Webster mice and found that epoxygenase inhibitors attenuated hypoxic pulmonary constriction, whereas soluble epoxide hydrolase inhibitors potentiated this response, suggesting that CYP-epoxygenase-derived epoxyeicosatrienoic acids may cause pulmonary vasoconstriction. Aerosol gene transfer of a recombinant adenovirus containing human CYP2C9 substantially increased the mean pulmonary arterial pressure and total pulmonary resistance index, both of which were sensitive to sulfaphenazole inhibitors. Prolonged hypoxia substantially increased CYP2C29 expression and EET production in mice. Chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were substantially attenuated in animals continuously treated with the CYP epoxygenase inhibitor (Pokreisz et al., 2006). These observations highlight the key role of CYP in the pulmonary hypoxic response. The role of CYP in the regulation of pulmonary artery pressure under hypoxia was further confirmed by Hashimoto et al., who found that disruption of CYP2C44 (a functional homolog of CYP2C9) exacerbated chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice and increased the number of hematopoietic stem cells in the bone marrow and blood. Differentiation of these stem cells leads to an increase in circulating monocytes and macrophages, and contributes to chronic hypoxia-induced pulmonary arterial remodeling and hypertension (Hashimoto et al., 2017). Similarly, inhibition and knockdown studies of EET have shown that the dual role of EET in the regulation of pulmonary vascular tone may provide a basis for the development of new therapeutic strategies for treating hypoxia-induced lung injury diseases under hypoxia (Strielkov et al., 2020).