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).