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Funding Statement: Support was provided solely from institutional and/or departmental sources
Conflicts of Interest: The authors declare no competing interests
To the Editor:
The article by Archer et al.1 proposes a novel COVID-19 pathobiology: mitochondrial oxygen-sensing failure-induced loss of hypoxic pulmonary vasoconstriction (HPV) and impaired carotid body function, leading to “happy hypoxemia”. We write to propose an alternate model (Figure 1.) favoring pulmonary vasoconstriction (PV), with apoptotic-resistant, proliferative angiogenesis that may shift to “reperfusion-hyperoxia” model of cell-injury and inflammation in more severe stage of COVID-19 pneumonia.
  1. Warburg phenomenon and pseudohypoxic state: SARS-CoV-2 causes downregulation of ACE-2 and overactivity of ACE-Ang II-AT1R. AII induces epigenetic reduction, via Akt/mTOR/FOXO signaling, in mitochondrial SOD2 expression, decreases H2O2 production and creates a pseudohypoxic state. AII also activates Erk 1/2 resulting in increased expression of DNA methyltransferase (DNMT). DNMT-mediated changes in redox signaling causes normoxic activation of HIF-1α and increases pyruvate dehydrogenase kinase (PDK) expression. PDK phosphorylates and inhibits pyruvate dehydrogenase, increasing uncoupled aerobic glycolysis (Warburg phenomenon).2 Warburg metabolism changes one or more mitochondrial metabolic pathways, altering aerobic glycolysis or fatty-acid oxidation and/or induction of glutaminolysis.2 SARS-CoV-2 facilitates Akt1-dependent degradation of autophagy and a switch from oxidative-phosphorylation to lactic-acid formation.3This results in upregulation of glutathione metabolism, limiting mitochondrial-derived redox signaling,3 creating a pseudohypoxic state and HIF-1α upregulation.
  2. HIF-1 α, vasoconstriction and COVID-19: HIF-1α activation reduces the expression of various ion channels, including Kv1.5, leading to depolarized, calcium-overloaded pulmonary artery smooth muscle (PASM) producing PV.2 High levels of HIF-1 α gene expression along with other angiogenesis-associated genes including VEGFs in lungs from COVID-19 patients supports a hyperproliferative vasoactive model.4
  3. Mitophagy: Altered mitochondria-derived ROS production (high O2, low H2O2), increased mitochondrial membrane potentials (Δψm), and mitochondrial morphology (increased mitotic fission) favors a hyperproliferative, apoptosis-resistant phenotype in PASM, endothelial cells, and fibroblasts, contributing to obstructive vasculopathy2.
  4. Ang II and NOXs: Ang II-AT1R-NOX-ROS derived cytoplasmic ROS triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in positive feedback loop, thus developing the “reperfusion-hyperoxia” model of cell-injury resulting in an abrupt collapse of Δψm, and mitochondrial death. Ang II has also been implicated in decreasing the activity of scavenging enzymes. In endothelial cells, increased O2 inactivate the vasodilator NO by uncoupling of eNOS, leading to endothelial-dysfunction and PV.
We speculate that the hypoxemia in early COVID-19 pneumonia is from heterogenous PV and recruitment of pulmonary capillaries experiencing relatively less vasoconstriction, causing regional over-perfusion, reduced diffusion-capacity, and increased shunt. This explains the benefits of prone ventilation in COVID-19 patients compared to typical ARDS.
In both COVID-19 and high-altitude pulmonary edema (HAPE), patients typically appear better than expected given the hypoxemia severity.5 However, we speculate that COVID-19 and HAPE behave differently due to differences in PV patterns, with the severity of PAH diminished in COVID-19. The initial presentation of respiratory alkalosis in COVID-19 suggests intact carotid body sensing with functioning ventilatory mechanics early in the disease producing “silent hypoxia”.
Thus, pathological PV (with dysregulated HPV) instead of pulmonary vasoplegia should be a plausible mechanism for severe hypoxia in COVID-19 pneumonia. Moreover, orthodeoxia and platypnea, the usual signs of pulmonary vasoplegia are not seen in COVID-19 patients.