Word and Element Counts:
Word Count: 500
Number of references: 5
Number of figures: 1
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.
- 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.
- 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
- 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.
- 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.