PAH: The Compass of COVID-19

October 17, 2021

Human Pulmonary Arterial Hypertension Viral Syndrome (H-PAHVS)

This thing, what is it in itself, in its own constitution? What is its substance and material? – Marcus Aurelius

We have now observed iron overload, paracrine senescence, telomere shortening, oncogenesis, neuroinflammation, protein aggregation, mitochondrial dysfunction and endothelial dysfunction. But, what is thing “in itself?” If we were to find a common focus for all that we have observed in COVID-19, we discover that all roads lead to PULMONARY ARTERIAL HYPERTENSION.

IRON

Associations between disrupted iron homeostasis and pulmonary artery hypertension (PAH) have been described with the suggestion that there is a contributory link with disease.

There are a number of recently published studies, which have investigated the relationship between iron availability, or deficiency, and proliferative responses in settings of relevance to PAH. In one study the use of iron chelation via the administration of desferrioxamine to rats was found to inhibit chronic hypoxia induced PH and remodeling suggesting that iron is requisite for vascular proliferation in these circumstances; an assertion further supported by in vitro studies by the same authors which showed that an iron chelation strategy also inhibited proliferation of cultured PASMCs

PARACRINE SENESCENCE AND TELOMERE SHORTENING

Findings from 124 patients with COPD who underwent right heart catheterization (RHC) and telomere length measurement (in circulating white blood cells). The majority of these patients have been previously reported by this group in publications that suggest that interleukin 6 (IL-6) levels are elevated and contribute to Group 3 PH and that telomeres are shortened in leukocytes from COPD patients, consistent with increased cellular aging in COPD9, 10. They have previously concluded that leukocyte telomere shortening is correlated with the patient’s age as well as PaO2 and PaCO210. What is new in the current report is the demonstration of senescence and a related paracrine proliferative diathesis in PASMC explanted from a new cohort of 14 COPD patients during lung resection for localized tumors.

This leads to the question. “How can cells that don’t proliferate be associated with increased proliferation?” Noureddine et al demonstrate that culture media of PASMC from COPD patients (enriched in senescent cells, evident from reduced population doubling level, PDL) stimulate more proliferation than does media from PASMC derived from control smokers without COPD. The COPD-senescent cell cultures appeared to be causing proliferation by their exaggerated secretion of IL-6, IL-8, and TNF-α (a paracrine mechanisms) and by local contact mechanisms (that enhance PASMC migration).

  1. Triggers that induce senescence also induce PAH.
  2. Pulmonary vascular remodeling occurs in chronic lung diseases associated with cellular senescence.
  3. Pathways disturbed in PAH are also causally associated with senescence.
  4. Interventions that target senescence also target pulmonary vascular remodeling in vivo.

CANCER

There are robust hallmarks, which are shared between PAH and cancer: the phenotypic switch, the angiogenic switch, and the glycolytic switch. On the cellular level, the issue is one of cell survival and cell fate. In PAH, too many cells in the vascular wall are surviving, and too many cells are abnormal.

NEUROINFLAMMATION

Pulmonary hypertension (PH) is a progressive lung disease characterized by elevated pressure in the lung vasculature, resulting in right-sided heart failure and premature death. The pathogenesis of PH is complex and multifactorial, involving a dysregulated autonomic nervous system and immune response. Inflammatory mechanisms have been linked to the development and progression of PH; however, these are usually restricted to systemic and/or local lung tissue. Inflammation within the CNS, often referred to as neuroinflammation involves activation of the microglia, the innate immune cells that are found specifically in the brain and spinal cord. Microglial activation results in the release of several cytokines and chemokines that trigger neuroinflammation, and has been implicated in the pathogenesis of several disease conditions such as Alzheimer’s, Parkinson’s, hypertension, atherosclerosis, and metabolic disorders. In this review, we introduce the concept of neuroinflammation in the context of PH, and discuss possible strategies that could be developed for PH therapy based on this concept.

MITOCHONDRIAL DYSFUNCTION

Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission.

ENDOTHELIAL DYSFUNCTION

Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death.

The focal pathology of COVID-19 is Pulmonary Arterial Hypertension. Does early treatment avoid its induction? Or, does any infection with SARS-CoV-2 or exposure to the spike protein induce a cascade of senescence, mitochondrial dysfunction, endothelial dysfunction, neuroinflammation and paracrine senescence that induces PAH?

Referenced/Related Papers

Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798691/

MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype

https://www.atsjournals.org/doi/10.1164/rccm.201604-0814OC

Neuroinflammation in Pulmonary Hypertension: Concept, Facts, and Relevance

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167643/

Where Metabolism Meets Senescence: Focus on Endothelial Cells

https://www.frontiersin.org/articles/10.3389/fphys.2019.01523/full

The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis—ten years later

https://journals.physiology.org/doi/pdf/10.1152/ajplung.00476.2019

Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence

https://www.atsjournals.org/doi/10.1165/rcmb.2018-0329TR

Paracrine Proliferative Signaling by Senescent Cells in WHO Group 3 Pulmonary Hypertension? Age Corrupting Youth

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178329/

Pulmonary Arterial Hypertension: Iron Matters

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990599/