Interference of SARS-CoV-2 with the Homeostasis of Ventilation and Perfusion in the Lung

A growing number of studies suggest that SARS-CoV-2 could interfere with homeostatic mechanisms in the lung but the implications of this possible interference have not been fully explored in the literature. In this work, we examine the consequences that can be drawn from this hypothesis according to currently available knowledge. We suggest that one such consequence is the potential disruption of normal ventilation and perfusion of lung regions that may be distant from the infection sites. Loss of ventilation might result in local alveolar hypoxia and contribute to hypoxemia, which in turn could trigger homeostatic responses that enhance blood oxygenation by redistributing pulmonary blood circulation. Sudden changes in perfusion might then lead to the development of hydrostatic edema and eventually to vascular remodeling and inflammation. Therefore, the immune response might not be the only source of the substantial inflammation observed in lung tissues of patients with severe COVID-19, as is often assumed in the literature. The balance between the homeostatic and the immune reaction in each patient could account for the observed heterogeneity of the clinical manifestations of COVID-19.

Regional pulmonary perfusion patterns in humans are not significantly altered by inspiratory hypercapnia

Pulmonary vascular tone is known to be sensitive to both local alveolar Po2 and Pco2. Although the effects of hypoxia are well studied, the hypercapnic response is relatively less understood. We assessed changes in regional pulmonary blood flow in humans in response to hypercapnia using previously developed MRI techniques. Dynamic measures of blood flow were made in a single slice of the right lung of seven healthy volunteers following a block-stimulus paradigm (baseline, challenge, recovery), with CO2 added to inspired gas during the challenge block to effect a 7-Torr increase in end-tidal CO2. Effects of hypercapnia on blood flow were evaluated based on changes in spatiotemporal variability (fluctuation dispersion, FD) and in regional perfusion patterns in comparison to hypoxic effects previously studied. Hypercapnia increased FD 2.5% from baseline (relative to control), which was not statistically significant ( P = 0.07). Regional perfusion patterns were not significantly changed as a result of increased [Formula: see text] ( P = 0.90). Reanalysis of previously collected data using a similar protocol but with the physiological challenge replaced by decreased [Formula: see text] ([Formula: see text] = 0.125) showed marked flow redistribution ( P = 0.01) with the suggestion of a gravitational pattern, demonstrating hypoxia has the ability to affect regional change with a global stimulus. Taken together, these data indicate that hypercapnia of this magnitude does not lead to appreciable changes in the distribution of pulmonary perfusion, and that this may represent an interesting distinction between the hypoxic and hypercapnic regulatory response. NEW & NOTEWORTHY Although it is well known that the pulmonary circulation responds to local alveolar hypoxia, and that this mechanism may facilitate ventilation-perfusion matching, the relative role of CO2 is not well appreciated. This study demonstrates that an inspiratory hypercapnic stimulus is significantly less effective at inducing changes in pulmonary perfusion patterns than inspiratory hypoxia, suggesting that in these circumstances hypercapnia is not sufficient to induce substantial integrated feedback control of ventilation-perfusion mismatch across the lung.

Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4−/−) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4−/− mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4−/− and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4−/− mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4−/− mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.

Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases

Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia. We demonstrate that microvascular endothelial cells (ECs) from Anxa2−/− mice display reduced barrier function and excessive Src-related tyrosine phosphorylation of the adherens junction protein vascular endothelial cadherin (VEC). Moreover, unlike Anxa2+/+ controls, Anxa2−/− mice develop pulmonary edema and neutrophil infiltration in the lung parenchyma in response to subacute alveolar hypoxia. Mice deficient in the ANXA2-binding partner, S100A10, failed to demonstrate hypoxia-induced pulmonary edema under the same conditions. Further analyses reveal that ANXA2 forms a complex with VEC and its phosphatases, EC-specific protein tyrosine phosphatase (VE-PTP) and Src homology phosphatase 2 (SHP2), both of which are implicated in vascular integrity. In the absence of ANXA2, VEC is hyperphosphorylated at tyrosine 731 in response to vascular endothelial growth factor, which likely contributes to hypoxia-induced extravasation of fluid and leukocytes. We conclude that ANXA2 contributes to pulmonary microvascular integrity by enabling VEC-related phosphatase activity, thereby preventing vascular leak during alveolar hypoxia.

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler–Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulatedin vivoby the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCsviadirect or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV.