Nitric oxide (NO) is a powerful signaling agent throughout the human body, particularly important in the cardiovascular system where it regulates blood pressure and blood flow. Produced by various enzymes, NO maintains the health and function of the lungs, making it a focus of research during the COVID-19 pandemic. Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory system, understanding how the virus interferes with NO pathways provides insight into NO-based therapies as potential treatment options.
Nitric Oxide’s Protective Role in Respiratory Health
Within the healthy respiratory system, endogenous nitric oxide (NO) is produced by nitric oxide synthases (NOS), including the endothelial (eNOS) and neuronal (nNOS) isoforms. These enzymes regulate the tone of smooth muscle cells in the airways and blood vessels. This action causes vasodilation, widening pulmonary arteries and capillaries to improve blood flow and oxygen uptake. NO also contributes to bronchodilation by relaxing the smooth muscles surrounding the bronchioles, opening the airways. This dual action ensures blood flows to the best-ventilated parts of the lung, optimizing the ventilation-perfusion (V/Q) ratio.
Furthermore, the inducible form (iNOS) is activated by inflammation, producing large amounts of NO with antimicrobial properties as part of the body’s defense system. These physiological effects collectively maintain a delicate balance that supports efficient oxygenation. Disruption of this balance by an infection like SARS-CoV-2 leads directly to the severe respiratory distress seen in advanced COVID-19 cases.
How SARS-CoV-2 Disrupts Nitric Oxide Pathways
In severe COVID-19, SARS-CoV-2 initiates events that reduce nitric oxide bioavailability, contributing to the disease’s dangerous features. The virus binds to the angiotensin-converting enzyme 2 (ACE2) receptor, which is abundant on the surface of endothelial cells lining the blood vessels. This interaction and the subsequent inflammatory response lead to widespread endothelial damage, often referred to as endotheliitis. The damage to the endothelium impairs the function of eNOS, resulting in decreased production of natural nitric oxide. Simultaneously, the inflammation and “cytokine storm” increase the production of reactive oxygen species (ROS), such as superoxide anion.
Reduced NO readily reacts with these excess superoxide radicals to form peroxynitrite, a highly toxic oxidant. This formation effectively scavenges the already scarce NO, further depleting its levels and exacerbating oxidative stress. The resulting lack of functional nitric oxide removes its protective antithrombotic and vasodilatory effects, promoting a pro-coagulant, vasoconstrictive state. This microvascular dysfunction leads to the formation of microthrombi, or tiny blood clots, throughout the pulmonary vasculature, a hallmark of severe COVID-19. The resulting widespread clotting and poor blood flow contribute to the development of acute respiratory distress syndrome (ARDS) and pulmonary hypertension.
Inhaled Nitric Oxide as a Clinical Treatment
The understanding of NO deficiency led to the therapeutic use of inhaled nitric oxide (iNO) as a clinical intervention for hospitalized COVID-19 patients. Inhaled NO is administered as a gas, acting as a selective pulmonary vasodilator. When delivered through mechanical ventilation or other respiratory support devices, the gas travels directly to the alveoli that are still open and being ventilated. This localized delivery causes blood vessels surrounding only the ventilated alveoli to widen, improving the V/Q matching.
By selectively diverting blood flow toward functional areas, iNO enhances the patient’s systemic oxygenation, aiding those with severe hypoxemia and ARDS. The therapy has shown promise in improving respiratory outcomes for various patient groups. However, large-scale clinical trials have been inconclusive regarding its ability to reduce overall mortality or the total time spent on mechanical ventilation, despite improving oxygenation and reducing pulmonary vascular resistance. Nonetheless, the physiological benefits of iNO in improving gas exchange make it an important tool for stabilizing patients in the intensive care unit setting.
Direct Antiviral Mechanisms
Beyond its vascular and pulmonary effects, nitric oxide and its donor compounds exhibit a molecular action directly against the SARS-CoV-2 virus itself. Laboratory studies using NO-donating molecules, such as S-nitroso-N-acetylpenicillamine (SNAP), have demonstrated a dose-dependent inhibitory effect on viral replication. This antiviral activity is achieved through a process called S-nitrosylation. S-nitrosylation involves transferring a nitrosonium ion from NO metabolites to a cysteine residue in the active site of key viral enzymes, such as the SARS-CoV-2 3CL protease.
By covalently modifying this cysteine, the protease is inhibited, preventing the virus from assembling new infectious particles. Furthermore, NO interferes with the palmitoylation of the viral Spike (S) protein, which is necessary for the virus to bind to the host ACE2 receptor and enter the cell. These mechanisms suggest that NO not only treats the symptoms of severe disease but may also directly reduce the viral burden within the host.