Nitric Oxide and Immune Health

The below is a summary of the Nitric Oxide and Immune Health article originally published by Beth Shirley, RPh, CCN in The Townsend Letter in June, 2022.

One aspect of immune health that often does not receive the attention it deserves is Nitric Oxide’s (NO) role in immune competence. Nitric Oxide synthesis drops with age. Production of NO through NOS decreases to around 50% by the time we are 40 and to around 15% by the time we are 60. Furthermore, patients with chronic vascular inflammation, such as in type 2 diabetes, metabolic syndrome, chronic obstructive pulmonary disease, obesity, autoimmune disorders, and hemoglobinopathies may produce less NO.

Other factors that impair the production of Nitric Oxide are the SAD (Standard American Diet) devoid of essential nutrients, co-factors, and lack of nitrate rich vegetables, lack of exercise, medications such as antibiotics, antidepressants, birth control pills, NSAIDS, and proton pump inhibitors (PPIs), pollution, EMF’s and any process that increases oxidative stress.

Each of these factors is highly common in today’s world and may predispose to susceptibility to immune threats.

Nitric Oxide’s Role in the Immune Response

NO is a gasotransmitter, a gaseous neurotransmitter. It plays an important role in development of the innate immune response to many bacterial and viral threats. At the same time, it regulates vascular physiology. NO plays an essential role in the function of the immune response as defense against infectious organisms, an inducer or suppressor of apoptosis, or an immunoregulator.

Inducible NOS (iNOS) or NOS2 production of Nitric Oxide is part of the immune response. NO is toxic to viruses, bacteria, fungi, and other pathogens. NO regulates the functional activity, growth, and death of many immune and inflammatory cell types, including macrophages, T lymphocytes, antigen presenting cells, mast cells, neutrophils, and natural killer (NK) cells.

NO may inhibit an early stage in viral replication and prevent viral spread and promote viral clearance and recovery. Likewise, NO donors have been shown to inhibit viral replication.

Promotion of Immunity and Vascular Integrity

Enhanced clotting and sluggish blood flow result in systemic hypoxia in oxygen-sensitive organs such as the kidneys. The lung is the beneficiary of the most blood flow of any organ of the body, so the potential for trouble to develop in the lung due to vascular insult is very high. Vasculature depleted of NO suffers from persistent inflammation and blunted delivery of oxygen and removal of toxic byproducts through stagnant blood flow into and out of hypoxic tissue.

According to Nathan S. Bryan, PhD, “Pathology is taught during the first and sometimes second year of medical school. The primary textbook used in many medical schools is Robbins Pathology. On page 58, it clearly states,

“Well vascularized tissues are more resistant to infections and capable of localizing/containing off ending agents.”

 “By contrast, poorly vascularized tissues are relatively inefficient in responding to inflammatory stimuli.’ This means that if you have good circulation and blood flow to every tissue in the body, then this allows your immune system to mobilize a strong defense against any invading pathogen. If you don’t have good blood flow and circulation, the infection takes hold and makes you sick. This is basic physiology. The regulation of blood flow and circulation is based on your ability to produce Nitric Oxide.”

Nitric Oxide, Nitrates, and Immunity Modulation.

The stress response, no matter if it’s physical, psychological, or emotional, increases cortisol production. Cortisol inhibits iNOS (affecting the immune response. Stress also increases ROS in the mitochondria, from NADPH oxidase (NOX) and xanthine oxidase. This increased oxidative stress uncouples the NOS enzyme increasing superoxide production and oxidative stress. Additionally, cortisol decreases the membrane transport of l-arginine. All of these cortisol-mediated effects decrease the production of and/or bioavailability of NO.

During inflammatory states, supporting the nitrate – nitrite – Nitric Oxide pathway blocks cytokine storm, restores the functional capillary density, essential for oxygen delivery and removal of waste, stops hypoxia/reperfusion injury, and is protective of organs that are oxygen sensitive such as the kidneys.

Restoring NO/ROS balance may reduce cellular damage by reoxygenation and reperfusion. NO down-regulates inflammatory cytokines and decreases mast cell degranulation and histamine release.

A good portion of our immune system is located in our intestinal tract. Therefore, supporting the health of our intestinal tract increases the health of our immune response. Addressing the gut microbiome using nitrate therapy and probiotic therapies might help decrease inflammatory response of viral pathogenesis and respiratory symptoms by strengthening the host immune system, ameliorating gut dysbiosis, and improving gut barrier function.

Nitrate helps support the health, richness, and diversity of the microbiomes. Nitrate, nitrite, and Nitric Oxide support the health of the intestinal mucus lining as well as mucous membranes throughout the body, our first defense against pathogens. Nitrate, nitrite, and NO also enhance mucosal blood flow and mucus thickness and suppress microbial infections.

Nitrate prevents the loss of tight junction proteins that control intestinal permeability and regulates events leading to inflammation.

Another way in which Nitric Oxide is involved in immunity is through oxygen availability. NO synthesis by the NOS enzyme requires oxygen and is inhibited in hypoxic conditions. In lung damage that involves respiratory and/or metabolic acidosis – for example, in acute respiratory distress syndrome (ARDS) – a reduced local pH in the injured capillary may allow for the reduction of nitrite to Nitric Oxide because that pathway is stimulated under hypoxic and acidic conditions.

Restoring Nitric Oxide through the nitrate/nitrite/NO pathway may prevent endotheliitis and play a role in pulmonary vasodilation as well as suppress thrombosis and viral activity.

NO and NO donors show promise in treating viral conditions due to their combined role as antimicrobials and antithrombotic.

Full copy of this article with complete citations can be found within the original print of this article in The Townsend Letter.

For more information on gut health, brain health, and immune health, check out this post, also authored by Beth Shirley.