Boosting nitric oxide in stress and respiratory infection: Potential relevance for asthma and COVID-19

Abstract

Nitric oxide (NO) is a ubiquitous signaling molecule that is critical for supporting a plethora of processes in biological organisms. Among these, its role in the innate immune system as a first line of defense against pathogens has received less attention. In asthma, levels of exhaled NO have been utilized as a window into airway inflammation caused by allergic processes. However, respiratory infections count among the most important triggers of disease exacerbations. Among the multitude of factors that affect NO levels are psychological processes. In particular, longer lasting states of psychological stress and depression have been shown to attenuate NO production. The novel SARS-CoV-2 virus, which has caused a pandemic, and with that, sustained levels of psychological stress globally, also adversely affects NO signaling. We review evidence on the role of NO in respiratory infection, including COVID-19, and stress, and argue that boosting NO bioavailability may be beneficial in protection from infections, thus benefitting individuals who suffer from stress in asthma or SARS-CoV-2 infection.

Keywords: Asthma; Dietary nitrate; Nitric oxide donor; Psychological stress; Respiratory infection; SARS-CoV-2; nitric oxide.

Fig. 1

Mechanisms involved in antiviral effects of NO. A range of viral enzymes and proteins that are critical for viral replication can be inactivated by S-nitrosylation of their cysteine residues. NO can also react with superoxide anions to form the highly reactive peroxynitrite, which oxidizes DNA and the amino acids of capsids that form the envelope of the virus, and thus interfere with entry of the virus into the host cell by cross-linking the capsids. In coronavirus strains, NO reduces the addition of palmitate, a saturated fatty acid, to the spike proteins on the envelope of the virus and thereby interferes with binding to the host cell’s angiotensin-converting enzyme (ACE)-2 receptor. Airway epithelial cells are the first to contact respiratory viruses and play the main role in NO defenses, but other cells can also participate in antiviral NO activity.

Fig. 2

Alternative pathways of NO production: The regular physiological pathways is through breakdown of the conditionally essential amino acid L-arginine by nitric oxide synthase (NOS) under participation of cofactors such as oxygen and nicotinamide adenine dinucleotide phosphate. In the epithelial cells, this happens through inducible NOS (NOS2, one of three types of NOS). The alternative dietary pathway is through intake of dietary nitrate (e.g., in vegetables), which is converted to nitrite in the oral cavity by bacterial nitrate reductase. The nitrite is then further converted to NO in the stomach and various tissues by bacterial and mammalian reductases under acidic or low oxygen conditions.

Fig. 3

a) Fe_NO increases after acute ingestion of 70 ​mL of beetroot juice (6.5 ​mmol of dietary nitrate) (reproduced from Kroll et al., 2018), b) Cold symptom severity across baseline, 7 days of academic finals stress with or without beetroot juice supplementation, and follow-up 7 days after finals in students (reproduced with permission from Ritz et al., 2019).