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.

The potential impact of COVID-19 on male reproductive health

“…Elevated CCL-11 [ 82 , 83 ] plasma levels were significantly higher in all COVID infected patient groups than healthy donors and have been reported in other studies [ 84 ]. A recent study [ 86 ] suggested eosinophilic (≥ 150 cells/μL of blood) asthmatic patients (Th2-phenotype) with elevated IL-13 levels infected with COVID-19 were associated with decreased hospital admissions and less severe outcomes. Furthermore, IL-13 was reported to reduce ACE2 expression and increase TMPRSS2 expression in bronchial epithelial cells ex vivo in asthmatic and nonasthmatic atopic groups [ 85 ].…”

“…Blood eosinophils are predominantly mediated by IL-5 and in part by IL-13, whereas fractional exhaled nitric oxide (FeNO) is mediated by IL-13. However, the function of elevated NO levels in asthma remains ambiguous, with both detrimental (exacerbation) as well as beneficial (antiviral) effects of airway NO being reported [ 86 , 87 ]. For example, data from human eosinophils suggest direct antiviral binding capacity may be reduced in asthma and is shown to correlate with disease severity [ 88 ].…”

“…CMV cytomegalovirus, EBV Epstein-Barr virus, HBV Hepatitis B virus, HCV Hepatitis C virus, HHV Human herpesvirus 6, HIV human immunodeficiency virus, HPV Human papillomavirus, HSV Herpes simplex virus 1 and 2, HTLV human T-lymphotropic virus type 1, VZV Varicella zoster virus, ZIKV Zika virus, SARS-CoV severe acute respiratory syndromeassociated-coronavirus, SARS-CoV-2 severe acute respiratory syndrome-associated-coronavirus type 2 mediated by IL-13. However, the function of elevated NO levels in asthma remains ambiguous, with both detrimental (exacerbation) as well as beneficial (antiviral) effects of airway NO being reported [86,87]. For example, data from human eosinophils suggest direct antiviral binding capacity may be reduced in asthma and is shown to correlate with disease severity [88].…”

NO in Viral Infections: Role and Development of Antiviral Therapies

“…Coronavirus-like SARS-CoV-1, MERS-CoV and SARS-CoV-2, which have been shown to infect endothelial cells, lead to a decrease in endothelial NO [ 14 ]. Indeed, SARS-CoV-2 infection seems to disrupt the signaling for endothelial NO production [ 36 ] and significantly decreased endothelial NO levels were measured in patients with COVID-19 [ 37 ]. Angiotensin-converting enzyme 2 (ACE2), which is the virus gateway into cells, converts angiotensin II to angiotensin 1-7, activating a pathway that increases NO production, among other effects.…”

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

“…Among its antimicrobial effects, NO has shown antiviral effects against DNA and RNA viruses, including SARS-CoV-2, by partially inhibiting virus replication ( Rolim et al, 2019 ; Akaberi et al, 2020 ; Pieretti et al, 2021 ). However, it has been shown that viral activity can also compromise host NO production ( Ritz et al, 2021 ). Finally, NO is an important modulator of epithelial ciliary beating, important for the clearance of pathogens, through the activation of the sGC-GMPc-PKG pathway ( Li et al, 2000 ).…”