High Doses of Inhaled Nitric Oxide As an Innovative Antimicrobial Strategy for Lung Infections

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2022 Jul 27

PMID 35884830

Authors

Lorenzo Del Sorbo

Vinicius S Michaelsen

Aadil Ali

Aizhou Wang

Rafaela V P Ribeiro

Marcelo Cypel

Affiliations

Soon will be listed here.

Abstract

Since the designation of nitric oxide as "Molecule of the Year" in 1992, the scientific and clinical discoveries concerning this biomolecule have been greatly expanding. Currently, therapies enhancing the release of endogenous nitric oxide or the direct delivery of the exogenous compound are recognized as valuable pharmacological treatments in several disorders. In particular, the administration of inhaled nitric oxide is routinely used to treat patients with pulmonary hypertension or refractory hypoxemia. More recently, inhaled nitric oxide has been studied as a promising antimicrobial treatment strategy against a range of pathogens, including resistant bacterial and fungal infections of the respiratory system. Pre-clinical and clinical findings have demonstrated that, at doses greater than 160 ppm, nitric oxide has antimicrobial properties and can be used to kill a broad range of infectious microorganisms. This review focused on the mechanism of action and current evidence from in vitro studies, animal models and human clinical trials of inhaled high-dose nitric oxide as an innovative antimicrobial therapy for lung infections.

Citing Articles

Harnessing the Power of Our Immune System: The Antimicrobial and Antibiofilm Properties of Nitric Oxide.

Roberts J, Milo S, Metcalf D Microorganisms. 2025; 12(12.

PMID: 39770746 PMC: 11677572. DOI: 10.3390/microorganisms12122543.

Mimicking the Effects of Antimicrobial Blue Light: Exploring Single Stressors and Their Impact on Microbial Growth.

Kruszewska-Naczk B, Grinholc M, Rapacka-Zdonczyk A Antioxidants (Basel). 2025; 13(12.

PMID: 39765911 PMC: 11673782. DOI: 10.3390/antiox13121583.

A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study.

Wolak T, Dicker D, Shifer Y, Grossman A, Rokach A, Shitrit M Sci Rep. 2024; 14(1):17201.

PMID: 39060420 PMC: 11282178. DOI: 10.1038/s41598-024-68055-w.

The impact and relevance of techniques and fluids on lung injury in machine perfusion of lungs.

Ponholzer F, Dumfarth J, Krapf C, Pircher A, Hautz T, Wolf D Front Immunol. 2024; 15:1358153.

PMID: 38510260 PMC: 10950925. DOI: 10.3389/fimmu.2024.1358153.

New Antimicrobial Strategies to Treat Multi-Drug Resistant Infections Caused by Gram-Negatives in Cystic Fibrosis.

Scoffone V, Barbieri G, Irudal S, Trespidi G, Buroni S Antibiotics (Basel). 2024; 13(1).

PMID: 38247630 PMC: 10812592. DOI: 10.3390/antibiotics13010071.

References

Garfield B, McFadyen C, Briar C, Bleakley C, Vlachou A, Baldwin M . Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia. Br J Anaesth. 2020; 126(2):e72-e75. PMC: 7666572. DOI: 10.1016/j.bja.2020.11.006. View

Umbreit J . Methemoglobin--it's not just blue: a concise review. Am J Hematol. 2006; 82(2):134-44. DOI: 10.1002/ajh.20738. View

Murad F . Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest. 1986; 78(1):1-5. PMC: 329522. DOI: 10.1172/JCI112536. View

Ghaffari A, Miller C, McMullin B, Ghahary A . Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide. 2005; 14(1):21-9. DOI: 10.1016/j.niox.2005.08.003. View

Fraser D, Patterson E, Slessarev M, Gill S, Martin C, Daley M . Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation. Crit Care Explor. 2020; 2(9):e0194. PMC: 7449254. DOI: 10.1097/CCE.0000000000000194. View

Cai Y, Zhang Y, Yang L . NO donors and NO delivery methods for controlling biofilms in chronic lung infections. Appl Microbiol Biotechnol. 2021; 105(10):3931-3954. PMC: 8140970. DOI: 10.1007/s00253-021-11274-2. View

Divithotawela C, Cypel M, Martinu T, Singer L, Binnie M, Chow C . Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion. JAMA Surg. 2019; 154(12):1143-1150. PMC: 6802423. DOI: 10.1001/jamasurg.2019.4079. View

Akerstrom S, Mousavi-Jazi M, Klingstrom J, Leijon M, Lundkvist A, Mirazimi A . Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005; 79(3):1966-9. PMC: 544093. DOI: 10.1128/JVI.79.3.1966-1969.2005. View

Wiegand S, Safaee Fakhr B, Carroll R, Zapol W, Kacmarek R, Berra L . Rescue Treatment With High-Dose Gaseous Nitric Oxide in Spontaneously Breathing Patients With Severe Coronavirus Disease 2019. Crit Care Explor. 2020; 2(11):e0277. PMC: 7671879. DOI: 10.1097/CCE.0000000000000277. View

10.

Miller C, McMullin B, Ghaffari A, Stenzler A, Pick N, Roscoe D . Gaseous nitric oxide bactericidal activity retained during intermittent high-dose short duration exposure. Nitric Oxide. 2008; 20(1):16-23. DOI: 10.1016/j.niox.2008.08.002. View

11.

Deppisch C, Herrmann G, Graepler-Mainka U, Wirtz H, Heyder S, Engel C . Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection. 2016; 44(4):513-20. DOI: 10.1007/s15010-016-0879-x. View

12.

Bogdan C . Nitric oxide and the immune response. Nat Immunol. 2001; 2(10):907-16. DOI: 10.1038/ni1001-907. View

13.

Michaelsen V, Ribeiro R, Brambate E, Ali A, Wang A, Pires L . A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide. PLoS One. 2021; 16(10):e0258368. PMC: 8513841. DOI: 10.1371/journal.pone.0258368. View

14.

Kamenshchikov N, Berra L, Carroll R . Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients. Biomedicines. 2022; 10(2). PMC: 8962307. DOI: 10.3390/biomedicines10020369. View

15.

Scott J, Maarsingh H, Holguin F, Grasemann H . Arginine Therapy for Lung Diseases. Front Pharmacol. 2021; 12:627503. PMC: 8022134. DOI: 10.3389/fphar.2021.627503. View

16.

Cypel M, Yeung J, Liu M, Anraku M, Chen F, Karolak W . Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011; 364(15):1431-40. DOI: 10.1056/NEJMoa1014597. View

17.

Gianni S, Di Fenza R, Morais C, Safaee Fakhr B, Mueller A, Yu B . High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air. Respir Care. 2021; 67(2):201-208. DOI: 10.4187/respcare.09308. View

18.

Safaee Fakhr B, Wiegand S, Pinciroli R, Gianni S, Morais C, Ikeda T . High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19). Obstet Gynecol. 2020; 136(6):1109-1113. PMC: 7673637. DOI: 10.1097/AOG.0000000000004128. View

19.

Regev-Shoshani G, Vimalanathan S, McMullin B, Road J, Av-Gay Y, Miller C . Gaseous nitric oxide reduces influenza infectivity in vitro. Nitric Oxide. 2013; 31:48-53. PMC: 7110511. DOI: 10.1016/j.niox.2013.03.007. View

20.

Dotsch J, Demirakca S, Kratz M, Repp R, Knerr I, Rascher W . Comparison of methylene blue, riboflavin, and N-acetylcysteine for the reduction of nitric oxide-induced methemoglobinemia. Crit Care Med. 2000; 28(4):958-61. DOI: 10.1097/00003246-200004000-00008. View