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While definitive evidence is still lacking, this narrative review synthesizes the emerging clinical and mechanistic properties supporting high-dose iNO as a potential therapeutic strategy for lower respiratory tract infections, including drug-resistant bacterial pneumonias, COVID-19, nontuberculous mycobacteria, and bronchiolitis. We summarize safety data from laboratory studies, Phase I trials, clinical findings from 27 predominantly early-phase studies, and highlight its as both hospital-based and home-based therapy. High-dose iNO acts through multiple pathways, including direct microbial killing, biofilm disruption, immune modulation, and mucociliary enhancement, and holds promise in addressing unmet needs in respiratory infection management. We also propose a roadmap for future research to optimize dosing, delivery, and efficacy endpoints in well-defined patient populations.<\/jats:p>","DOI":"10.1186\/s40635-026-00852-1","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T02:58:45Z","timestamp":1770260325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The therapeutic potential of high-dose inhaled nitric oxide for antimicrobial effects: a narrative review and future directions"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2702-2093","authenticated-orcid":false,"given":"Lorenzo","family":"Berra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay","family":"Kamenshchikov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asher","family":"Tal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijan","family":"Safaee Fakhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Rezoagli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binglan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the High-Dose Inhaled Nitric Oxide Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Elalem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Mereto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bolchini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Miett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Spina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatus","family":"Wanderley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"852_CR1","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.niox.2005.01.006","volume":"12","author":"A Ghaffari","year":"2005","unstructured":"Ghaffari A, Neil DH, Ardakani A, Road J, Ghahary A, Miller CC (2005) A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures. 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