Inhaled nitric oxide in fibrotic and advanced interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials
Shun Nakahara, Yusuke Hirao, Bradley Fujiuchi, Brent Matsuda
Abstract
Purpose
Interstitial lung disease (ILD) can lead to pulmonary hypertension (PH), contributing to reduced exercise capacity in patients with ILD. Inhaled nitric oxide (iNO) reduces pulmonary artery pressure and pulmonary vascular resistance and may improve exercise capacity in this population; however, the available evidence remains limited. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of iNO versus placebo in patients with ILD.
Introduction
Interstitial lung disease (ILD) represents a heterogeneous group of disorders with considerable diagnostic complexity, in which inflammatory and fibrotic processes frequently coexist, complicating treatment strategies [1]. Currently FDA-approved antifibrotic agents such as nintedanib, pirfenidone, and nerandomilast are the standard treatments for patients with progressive pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF) [2].
Methods
This systematic review and meta-analysis was performed following the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (S1 Table) [14]. Additionally, our study protocol was registered using the following registration number CRD420251267394 in the International Prospective Register of Systematic Reviews.
Results
The initial search yielded 261 results on December 21, 2025. After removing duplicate results and applying the eligibility criteria, 27 records were selected for the full-text review, as detailed in Fig 1. Of these, four RCTs, including one crossover trial, were included in this systematic review and meta-analysis [6,12,13,21]. A total of 274 participants were included, of whom 172 received iNO. A total of 142 (51.8%) patients were classified as having PH, either confirmed by right heart catheterization or based on an intermediate to high echocardiographic probability according to the European Society of Cardiology/European Respiratory Society guidelines.
Discussion
In this systematic review and meta-analysis of four RCTs with 274 patients, iNO was compared with placebo in patients with fibrotic and advanced ILD. Our main results were as follows: (1) there was no difference in 6MWD and MVPA between the iNO and placebo groups and (2) the safety profile of iNO was supported due to similarities in any adverse events endpoint.
Conclusion
In this meta-analysis, iNO did not demonstrate benefit in 6MWD or MVPA compared with placebo in patients with advanced and fibrotic ILD. There was no difference in any adverse events between the iNO and placebo groups. Overall, current RCTs suggest no clinically meaningful improvement in functional exercise capacity or daily physical activity with iNO in the study populations included in this meta-analysis.
Citation: Nakahara S, Hirao Y, Fujiuchi B, Matsuda B (2026) Inhaled nitric oxide in fibrotic and advanced interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials. PLoS One 21(6): e0351862. https://doi.org/10.1371/journal.pone.0351862
Editor: Selvakumar Subbian, Rutgers Biomedical and Health Sciences, UNITED STATES OF AMERICA
Received: March 9, 2026; Accepted: June 2, 2026; Published: June 22, 2026
Copyright: © 2026 Nakahara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
