Response to “Critical Appraisal on Hydrogen Inhalation Therapy Alone May Not Alleviate Intestinal Mucosal Damage in NOMI Without Total-Layer Necrosis: An Experimental Swine Model Study”

Abstract

We sincerely thank Dr. Mishba Ur Haq et al. for their thoughtful comments, which provided valuable insight and critical appraisal of our publication “Hydrogen inhalation therapy alone may not alleviate intestinal mucosal damage in NOMI without total-layer necrosis: An experimental swine model study”. We would like to address two key comments raised.

First, we agree that both the 4-h observation period and treatment intensity are areas for future consideration. Previous studies [1-3] implemented hydrogen inhalation therapy for only a few hours. Therefore, extending the duration of hydrogen inhalation could potentially yield.

Unlike conditions characterized by complete ischemia–reperfusion injury, such as cardiac arrest, large-vessel occlusive stroke, or coronary artery occlusion, our NOMI model did not involve superior mesenteric artery occlusion and did not induce full-thickness necrosis. Under these conditions, a lower quantity of reactive oxygen species (ROS) potentially attenuated the measurable effects of hydrogen as an antioxidant adjunct. This interpretation aligns with our findings showing no intergroup differences in 8-OHdG levels and similar progression of histological injury grades over time. We also note that achieving uniform intensity was technically challenging due to variations in individual responses to vasopressors. While macroscopic serosal images occasionally suggested transmural necrosis, histological confirmation consistently revealed only partial layer injury. Given the limited number of animals, comprehensive histological sampling at multiple time points was not feasible.

Second, we acknowledge that the limited sample size, imposed by ethical constraints of large-animal research, restricted statistical power. This study was designed as a pilot feasibility experiment, intended to generate preliminary data for subsequent investigations with adequate power and longer observation periods.

In conclusion, we appreciate the reviewers' constructive criticism and share the goal of improving outcomes in NOMI. We believe that further studies exploring hydrogen therapy, as part of a multifaceted strategy, under optimized timing and dosage conditions, represent the most promising path. We hope that our preliminary findings, together with such academic dialogue, will contribute to future translational research in this challenging field.

The Committee for Animal Ethics at Jichi Medical University approved the present experimental study (Approval number: 21054-01).

The authors have nothing to report.

The authors declare no conflicts of interest.