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Updated: Apr 30, 2026
Oropharyngeal Administration of Bleomycin in the Murine Model of Pulmonary Fibrosis
Published on: May 9, 2025
Ameliorative effect of mepenzolate bromide against pulmonary fibrosis
Shota Kurotsu1, Ken-ichiro Tanaka1, Tomomi Niino1
1Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan (S.K., K.-i.T., T.N., T.A., T.S., T.M.); Department of Internal Medicine, Division of Respiratory, Infection and Oncology, Nippon Medical School, Tokyo, Japan (A.A.); and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan (H.S.).
Abstract:
Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST.
Insights
Mepenzolate bromide effectively reduced pulmonary fibrosis and improved lung function in mice by lowering reactive oxygen species (ROS) and inhibiting key fibrotic pathways, offering a potential new treatment for lung diseases.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Toxicology
Background:
- Idiopathic pulmonary fibrosis involves lung injury from reactive oxygen species (ROS) and abnormal fibrosis driven by transforming growth factor-beta 1 (TGF-β1).
- Mepenzolate bromide, a drug for gastrointestinal disorders, possesses ROS-reducing properties.
Purpose of the Study:
- To investigate the efficacy of mepenzolate bromide in mitigating bleomycin-induced pulmonary fibrosis and lung dysfunction in a mouse model.
- To explore the underlying mechanisms of mepenzolate's therapeutic effects on pulmonary fibrosis.
Main Methods:
- Pulmonary fibrosis severity was evaluated via histopathology and hydroxyproline levels.
- Lung mechanics (elastance) and respiratory function (forced vital capacity, SpO2) were assessed using mechanical ventilation and SpO2 monitoring.
- Cellular responses, including cell death, inflammation, and myofibroblast proliferation, were analyzed. Biochemical assays measured NADPH oxidase activity, active TGF-β1 levels, and glutathione S-transferase (GST) activity.
Main Results:
- Intratracheal mepenzolate administration significantly reduced pulmonary fibrosis, improved lung mechanics, and restored forced vital capacity (FVC) and SpO2 in bleomycin-treated mice.
- Mepenzolate demonstrated therapeutic benefits even when administered post-fibrosis development.
- The drug inhibited bleomycin-induced pulmonary cell death and inflammation, reduced myofibroblast numbers, decreased NADPH oxidase and active TGF-β1 levels, and increased GST activity.
Conclusions:
- Intratracheal mepenzolate effectively ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice.
- Mepenzolate's therapeutic actions are attributed to the inhibition of NADPH oxidase and TGF-β1 pathways and the stimulation of GST activity.
- Mepenzolate bromide presents a promising therapeutic agent for pulmonary fibrosis, potentially through its antioxidant and anti-fibrotic mechanisms.
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