Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Oxidative and nitrosative stress is implicated as one of the main pathogenic pathways in IPF. The rationale for the use of antioxidants to treat lung fibrosis is appealing, however to date a consistent beneficial effect for such an approach has not been observed. We have recently demonstrated that nitroxides, particularly 3-carbamoyl-proxyl (3-CP), markedly reduce airway inflammation, airway hyper-responsiveness, and protein nitration of the lung tissue in a mouse model of ovalbumin-induced acute asthma, thus prompting its use for the treatment of IPF. The present study investigates the effect of 3-CP on the development of lung fibrosis using the murine intratracheal bleomycin model. 3-CP was administered either intranasally or orally during the entire experiment or starting 7 days after induction of the lung injury. 3-CP was found to be both a preventive and a therapeutic drug reducing the lung fibrosis (histological score), the increase in collagen content, protein nitration, TGF-β levels, the degree of weight loss as well as inhibiting the impairment of lung function. Nitroxides are catalytic antioxidants that preferentially detoxify radicals, and therefore the effect of 3-CP on the severity of the disease supports the involvement of reactive oxygen and nitrogen species in the disease pathology.
|Original language||American English|
|Number of pages||8|
|Journal||Free Radical Biology and Medicine|
|State||Published - 1 Aug 2021|
Bibliographical noteFunding Information:
Once we established the potential of 3-CP to reduce lung fibrosis when administered in a preventive manner (during the entire experiment), we examined whether 3-CP is effective when administered as a therapeutic agent delivered after disease onset. To this end, 3-CP was delivered orally via gavage starting on day 7 until the end of the experiment. For this study, we included a positive control arm in which a study group was treated with Nintedanib (FDA approved for treatment of IPF). This part of the study was performed by an independent CRO company and funded by Integra Holdings Inc. (The biotechnology holdings of Yissum, the technology transfer company of the Hebrew University of Jerusalem ).
This work was supported by the Industry-Academy Program (NOFAR) of the Chief Scientist of the Israeli Ministry and by Integra Holdings Inc . (The biotechnology holdings of Yissum, the technology transfer company of the Hebrew University of Jerusalem ).
© 2021 Elsevier Inc.
- Collagen content
- Lung fibrosis
- Oxidative stress
- Protein nitration