3-Carbamoyl-proxyl nitroxide radicals attenuate bleomycin-induced pulmonary fibrosis in mice

Miri Assayag; Sara Goldstein; Amram Samuni; Neville Berkman

doi:10.1016/j.freeradbiomed.2021.05.010

3-Carbamoyl-proxyl nitroxide radicals attenuate bleomycin-induced pulmonary fibrosis in mice

Miri Assayag, Sara Goldstein^*, Amram Samuni, Neville Berkman

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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
Pages (from-to)	135-142
Number of pages	8
Journal	Free Radical Biology and Medicine
Volume	171
DOIs	https://doi.org/10.1016/j.freeradbiomed.2021.05.010
State	Published - 1 Aug 2021

Bibliographical note

Funding 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 ).

Funding Information:
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 ).

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

3-CP
Collagen content
IPF
Lung fibrosis
Nitroxide
Oxidative stress
Protein nitration
TGF-β
TGF-beta

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title = "3-Carbamoyl-proxyl nitroxide radicals attenuate bleomycin-induced pulmonary fibrosis in mice",

abstract = "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.",

keywords = "3-CP, Collagen content, IPF, Lung fibrosis, Nitroxide, Oxidative stress, Protein nitration, TGF-β, TGF-beta",

author = "Miri Assayag and Sara Goldstein and Amram Samuni and Neville Berkman",

note = "Funding 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 ). Funding Information: 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 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

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doi = "10.1016/j.freeradbiomed.2021.05.010",

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AU - Assayag, Miri

AU - Goldstein, Sara

AU - Samuni, Amram

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N2 - 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.

AB - 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.

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KW - Collagen content

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KW - Lung fibrosis

KW - Nitroxide

KW - Oxidative stress

KW - Protein nitration

KW - TGF-β

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U2 - 10.1016/j.freeradbiomed.2021.05.010

DO - 10.1016/j.freeradbiomed.2021.05.010

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AN - SCOPUS:85106343832

SN - 0891-5849

VL - 171

SP - 135

EP - 142

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -

3-Carbamoyl-proxyl nitroxide radicals attenuate bleomycin-induced pulmonary fibrosis in mice

Abstract

Bibliographical note

Keywords

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