CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome
Abstract Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) fo...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-07-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.471 |
| _version_ | 1811323151979642880 |
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| author | Resat Cinar Joshua K. Park Charles N. Zawatsky Nathan J. Coffey Steven P. Bodine Jasmina Abdalla Tadafumi Yokoyama Tony Jourdan Lindsey Jay Mei Xing G. Zuo Kevin J. O'Brien Junfeng Huang Ken Mackie Asaf Alimardanov Malliga R. Iyer William A. Gahl George Kunos Bernadette R. Gochuico May Christine V. Malicdan |
| author_facet | Resat Cinar Joshua K. Park Charles N. Zawatsky Nathan J. Coffey Steven P. Bodine Jasmina Abdalla Tadafumi Yokoyama Tony Jourdan Lindsey Jay Mei Xing G. Zuo Kevin J. O'Brien Junfeng Huang Ken Mackie Asaf Alimardanov Malliga R. Iyer William A. Gahl George Kunos Bernadette R. Gochuico May Christine V. Malicdan |
| author_sort | Resat Cinar |
| collection | DOAJ |
| description | Abstract Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF. |
| first_indexed | 2024-04-13T13:50:03Z |
| format | Article |
| id | doaj.art-6b58354bc8cd41de976ad8a5c91da796 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-13T13:50:03Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-6b58354bc8cd41de976ad8a5c91da7962022-12-22T02:44:22ZengWileyClinical and Translational Medicine2001-13262021-07-01117n/an/a10.1002/ctm2.471CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndromeResat Cinar0Joshua K. Park1Charles N. Zawatsky2Nathan J. Coffey3Steven P. Bodine4Jasmina Abdalla5Tadafumi Yokoyama6Tony Jourdan7Lindsey Jay8Mei Xing G. Zuo9Kevin J. O'Brien10Junfeng Huang11Ken Mackie12Asaf Alimardanov13Malliga R. Iyer14William A. Gahl15George Kunos16Bernadette R. Gochuico17May Christine V. Malicdan18Section on Fibrotic Disorders National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USATherapeutics Development Branch Division of Preclinical Innovation National Center for Advancing Translational Sciences National Institutes of Health Rockville Maryland USADepartment of Psychological and Brain Sciences Indiana University Bloomington Indiana USATherapeutics Development Branch Division of Preclinical Innovation National Center for Advancing Translational Sciences National Institutes of Health Rockville Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USALaboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Rockville Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USASection of Human Biochemical Genetics Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda Maryland USAAbstract Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF.https://doi.org/10.1002/ctm2.471endocannabinoidsfibrosislung diseasepolypharmacologyrare disease |
| spellingShingle | Resat Cinar Joshua K. Park Charles N. Zawatsky Nathan J. Coffey Steven P. Bodine Jasmina Abdalla Tadafumi Yokoyama Tony Jourdan Lindsey Jay Mei Xing G. Zuo Kevin J. O'Brien Junfeng Huang Ken Mackie Asaf Alimardanov Malliga R. Iyer William A. Gahl George Kunos Bernadette R. Gochuico May Christine V. Malicdan CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome Clinical and Translational Medicine endocannabinoids fibrosis lung disease polypharmacology rare disease |
| title | CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome |
| title_full | CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome |
| title_fullStr | CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome |
| title_full_unstemmed | CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome |
| title_short | CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome |
| title_sort | cb1r and inos are distinct players promoting pulmonary fibrosis in hermansky pudlak syndrome |
| topic | endocannabinoids fibrosis lung disease polypharmacology rare disease |
| url | https://doi.org/10.1002/ctm2.471 |
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