CB1 R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome.
Clin Transl Med
; 11(7): e471, 2021 07.
Article
in En
| MEDLINE
| ID: mdl-34323400
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/CB1 R 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 CB1 R 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 CB1 R 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 CB1 R inhibition. Dual inhibition of CB1 R and iNOS is an effective antifibrotic strategy for HPSPF.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Pulmonary Fibrosis
/
Hermanski-Pudlak Syndrome
/
Receptor, Cannabinoid, CB1
/
Nitric Oxide Synthase Type II
Type of study:
Prognostic_studies
Language:
En
Journal:
Clin Transl Med
Year:
2021
Type:
Article
Affiliation country:
United States