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CB₁ R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome

Resat Cinar^1,2, Joshua K Park², Charles N Zawatsky²

¹Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Maryland, USA.

Clinical and Translational Medicine

|July 29, 2021

Insights

Dual targeting of CB1 receptor and iNOS shows promise for treating Hermansky-Pudlak syndrome (HPS) related pulmonary fibrosis (PF). This novel therapeutic strategy effectively reduced fibrosis in preclinical models, offering hope for a condition with no current treatments.

Area of Science:

Pulmonary Medicine
Genetics
Pharmacology

Background:

Hermansky-Pudlak syndrome (HPS), particularly HPS-1, causes fatal adult-onset pulmonary fibrosis (PF) with no effective treatments.
The endocannabinoid system (ECS) and inducible nitric oxide synthase (iNOS) are implicated in fibrotic lung diseases.

Purpose of the Study:

To investigate the role of the ECS/CB1 receptor and iNOS in HPS-associated pulmonary fibrosis.
To evaluate a dual-target therapeutic strategy using a novel compound (MRI-1867) for HPS-PF.

Main Methods:

Analysis of human bronchoalveolar lavage fluid (BALF) and lung tissues from HPS patients and controls.
Assessment of bleomycin-induced pulmonary fibrosis in pale ear mice (HPS1ep/ep).
Evaluation of the dual-target compound MRI-1867 in preclinical models.

Main Results:

Overexpression of CB1 receptor and iNOS was observed in fibrotic lungs of HPS-PF patients and mouse models.
Elevated anandamide levels in BALF correlated with reduced pulmonary function.
MRI-1867 demonstrated superior antifibrotic efficacy compared to single-target inhibition, attenuating key fibrotic pathways, including IL-11 production and mitochondrial dysfunction.

Conclusions:

Dual inhibition of CB1 receptor and iNOS represents a promising antifibrotic strategy for HPS-associated pulmonary fibrosis.
MRI-1867 effectively targets critical pathological pathways involved in HPS-PF.
This dual-target approach offers a potential therapeutic avenue for a currently untreatable condition.

Read full analysis

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 (HPS1^ep/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.

Keywords:

endocannabinoids fibrosis lung disease polypharmacology rare disease

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