CB(1)R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome

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/CB(1)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 CB(1)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 CB(1)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 CB(1)R inhibition. Dual inhibition of CB(1)R and iNOS is an effective antifibrotic strategy for HPSPF.