Fibroproliferative mechanisms in organ fibrosis

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

The Section on Fibrotic Disorders (SFD) was established in January 2021. There are three major lines of research in this project as detailed below. Exploring a multi-target therapeutic approach for improving efficacy in fibrotic disorders For multifactorial chronic diseases, such as fibrosis, simultaneous targeting of multiple pathways has been recommended as a way to improve therapeutic efficacy. Previously, we identified that simultaneous dual-targeting of cannabinoid receptor 1 (CB1R) and inducible nitric oxide synthase (iNOS) for inhibition by an in-house generated hybrid inhibitor provided improved antifibrotic efficacy in liver (Cinar et al., 2016 JCI Insight, PMID:27525312) and lung fibrosis (Cinar et al., 2017 JCI Insight, PMID:28422760) compared to inhibiting a single target. In collaboration with NHGRI scientists, we found that overactivity of CB1R and iNOS contributes to Hermansky-Pudlak syndrome pulmonary fibrosis, which is a rare genetic disorder with poor progression and high mortality. Development and progression of the disease is via multiple critical pathological process including dysregulation of mitochondrial function and interleukin-11 (IL-11). Our findings also uncovered a previously unrecognized role of iNOS regulating IL-11 in pulmonary fibroblast activation and fibrosis. Furthermore, our research identified that simultaneous inhibition of lung CB1R and iNOS by a hybrid inhibitor (MRI-1867) is a rational therapeutic strategy for achieving efficacy in treating HPSPF by attenuating fibrosis, improving pulmonary function and survival. These findings have been published in Clinical and Translational Medicine (Cinar et al, 2021 PMID:34323400). Scleroderma and Skin fibrosis is another form of fibrotic disorder, where CB1R and iNOS overactivity also contributes to pathology. Using s bleomycin-induced Skin fibrosis model we found that dual target inhibition of CB1R and iNOS by MRI-1867 provided superior anti-fibrotic efficacy in skin fibrosis compared to CB1R antagonism alone, which would make MRI-1867 also an emerging therapeutic candidate for skin fibrosis (Zawatsky et al, 2021 PMID:34650521). To identify that critical fibroproliferative pathways exist in both mouse model of Pulmonary fibrosis and human IPF patients, we employed an integrative multiomics approach using a bleomycin-induced PF model to establish a multiomics framework to identify rational therapeutic targets for PF (Arif et al., 2023 PMID:37038090). Our integrative multiomics framework endorses peripheral CB1R antagonism as a rational therapeutic strategy in PF. Furthermore, our study demonstrates that systems biology and systems pharmacology approaches could be employed to identify and prioritize druggable therapeutic targets that regulate multiple pathologic pathways (Arif et al., 2023 PMID:37038090). Exploring the role of cannabinoid CB1Rs in lung injury and fibrosis Previously we demonstrated that overactivity of the endocannabinoid/CB1R system contributes to development of Idiopathic Pulmonary Fibrosis (Cinar et al., 2017 JCI Insight, PMID:28422760) or Hermansky-Pudlak syndrome pulmonary fibrosis (Cinar et al, 2021 PMID:34323400). Additionally, we identified CB1R as a therapeutic target in pulmonary fibrosis. However, cell specific roles of CB1R in lung are not yet known. One of our major research projects focuses on understanding the role of the endocannabinoid/CB1R system in lung injury and pulmonary fibrosis. Currently, we are working on developing conditional CB1R knock-out mice that will delete CB1R in different lung cells using the Cre-Lox system to test these mutant mice in the bleomycin-induced pulmonary fibrosis model. Outcomes of this research could uncover cell specific roles of CB1R in lungs during injury and fibrosis. This research may also identify specific therapeutic modalities considering drug delivery route to improve safety and efficacy. Exploring the impact of chronic alcohol drinking on lung health Chronic alcohol drinking induces tissue injury in multiple organs including lungs. Accordingly, chronic alcohol drinking predisposes lungs to the development of acute lung injury, pneumonia, and alcoholic lung disease. It is known that chronic alcohol ingestion alters the function of alveolar macrophages (AM). One of our projects explores alcohol impact on lung immunity, immunometabolism and pulmonary function in experimental murine models. We are currently testing available animal models of alcohol drinking, which also induce an injury in lungs in addition to other organs like liver. We found that the NIAAA alcohol drinking model with chronic and binge alcohol ingestion in mice increased oxidative stress and an inflammatory microenvironment in lungs (Appolonia et al, 2022 PMID:35685280), which is the hallmark of Alcohol-induced lung injury in human. Therefore, the NIAAA model could be instrumental in our research to explore alcohol-induced alterations in lung physiology and immunity. Outcomes of our research will help us to understand the impact of alcohol drinking on lung pathophysiologies.