Evaluation of Anti fibrotic Effect of EMT modulators in Experimental Models of Pulmonary Fibrosis Elucidation of Novel Targets

Abstract

Aberrant lung remodeling due to extensive parenchymal scarring leading to respiratory functional impairment are the characteristics of Pulmonary Fibrosis ( Prognosis is usually poor with low life expectancy of 3 to 5 years post diagnosis. Pirfenidone a nd Nintedanib are the only two US FDA drugs approved to treat PF in clinics. Genetic as well as various non newlinegenetic factors have been identified as triggers and potent contributors to development of PF. However, the key initiator is injury to alveolar epit helium which triggers several molecular signaling cascades. Among the most studied pathogenic molecular mechanisms pertaining to fibrosis include inflammation, TGF and#946;/SMAD signaling and Epithelial to Mesenchymal Transition ( In the current research wo rk, we propose three EMT modulators, a natural compound ( a peptide ( and an US FDA approved drug ( as pharmacological interventions to mitigate PF in TGF and#946;1 induced in vitro and Bleomycin induced in vivo experimental models. We emphasized largely on modulation of novel targets by pharmacological interventions in order to elucidate these targets as promising leads to develop therapeutics against PF. Also, we focused on localized drug delivery of active ingredient to the lungs. We investigated the effect of Honokiol, ATWLPPR and Clofazimine on various macroscopic, microscopic, and molecular fibrotic parameters and markers. Honokiol, a polyphenol neolignan showed remarkable anti fibrotic effects in in vitro and in vivo experime ntal models of PF by inhibition of critical pathways involved in pathogenesis of newlinePF such as EMT, TGF and#946;/SMAD signaling and ECM deposition. Additionally, Honokiol also attenuated CD44/IL 6/STAT3 signaling cascade which also appreciably contributed toregress ion of fibrotic changes. We for the first time performed a study to validate NRP 1 as a promising target to ameliorate PF by NRP 1 specific inhibitor ATWLPPR ( which is an important activator of TGF and#946; corroborates TGF and#946;/SMAD signaling as well as promotes EMT.