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Concomitant inhibition of hedgehog signalling and activation of retinoid receptors abolishes bleomycin‐induced lung fibrosis
Author(s) -
Eleraky Ahmed Fawzy,
Helal Gouda Kamel,
Elshafie Mohamed F.,
Ismail Raed S.
Publication year - 2021
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13486
Subject(s) - retinoid , bleomycin , retinoic acid , pulmonary fibrosis , endocrinology , tretinoin , oxidative stress , medicine , fibrosis , chemistry , biology , cancer research , pharmacology , biochemistry , chemotherapy , gene
Pulmonary fibrosis is a devastating disease with unknown treatment. All‐trans retinoic acid (ATRA) attenuates bleomycin‐induced lung fibrosis by different mechanistic pathways. However, the role of retinoid receptors in lung fibrosis is still unclear. Forskolin (FSK), a potent inhibitor for the revolutionary hedgehog (Hh) signalling pathway, has a promising antifibrotic effect on other organs such as the liver. This study investigates the interplay between the retinoid receptors modulation and the Hh signalling pathway in bleomycin (BLM)‐induced pulmonary fibrosis. Rats were randomised and administrated a single dose of 7.5 mg/kg of BLM alone and with ATRA, FSK and both of them. The effects of FSK and ATRA on lung functions, oxidative stress markers (malondialdehyde [MDA], glutathione [GSH], superoxide dismutase [SOD] and catalase [CAT]), retinoid markers (retinoic acid receptors [RAR] and rexinoid X receptors [RXR]) and Hh signalling markers (patched homolog 1 [Ptch‐1], Smoothened [Smo] and glioblastoma‐2 [Gli‐2]) were assessed. In single therapies, ATRA and FSK ameliorated BLM‐induced lung fibrosis. On the contrary, a combination of both drugs synergistically reversed the effect of BLM‐induced lung fibrosis, as indicated by the enhancement of lung functions and the decrease of the α‐smooth muscle actin (α‐SMA) expression and collagen deposition. Additionally, FSK and ATRA ameliorated oxidative stress and inflammation, reduced transforming growth factor β1 (TGF‐β1) levels and reversed the effect of BLM on the mRNA expression of Ptch‐1, Smo and Gli‐2. FSK inhibited the Hh pathway and also activated protein kinase A (PKA) that is, in part, involved in phosphorylation of RAR/RXR heterodimer (a key step in retinoid receptor activation). The present results suggest that a combination of FSK and ATRA has a promising therapeutic value for lung fibrosis management.