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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)\u2010induced pulmonary fibrosis. Rats were randomised and administrated a single dose of 7.5\u00a0mg\/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\u20101], Smoothened [Smo] and glioblastoma\u20102 [Gli\u20102]) were assessed. In single therapies, ATRA and FSK ameliorated BLM\u2010induced lung fibrosis. On the contrary, a combination of both drugs synergistically reversed the effect of BLM\u2010induced lung fibrosis, as indicated by the enhancement of lung functions and the decrease of the \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA) expression and collagen deposition. Additionally, FSK and ATRA ameliorated oxidative stress and inflammation, reduced transforming growth factor \u03b21 (TGF\u2010\u03b21) levels and reversed the effect of BLM on the mRNA expression of Ptch\u20101, Smo and Gli\u20102. 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.<\/jats:p>","DOI":"10.1111\/1440-1681.13486","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T07:36:19Z","timestamp":1613115379000},"page":"1024-1040","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Concomitant inhibition of hedgehog signalling and activation of retinoid receptors abolishes bleomycin\u2010induced lung fibrosis"],"prefix":"10.1111","volume":"48","author":[{"given":"Ahmed Fawzy","family":"Eleraky","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gouda Kamel","family":"Helal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"},{"name":"Department of Pharmacology Faculty of Pharmacy Heliopolis University Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed F.","family":"Elshafie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6231-6292","authenticated-orcid":false,"given":"Raed S.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13115"},{"issue":"4","key":"e_1_2_10_3_1","first-page":"772","article-title":"WNT1\u2010inducible signaling protein\u20131 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis","volume":"119","author":"K\u00f6nigshoff M","year":"2009","journal-title":"J Clin Invest"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050062"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2008-0201OC"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0108OC"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00184.2012"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13611"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130303"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2010.10.007"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.10.9.8801176"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(05)70007-8"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2013.108"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(02)00115-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.21.6452"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509717103"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471141755.ph0546s40"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(77)80099-5"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr980449z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00394"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02034932"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3109\/01902149209020649"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0154OC"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0132TR"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2011.10.001"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02713874"},{"key":"e_1_2_10_27_1","first-page":"611","article-title":"Protective effect of ATRA on bleomycin induced lung fibrosis in rat","volume":"4","author":"Raja S","year":"2014","journal-title":"Med Chem"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200606-862OC"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3109\/08923973.2011.604087"},{"key":"e_1_2_10_30_1","unstructured":"MastruzzoC CrimiN VancheriC.Role of oxidative stress in pulmonary fibrosis. 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