Pimitespib, an HSP90 inhibitor, augments nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop in rats with bleomycin-challenged lungs: Evolutionary perspective in managing pulmonary fibrosis.

Autor: El-Kashef DH; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: dalia_elkashef@mans.edu.eg., Youssef ME; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: mahmoodelsaid@hotmail.com., Nasr M; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt; Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: m2nasr@yahoo.com., Alrouji M; Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra 11961, Saudi Arabia. Electronic address: malrouji@su.edu.sa., Alhajlah S; Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra 11961, Saudi Arabia. Electronic address: alhjlah@su.edu.sa., AlOmeir O; Department of Pharmacy Practice, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia. Electronic address: aalomear@su.edu.sa., El Adle Khalaf N; Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: nouraeladle@mans.edu.eg., Ghaffar DMA; Department of Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: Dalia.mr@mans.edu.eg., Jamil L; Department of Histology, Faculty of Medicine, October 6 University, Giza 12511, Egypt. Electronic address: drlubnajamil1978@gmail.com., Abdel-Nasser ZM; Department of Biochemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza 11787, Egypt. Electronic address: zmohamed@msa.edu.eg., Ibrahim S; Department of Pharmacy Practice, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt. Electronic address: samaribrahim370@gmail.com., Abdeldaiem MSI; Clinical Pharmacy Discipline, School of pharmaceutical sciences, Universiti Sains Malaysia, Penang, Malaysia; Pharmacy Practice Department, Faculty of Pharmacy, Sinai University, Ismailia, Egypt. Electronic address: mahmoud.said@su.edu.eg., Donia SS; Department of Clinical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt. Electronic address: sallydonia@yahoo.com., Mohammed OA; Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha 61922, Saudi Arabia. Electronic address: osamaabbass@med.asu.edu.eg., Morsy NE; Pulmonary medicine Department, Mansoura university sleep center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: neselmorsy@mans.edu.eg., Shata A; Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: ahmedmhes@mans.edu.eg., Saber S; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: sampharm81@gmail.com.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Sep; Vol. 153, pp. 113487. Date of Electronic Publication: 2022 Jul 31.
DOI: 10.1016/j.biopha.2022.113487
Abstrakt: Idiopathic pulmonary fibrosis is a fatal lung disorder in which the etiology and pathogenesis are still unobvious. Effective treatments are urgently needed considering that lung transplantation is the only treatment that could improve outcomes. This study aimed to investigate the therapeutic significance of the dual administration of pimitespib, an HSP90 inhibitor, and nifuroxazide, a STAT3 inhibitor, against bleomycin-induced pulmonary fibrosis in rats. Our results revealed that pimitespib/nifuroxazide inhibited bleomycin-induced alterations in the structure and the function of the lungs. They demonstrated significant decreases in the BALF total and differential cell counts, LDH activity, and total protein. Concurrently, there was a reduction in the accumulation of collagen as proved by decreased hydroxyproline and the gene expression of COL1A1 accompanied by lower levels of PDGF-BB, TIMP-1, and TGF-β. The levels of IL-6 were also downregulated. Pimitespib-induced inhibition of HSP90 led to subsequent inhibition of HIF-1α and STAT3 client proteins since the closed HSP90 would not enclose its client proteins. Therefore, pimitespib resulted in the repression of HIF-1α/CREB-p300 HAT as well as the STAT3/CREB-p300 HAT nuclear interactions. On the other hand, nifuroxazide resulted in a notable decline in pSTAT3 and HIF-1α levels. Subsequently, the combined effects of both drugs led to a substantial reduction in ECM deposition. Herein, pimitespib augmented nifuroxazide-induced disruption in the IL-6/STAT3/HIF-1α autocrine loop. Our findings also disclose that this novel loop is a promising therapeutic attack site for possible pulmonary fibrosis repression studies. Therefore, the use of pimitespib/nifuroxazide embodies an evolutionary perspective in managing pulmonary fibrosis.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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