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    The melatonin agonist ramelteon attenuates bleomycin-induced lung fibrosis by suppressing the NLRP3/TGF-?1/HMGB1 signaling pathway
    (Elsevier Urban & Partner Sp Z O O, 2023) Aydin, Pelin; Aksakalli-Magden, Zeynep B.; Civelek, Maide S.; Karabulut-Uzuncakmak, Sevgi; Mokhtare, Behzad; Ozkaraca, Mustafa; Alper, Fatih
    Purpose: The possible effects of ramelteon, a melatonin receptor agonist on bleomycin-induced lung fibrosis were analyzed via transforming growth factor beta 1 (TGF-beta 1), the high mobility group box 1 (HMGB1) and Nod-like receptor pyrin domain-containing 3 (NLRP3) which are related to the fibrosis process. Materials and methods: Bleomycin (0.1 mL of 5 mg/kg) was administered by intratracheal instillation to induce pulmonary fibrosis (PF). Starting 24 h after bleomycin administration, a single dose of ramelteon was administered by oral gavage to the healthy groups, i.e. PF + RM2 (pulmonary fibrosis model with bleomycin + ramelteon at 2 mg/kg) and PF + RM4 (pulmonary fibrosis model with bleomycin + ramelteon at 4 mg/kg) at 2 and 4 mg/kg doses, respectively. Real-time polymerase chain reaction (real-time PCR) analyses, histopathological, and immunohistochemical staining were performed on lung tissues. Lung tomography images of the rats were also examined. Results: The levels of TGF-beta 1, HMGB1, NLRP3, and interleukin 1 beta (IL-1 beta) mRNA expressions increased as a result of PF and subsequently decreased with both ramelteon doses (p < 0.0001). Both doses of ramelteon partially ameliorated the reduction in the peribronchovascular thickening, ground-glass appearances, and reticulations, and the loss of lung volume. Conclusions: The severity of fibrosis decreased with ramelteon application. These effects of ramelteon may be associated with NLRP3 inflammation cascade.