The melatonin agonist ramelteon attenuates bleomycin-induced lung fibrosis by suppressing the NLRP3/TGF-Β1/HMGB1 signaling pathway


Aydin P., Aksakalli-Magden Z. B., Civelek M. S., Karabulut-Uzuncakmak S., Mokhtare B., ÖZKARACA M., ...Daha Fazla

Advances in Medical Sciences, cilt.68, sa.2, ss.322-331, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 68 Sayı: 2
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1016/j.advms.2023.09.004
  • Dergi Adı: Advances in Medical Sciences
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, EMBASE, Food Science & Technology Abstracts, MEDLINE
  • Sayfa Sayıları: ss.322-331
  • Anahtar Kelimeler: Fibrosis, Melatonin, NLRP3, Ramelteon, TGF-β1
  • Atatürk Üniversitesi Adresli: Evet

Özet

Purpose: The possible effects of ramelteon, a melatonin receptor agonist on bleomycin-induced lung fibrosis were analyzed via transforming growth factor β1 (TGF-β1), 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-β1, HMGB1, NLRP3, and interleukin 1 beta (IL-1β) 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.