Nintedanib Alleviates Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells via the JAK/STAT3 and ERK1/2 Pathways.

Autor: Han C; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.; The Hospital of 91876 Troops of Chinese People's Liberation Army, Qinhuangdao, 066299, Hebei, China., Wang LJ; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Dong ZQ; Department of Gastroenterology, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai, 200434, China., Wang PY; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Lv YW; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Wang D; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China., Hu LH; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China. lianghao-hu@smmu.edu.cn.; National Key Laboratory of Immunity and Inflammation, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China. lianghao-hu@smmu.edu.cn.
Jazyk: angličtina
Zdroj: Digestive diseases and sciences [Dig Dis Sci] 2023 Sep; Vol. 68 (9), pp. 3644-3659. Date of Electronic Publication: 2023 Aug 01.
DOI: 10.1007/s10620-023-08052-7
Abstrakt: Background: Nintedanib (Ninte) has been approved for the treatment of pulmonary fibrosis, and whether it can ameliorate chronic pancreatitis (CP) is unknown.
Aims: This study was conducted to investigate the effect and molecular mechanism of Ninte on pancreatic fibrosis and inflammation in vivo and in vitro.
Methods: The caerulein-induced CP model of murine was applied, and Ninte was orally administered. Pathological changes in pancreas were evaluated using hematoxylin & eosin, Sirius Red, Masson's trichrome, and anti-Ki-67 staining. For in vitro studies, the effects of Ninte on cell viability, apoptosis, and migration of pancreatic stellate cells (PSCs) were determined by CCK-8, flow cytometry, and wound healing assays, respectively. The potential molecular mechanisms of the effects of Ninte on PSCs were analyzed by RNA-Seq and verified at the gene expression and protein activity levels by qRT-PCR and Western Blot.
Results: Ninte significantly alleviated the weight loss in mice with caerulein-induced CP and simultaneously attenuated the pancreatic damage, as evidenced by reduced acinar atrophy, collagen deposition, infiltration of inflammatory cells, and inhibited cell proliferation/regeneration. Besides, Ninte markedly suppressed the transcription of fibrogenic and proinflammatory genes in pancreatic tissues. Further in vitro studies showed that Ninte significantly inhibited the transcription and protein expression of genes corresponding to fibrogenesis and proliferation in PSCs. The results of RNA-Seq analysis and subsequent verification assays indicated that Ninte inhibited the activation and proliferation of PSCs via the JAK/STAT3 and ERK1/2 pathways.
Conclusions: These findings indicate that Ninte may be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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