Abstract
Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGF-βRI), is the only known TGF-β pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-β and NF-κB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague-Dawley male rats (n=30). The rats (220±50 g) were administered galunisertib intragastrically [75 mg·kg-1·day-1 for 2 days (0 and 24 h)]. Serum IL-1β, IL-6, TNF-α, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); NF-κBp65 and TGF-β1 proteins, as well as TGF-βRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38±2.26) than in the AP group (8.14±1.27) and sham-operated group (1.82±0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-βRI and p-Smad2/3 and inhibited NF-κB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1β, IL-6, TNF-α, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-β signals and NF-κB as well as the secretion of pro-inflammatory cytokines.
Highlights
Acute pancreatitis (AP) is an inflammatory process in the pancreatic gland that may eventually lead to a severe systemic inflammatory response
Galunisertib alleviated the histopathological alterations of the pancreas To detect the effects of galunisertib on the experimental animal AP model, the pathological changes in the pancreas of experimental groups were observed with an optical microscope
Analyzing AP apoptosis in situ by triphosphate in situ nick end labeling (TUNEL) staining revealed that cell apoptosis was significantly increased in the galunisertib-treated group (16.38±2.26) than in the AP group (8.14±1.27) and sham-operated group (1.82±0.73) (Figure 2)
Summary
Acute pancreatitis (AP) is an inflammatory process in the pancreatic gland that may eventually lead to a severe systemic inflammatory response. Information from cellular and in vivo studies, as well as genetic studies in humans, suggests that pathological events that begin in the pancreatic acinar cell often initiate this disease [2]. Events in AP lead to the activation of several pathophysiological mechanisms that result in local and systemic complications and organ failure, which is responsible for the mortality associated with the disease [3]. The main mechanisms responsible for this systemic progression are pro-inflammatory cytokines, chemokines, reactive oxygen species (ROS), Ca2+, platelet activating factor, and adenosine, as well as neuronal and vascular responses [4]. Acinar cells act jointly with leukocytes triggering the inflammatory response after the local damage of the pancreas. Pathological responses arising from the pancreatic acinar cells have a central role in initiating AP
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