sirolimus and Pancreatitis

This study was to investigate the changes of autophagy in pancreatic tissue cells from hyperlipidemic acute pancreatitis (HLAP) rats and the molecular mechanism of autophagy to induce inflammatory injury in pancreatic tissue cells. Male Sprague Dawley (SD) rats were intraperitoneally injected with caerulein to establish acute pancreatitis (AP) model and then given a high fat diet to further prepare HLAP model. The HLAP rats were treated with autophagy inducer rapamycin or inhibitor 3-methyladenine. Pancreatic acinar (AR42J) cells were treated with caerulein to establish HLAP cell model. The HLAP cell model were treated with rapamycin or transfected with vascular endothelial growth factor (VEGF) siRNA. The inflammatory factors in serum and cell culture supernatant were detected by ELISA method. The histopathological changes of pancreatic tissue were observed by HE staining. The changes of ultrastructure and autophagy in pancreatic tissue were observed by electron microscopy. The expression levels of Beclin-1, microtubule- associated protein light chain 3-II (LC3-II), mammalian target of rapamycin complex 1 (mTORC1), and VEGF were measured by immunohistochemistry and Western blot. The results showed that, compared with control group, the autophagy levels and inflammatory injury of pancreatic tissue cells from HLAP model rats were obviously increased, and these changes were aggravated by rapamycin treatment, but alleviated by 3-methyladenine treatment. In HLAP cell model, rapamycin aggravated the autophagy levels and inflammatory injury, whereas VEGF siRNA transfection increased mTORC1 protein expression, thus alleviating the autophagy and inflammatory injury of HLAP cell model. These results suggest that VEGF-induced autophagy plays a key role in HLAP pancreatic tissue cell injury, and interference with VEGF-mTORC1 pathway can reduce the autophagy levels and alleviate the inflammatory injury. The present study provides a new target for prevention and treatment of HLAP.

Topics: Acute Disease; Animals; Autophagy; Ceruletide; Male; Mammals; Mechanistic Target of Rapamycin Complex 1; Microtubule-Associated Proteins; Pancreatitis; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Sirolimus; Vascular Endothelial Growth Factor A

Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK-eIF2α, ATF-6-GRP78, and IRE1-sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid-stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.

Topics: Animals; Autophagy; Cells, Cultured; Diet, High-Fat; Endoplasmic Reticulum Stress; Hypertriglyceridemia; Immunosuppressive Agents; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Sirolimus

The clinical benefit of second-generation drug-eluting stents (2nd DES) has been established, compared to first-generation drug-eluting stents (1st DES). However, pathological response after 2nd DES implantation remains unclear, particularly in the Japanese population.. Using specimens obtained by autopsy, we compared the histology between 2nd DES (41 sections) and 1st DES (38 sections) lesions within 1 year after stent implantation to evaluate early tissue reaction in Japanese patients. Stent segments were fixed with 10% buffered formalin and embedded in plastic, followed by hematoxylin-eosin and Masson's trichrome staining. Ratio of covered stent struts was calculated, and the area of fibrin deposition was morphometrically evaluated. The degree of inflammation around struts was examined semi-quantitatively (score 0-3).. The ratio of covered struts and mean fibrin area of 2nd DES were 0.69±0.05 and 658.0±173.4μm. Histopathological analysis showed advanced healing process in 2nd DES compared with 1st DES lesions. These results are consistent with clinical beneficial outcome of 2nd DES implantation.

Topics: Aged; Aneurysm, Ruptured; Colitis, Ischemic; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Fibrin; Heart Failure; Humans; Inflammation; Japan; Male; Middle Aged; Neointima; Pancreatitis; Pneumonia; Renal Insufficiency; Risk Factors; Sepsis; Sirolimus; Treatment Outcome

Topics: Acute Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreatitis; Sirolimus; Young Adult

Everolimus is an mTOR inhibitor commonly used to treat metastatic pancreatic neuroendocrine tumors (pNETs) and renal cell carcinoma, and for posttransplant immunosuppression. This report presents a case of a 36-year-old man being treated with everolimus for a metastatic pNET who developed severe hypertriglyceridemia and acute pancreatitis. The incidence of hypertriglyceridemia reported in large prospective randomized trials is reviewed and the management of hypertriglyceridemic pancreatitis is discussed. Careful monitoring of triglyceride levels and dose adjustments of everolimus together with lipid-lowering therapy can allow patients to continue this medication. Because there are increasing indications for the use of everolimus, prescribing oncologists must be cognizant of the common and serious side effects.

Topics: Adult; Antineoplastic Agents; Everolimus; Humans; Hypertriglyceridemia; Male; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatitis; Sirolimus

This study aimed at T-cell inhibition by immunosuppressants to reduce cell damage and improve the course of severe acute pancreatitis (SAP).. A taurocholate-induced SAP was used and 5 groups were compared: (1) rapamycin + FTY720, (2) rapamycin, (3) FTY720, (4) cortisol, and (5) control: sodium chloride. Drugs were applied intravenously at SAP induction; 6 hours later, rats were killed. Interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor α, platelet-activating factor, amylase, and lipase were measured in serum and myeloperoxidase tissue activity in pancreas, kidney, lung, liver, and spleen. Edema, inflammation, and necrosis were histologically determined in pancreas. CD4/CD8 immunohistochemistry was performed.. Inflammation was ameliorated in all 4 treated groups. Necrosis development was suppressed by FTY720, FTY720 + rapamycin, and cortisol. IL-6 and IL-10 were significantly lower in these groups. Amylase was higher in all treatment groups compared to the controls except for the cortisol group. Tumor necrosis factor α, lipase, and myeloperoxidase activity were not affected by therapy. CD4+/CD8+ cells were significantly less in FTY720-treated pancreata.. Rapamycin and FTY720 ameliorated the severity of SAP, which may be due to early suppression of helper T cells. FTY720 reduced the development of pancreatic necrosis. The combination of both immunosuppressants did not show advantage to treatment with FTY720 alone.

Topics: Acute Disease; Amylases; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Fingolimod Hydrochloride; Hydrocortisone; Immunosuppressive Agents; Interleukin-10; Interleukin-6; Pancreas; Pancreatitis; Propylene Glycols; Rats; Rats, Wistar; Sirolimus; Sphingosine; T-Lymphocytes; Taurocholic Acid

The discovery of novel and effective treatment methods would be of great help to patients with acute pancreatitis. The aims of this study were to determine the inhibitory effects of vitamin K3 (VK3) against cerulein-induced acute pancreatitis in mice and to examine the mechanisms behind these effects.. Acute pancreatitis in mice was induced by intraperitoneal injection of cerulein 6 times at hourly intervals. Vitamin K3 was administered once before the first injection of cerulein or twice before and after the first injection of cerulein. The degrees of inflammation and autophagy in the pancreatic tissue were estimated by histological examination, measurement of enzyme activity, confocal microscopy, and Western blotting. The inhibitory effects of VK3 against rapamycin-induced autophagy were also examined using HeLa cells stably expressing green fluorescent protein LC3.. Cerulein-induced acute pancreatitis was markedly attenuated by the administration of VK3. In addition, VK3 led to the inhibition of cerulein-evoked autophagic changes and colocalization of autophagosomes and lysosomes in the pancreatic tissue. Vitamin K3 also reduced rapamycin-induced autophagy in HeLa/green fluorescent protein LC3 cells.. Our data suggest that the administration of VK3 reduces pancreatic inflammation in acute pancreatitis through inhibition of the autophagic pathway. Vitamin K3 may be an effective therapeutic strategy against acute pancreatitis.

Topics: Acute Disease; Animals; Autophagy; Ceruletide; Female; HeLa Cells; Humans; Lysosomes; Mice; Mice, Inbred C57BL; Pancreatitis; Phagosomes; Sirolimus; Vitamin K 2; Vitamin K 3

Topics: Animals; Cyclosporine; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Duodenitis; Female; Gastritis; Graft Survival; Kidney Transplantation; Male; Pancreatitis; Polyenes; Sirolimus; Time Factors; Transplantation, Homologous