الفهرس 
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Abstract
Chronic pancreatitis (CP) is an inflammatory, progressive disease of the pancreas which leads to the progressive destruction of the pancreatic acinar cells that ultimately leading on to development of pancreatic fibrosis. Which is an irreversible process characterized by irreversible changes in the pancreatic morphology and destruction of the glands leads to eventual loss of exocrine and endocrine functions.
Mesenchymal stem cells (MSCs) could reduce pancreatic inflammation. it was found that infused MSCs reduced acinar cell degeneration, pancreatic edema, and inflammatory cells infiltration and increased expression of Foxp3(+) regulatory T cells.
This study was planned to evaluate the possible targeting of mesenchymal stem cells treatment against chronic pancreatitis induced by L-arginine in rats.
Six-weeks-old male Wistar rats (170 ± 30 g; n = 40) were used. Rats were allocated and randomly divided into four equal groups with 10 rats each to enable differences between treatment to be determined as follow:
Control group: Untreated normal rats.
CP group: Rats were given two intraperitoneal (I.P) injections of L-arginine hydrochloride (250 mg/100 g body mass) in normal saline as 2 repeated doses at 1-hour intervals on days (1, 5, 9, 13, and 17) and the rats were sacrificed after 12 weeks.
BM-MSCs group: Rats received one single dose I.V. into the tail vein with (1×107) cells in 0.2 mL labeled with PKH26 fluorescent linker dye in phosphate buffer saline (PBS) and after 12 weeks the rats were sacrificed.
CP+BM-MSCs group: Following the dosage of L-arginine hydrochloride, rats were treated with one injection as in the BM-MSCs group.
After 12 weeks, at the end of the experiment rats were anaesthetized by I.P. injection of urethane (1.2 g/kg b.w), then sacrificed by cervical decapitation. Blood was collected in non-heparinized tubes to separate serum for the assessment of the biochemical parameters include (CRP), Lipid Profile (TC, HDL, LDL,TG ) , Pancreatic enzymes ( Amylase , Lipase ) and Also pancreatic tissue samples.
The Bone Marrow was extracted from the femurs and tibias of rats 6-weeks-old, then suspended in a culture medium in vitro for preparation of MSCs. the obtained BM-MSCs were labeled with PKH26.
Dissected pancreas tissue specimens of different rat groups were collected and separated into 2 parts each; the first portion was stored at −80 °C for further biochemical analysis (IL-8, TGF-β1), molecular investigations (SMAD 2/3 and p-38 MAPK) and immunoblotting (phosphorylated SMAD 2/3 and phosphorylated p-38 MAPK). The second portion of pancreas tissues were fixed in 10% neutral formalin and processed for histological examination.
The results of the present study illustrated that injection of L-arginine resulted in CP and this was confirmed by the histopathological observations which showed changes in the pancreatic tissue morphology represented by acinar cell atrophy and fibrosis.
The obtained results showed that L-arginine induced pancreatitis was indicated by the higher level of serum pancreatic enzymes (Amylase, Lipase). Treatment with mesenchymal stem cells (MSCs) decreased the pancreatic enzymes levels.
Moreovere, there were significant increase in serum lipid profile (Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), Triglycerides (TG) in the CP group . Treatment with MSCs ameliorated the biochemical disturbances appeared in the lipid profile parameters under investigation.
Additionally, a significant increase in the tissue inflammatory markers Interleukin-8 IL-8, Tissue Growth Factor Beta-1 TGF-β1, with increase in tissue MPO enzyme level and also serum CRP was increased were seen in rats of CP group, in contrast treatments with BM- MSCs caused a significant decline.
Immunoblotting of SMAD 2/3 and p-38 MAPK signaling pathway demostrated that CP group induced markedly significant higher protein expression level of SMAD 2/3 and p-38 MAPK. In contrast treating CP group with BM-MSCs resulted in a significant decrease in SMAD 2/3 and p-38 MAPK protein expression levels.