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FTY720 ATTENUATES ACUTE PANCREATITIS IN HYPERTRIGLYCERIDEMIC APOLIPOPROTEIN CIII TRANSGENIC MICE Jinjiao Liu,* Pengfei Xu,* Ling Zhang,* Abudurexiti Kayoumu,* Yunan Wang,* Mengyu Wang,* Mingming Gao,* Xiaohong Zhang,† Yuhui Wang,* and George Liu* *Key Laboratory of Molecular Cardiovascular Science Ministry of Education, Institute of Cardiovascular Science, Peking University; and † Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China Received 19 Apr 2015; first review completed 22 Apr 2015; accepted in final form 28 Apr 2015 ABSTRACT—Hypertriglyceridemic pancreatitis (HTGP) is often encountered clinically as a common form of recurrent acute pancreatitis (AP). It is important to evaluate the management of severe hypertriglyceridemia (HTG) or anti-inflammation in the prophylaxis of HTGP in the clinic. FTY720 (2-amino-2[2-(4-octylphenyl) ethyl]-1, 3-propanediol) is a new anti-inflammatory agent with low toxicity and reported to ameliorate lung injury with pancreatitis in rat. We evaluated its protective affection on AP induced by seven hourly intraperitoneal injection of cerulein in apolipoprotein CIII transgenic mice with severe HTG. FTY720 at 1.5 mg/kg was administered by gastric lavage daily for 3 days before induction of AP. The effects of FTY720 to protect against HTGP were assessed by serum amylase, pancreatic pathological scores, immunostaining, and the expression of inflammatory cytokine genes. As a result, injection of cerulein resulted in more severe pathological changes of AP and higher monocyte chemoattractant protein 1 expression in the pancreas in transgenic than in nontransgenic mice. FTY720 pretreatment improved the pathological severity of AP and decreased the expression of monocyte chemoattractant protein 1 in the pancreas significantly, especially near fourfold reduction in transgenic mice. However, FTY720 did not affect plasma triglyceride levels, and other inflammatory factors and plasma amylase were not correlated with the extent of pancreatic damage in AP with or without FTY720 administration. In summary, our study in a new model, apolipoprotein CIII transgenic mice, demonstrated that HTG mice are susceptible to induction of AP. Prophylactic treatment of FTY720 can significantly attenuate cerulein-induced AP and hence warrant further investigation of sphingosine-1-phosphate receptors agonist for potential clinical application in recurrent attacks of HTGP. KEYWORDS—Hypertriglyceridemic pancreatitis, ApoCIII transgenic mice, cerulein, FTY720, MCP-1

! (TNF-!), interleukin 6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1), and so on, which have been shown elevated in the plasma of AP patients (4Y6). Endothelial cells, immunocytes (granulocytes, monocytes/macrophages, lymphocytes) and neutrophils are involved in the inflammatory reaction during the course of HTGP (7). In consideration of the inflammation being key events in AP, anti-inflammation may be able to reduce the susceptibility and severity of HTGP. A prototype of sphingosine-1-phosphate (S1P) modulator FTY720 (2-amino-2[2-(4-octylphenyl) ethyl]-1, 3propanediol) effectively reduces the number of lymphocytes and the concentrations of the proinflammatory cytokines, such as interferon +, TNF-!, IL-6, IL-12, and RANTES, in blood. Previous report showed FTY720 had significantly decreased pulmonary inflammation and pancreas injury by reducing inflammatory factors in rat taurocholate-induced AP model (8). However, whether FTY720 is also valid in prevention of HTGP is still unknown. Because the level of TG fluctuates in different condition, it is difficult to make a diagnosis of HTGP clinically. In fact, the direct association of HTG and AP was confirmed by some experiments in animal models (3, 9). Our group had used LPL knockout mice in HTGP study (3), but these mice were too difficult to breed because homozygous pups died within 48 h after birth (10). Apolipoprotein CIII is a natural inhibitor of LPL, and many clinical reports showed that HTG is associated with high ApoCIII level in patients_ plasma (11). Apolipoprotein CIII transgenic mice also have severe HTG but survive well through adulthood (12). Recent studies suggested that high ApoCIII directly provoke proinflammatory responses in vascular cells,

INTRODUCTION Acute pancreatitis (AP) is a clinically severe disorder characterized by acute inflammation in response to the pancreas self-digestion and the digestion of surrounding tissues caused by leakage of tryptic enzyme. Acute pancreatitis has a high mortality rate even in current clinical practice (1). Many epidemiological and laboratory studies had proven that severe hypertriglyceridemia (HTG), which means triglycerides (TGs) of 1,000 mg/dL or greater, is a well-established cause of AP and generally associated with recurrent attacks and distant organ damage (2, 3). As a consequence, it is more important to prevent from than to treat abdominal pain and the damage of organs after attack of HTGP for these severe HTG patients. The severe HTG can be caused by the mutations of lipoprotein lipase (LPL), apolipoprotein CII, apolipoprotein CIII (ApoCIII), apolipoprotein AV, lipase mature factor, and glycosylphosphatidylinositol highdensity lipoprotein-binding protein 1 primarily and secondarily by diabetes, obesity, or many drugs. It is widely accepted that the underling mechanisms in the progression of hypertriglyceridemic pancreatitis (HTGP) are upregulation of inflammatory factors, including tumor necrosis factor Address reprint requests to Yuhui Wang, PhD, Key Laboratory of Molecular Cardiovascular Science Ministry of Education; Institute of Cardiovascular Science, Peking University, No 38, Xueyuan Road, Haidian District, Beijing, 100191, China. E-mail: [email protected]. Supported by the National Nature Science Foundation, No. 30971102; National Nature Science Foundation for Young Scientists, No. 81300228. DOI: 10.1097/SHK.0000000000000400 Copyright Ó 2015 by the Shock Society

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including monocyte and endothelial cell (13). Apolipoprotein CIII is also involved in pancreatic "-cell biology and is attributed to diabetes (14). Therefore, in this experiment, we determine whether FTY720 can inhibit inflammatory response and attenuate pathological changes during cerulein-induced HTGP onset by a new HTG model, ApoCIII transgenic mice model. MATERIALS AND METHODS Animals Human ApoCIII transgenic mice in C57BL/6J background were obtained from JAX Mice Services (strain name: B6; CBA-Tg [APOC3]3707Bres/J; stock no. 006907), through a Chinese agent (Vital River Laboratories, Beijing, China). Female mice aged 10 weeks were used in this study. All mice were housed in an SPF standard room under 12-h/12-h light-dark cycle and received water and chow diet ad libitum. The BPrinciples of Laboratory Animal Care[ (NIH publication 85-23, revised 1996) was followed, and animal care and experimental procedures were performed according to the regulations of Peking University_s animal care committee (LA2010-061). In order to find out an appropriate dose of FTY720 for this study, female C57BL/6J mice were divided into three groups for gastric lavage with water (as control) and FTY720 (synthesized in Institute of Materia Medica, Chinese Academy of Medical Sciences) at 1.5 mg/kg or 3.0 mg/kg body weight. There were six mice in each group, and they received gastric lavage once every day for three times. We counted the number of white blood cells (WBCs), lymphocytes, and their ratios to monitor the effects of FTY720. We also quantified the weights of the spleen tissues respectively of each group with different FTY720 doses. In subsequent experiments, FTY720 1.5 mg/kg body weight was chosen once a day for 3 days before induction of AP by seven hourly intraperitoneal injection of cerulein at 50 2g/kg body weight. The anticoagulated whole blood was collected at 0, 6, 12, and 24 h after the first injection for blood cells counting, amylase analysis, and inflammatory cytokines_ determination. Their pancreatic tissues were collected at 24 h for further pathological analysis and RNA extraction.

Plasma lipid assay Blood was obtained after 4 h of fasting by puncture of the retro-orbital plexus at the beginning of the experiment. Total cholesterol (TC) and TG in plasma were determined enzymatically using commercial kits (Biosino Biotechnology and Science Inc, Changping District, Beijing, China).

Quantification of inflammatory cytokine serum levels Serum level of MCP-1 was evaluated by BDi Cytometric Bead Array (CBA), Mouse Inflammation Kit (BD Biosciences, San Jose, USA). During the assay procedure, the chemokine capture beads are mixed with the recombinant standards and unknown samples and incubated with the PE-conjugated detection antibodies to form sandwich complexes. The intensity of PE fluorescence of each sandwich complex reveals the concentration of that cytokine. The samples were analyzed by flow cytometer BD FACS Calibur (BD Biosciences, San Jose, USA) and FCAP Array software BD CellQuest (BD Biosciences, San Jose, USA).

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Beijing China). A total of 100 WBCs were counted, and the lymphocytes were identified by the morphologic characteristics for calculation of percentage.

Pathological observation and evaluation of pancreatic tissues Cerulein-induced mice with AP were killed 24 h after induction, and pancreatic tissues were fixed in buffered formalin and embedded in paraffin. The scoring standards used for evaluation of pancreatitis were described previously (3) as in Table 1. Paraffin-burred mice pancreata were sectioned at 3 2m and stained with Carazzi hematoxylin-eosin (HE). Two investigators blinded to experimental treatment scored the degree of pancreatic injury by light microscope, evaluating severity of edema, inflammation, hemorrhage, necrosis, and vacuolization as the standards in Table 1.

Immunostaining For immunohistochemistry, the sections were exposed to methanol. Sections were probed with MAC-2(1:200 rabbit polyclonal IgG; Santa Cruz Biotechnology, Santa Cruz, Calif) for macrophages. The sections were then incubated with appropriate biotinylated secondary antibodies (1:200, ABC Vectastain; Vector Laboratories, Burlingame, Calif) in 2% normal blocking serum and visualized using 3, 3¶-diaminobenzidine (DAB, Vectastain; Vector Laboratories).

RNA isolation and reverse transcriptaseYpolymerase chain reaction Total RNA was isolated from 50 mg pancreatic tissues by 2 mL extracted regent (Dingguo Biotechnology Limited Company, Beijing, China) and subjected to reverse transcription using Super Script II RT (Invitrogen, Carlsbad, Calif). The expressions of inflammatory cytokines were quantified by real-time polymerase chain reaction (PCR) with SYBR Green (Invitrogen). For each sample, duplicate test reactions were analyzed, and results were normalized to their 18S mRNA. The primers are as the follows: MCP-1: Sense:5¶-AGATGCAGTTAACGCCCCAC-3¶ Antisense: 5¶-GACCCATTCCTTCTTGGGGT-3¶ TNF-!: Sense: 5¶-CTGTGAAGG GAATGGGTGTT-3¶ Antisense: 5¶-CAGGGAAGAATCTGGAAAGGTC-3¶ IL-6: Sense: 5¶-TTCTTGGGACTGATGCTG-3¶ Antisense: 5¶-CTGGCTTTGTCTTTCTTGTT-3¶ IL-1": Sense: 5¶-AGGCTCCGAGATGAACAA-3¶ Antisense: 5¶-AAGGCATTAGAAACAGTCC-3¶ IL-10: Sense: 5¶-ACCTGGTAGAAGTGATGC-3¶ Antisense: 5¶-AAGGAGTTGTTTCCGTTA-3¶ Transforming growth factor "1 (TGF-"1): Sense: 5¶-GGCGGTGCTCGCTTTGTA-3¶ Antisense: 5¶-TCCCGAATGTCTGACGTATTGA-3¶ 18S: Sense: 5¶-GGAAGTGCACCACCAGGAGT-3¶ Antisense: 5¶-TGCAGCCCCGGACATCTAAG-3¶ Relative expression units of each sample were calculated by division of expression of the sample by average mRNA expression of control group.

WBC counting

Statistical analysis

For total WBC counting, 20 2L heparin anticoagulated blood samples were mixed with 380 2L 3% glacial acetic acid, and the number of WBCs in 10 2L was counted in counting pool. Then, peripheral blood smears were stained with Wright_s staining reagent (Beijing Tianlai Biotechnology Inc, Fengtai District,

All values in the figures and text are expressed as mean T SEM of n observation, and n represents the number of animals studied. The data of biochemistry measurements were analyzed in 1-way analysis of variance and the Student-Newman-Keuls test by SPSS software. In the histological evaluation,

TABLE 1. The standards for quantitative estimation of the morphological degrees of pancreatic injury Score Edema

1

2

3

4

5

Local interlobular swelling Global lobular swelling Swelling of acinar spaces Swelling of intercellular spaces Island-like acini or cells

Necrosis

G2%

2%Y5%

5%Y10%

10%Y20%

920%

Vacuolization

G1%

1%Y5%

5%Y10%

10%Y20%

920%

Inflammatory infiltration

G5 Cells

5Y10 Cells

10Y20 Cells

20Y30 Cells

930 Cells

The degree of parenchyma necrosis and vacuolization was evaluated as percent area of acinar cell necrosis. Inflammatory infiltration was counted as the average number of inflammatory cells per 10 fields at magnification 400.

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FIG. 1. The effects of FTY720 on blood WBCs and lymphocytes. A, Total blood WBC counting. B, The percentage of lymphocytes in total WBCs. C, The percentage of spleen weight to body weight. There were six wild-type mice in each group and *P G 0.05 or **P G 0.01 compared with control group. Control: control group with same water vehicle as the control of FTY720 administration.

the figures shown are representatives of at least two experiments performed on different experimental days. The results were analyzed by Mann-Whitney rank-sum test, and P G 0.05 was considered to be significant.

FTY720 reduced plasma amylase level in AP in nontransgenic mice but not in ApoCIII transgenic mice and did not decrease TG level.

RESULTS

Plasma amylase level is usually used as indication of pancreatitis severity. Compared with the control group, the amylase activity of FTY720-treated group was significantly reduced after the induction of AP in nontransgenic mice (Fig. 3A). However, although the amylase activity decreased after FTY720 treatment in ApoCIII transgenic mice, there was no significant difference compared with the control group. We also found that the amylase activity had not increased significantly in transgenic mice after induction of AP compared with nontransgenic mice, although there was more severe injury in the pancreas in transgenic mice. Maybe severe HTG would affect the amylase activity in plasma, so that we do not consider that amylase activity is a sensitive biomarker that can represent the severity of HTGP. Also, FTY720 did not ameliorate the level of TC and TG in plasma (Fig. 3B).

FTY720 decreased lymphocytes and inhibited their recirculation

White blood cells differential counting was determined before and after gastric lavage three times to confirm the effect of FTY720 and also spleen weights were checked after FTY720 administration. The results showed that both total leukocytes number and lymphocyte proportion decreased in 1.5 or 3.0 mg/kg body weight group after FTY720 administration (Fig. 1, A and B). Compared with the control group, we observed a weight loss of spleen tissues in both 1.5 and 3.0 mg/kg body weight groups (Fig. 1C). However, there were no specific changes between the two groups. The data above proved that FTY720 had exerted its maximal pharmacological properties through oral administration at 1.5 mg/kg. Therefore, we chose the dose in the following experiments with ApoCIII transgenic mice. FTY720 administration on ApoCIII transgenic mice also resulted similarly in reduced leukocytes numbers as in nontransgenic mice. ApoCIII transgenic mice displayed severe HTG and proinflammatory states

Apolipoprotein CIII transgenic mice had extremely high levels of TG in blood and slightly increased TC. (Fig. 2A). We also observed that ApoCIII transgenic mice were in a high state of inflammation because of more WBCs and a higher level of MCP-1 in blood than in nontransgenic mice (Fig. 2, B and C).

FTY720 attenuated pathological injury of pancreatic tissues

Through HE staining, after cerulein induction, pancreatic tissues display typical changes of AP including edema, infiltration of inflammatory cells, and necrosis in acinar cells. Hypertriglyceridemic pancreatitis in ApoCIII transgenic mice has a higher severity of pathological changes than the AP in nontransgenic mice as the representative photographs (Fig. 4, A and C). In comparison with the control group, the severity of edema, necrosis, and inflammatory infiltration of FTY720-treated group significantly

FIG. 2. Apolipoprotein CIII transgenic mice have severe HTG and proinflammatory state (n = 12). A, The concentration of TC and TGs in plasma. B, Monocyte chemoattractant protein 1 levels in serum of non-‘‘’’TG and ApoCIII-TG. C, Total WBC counting in blood. **P G 0.01 compared with nontransgenic mice. ApoCIII-TG indicates ApoCIII transgenic mice; non-Tg, nontransgenic mice.

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FIG. 3. FTY720 did not affect the level of plasma lipids and the amylase activities in plasma of cerulein treated mice. A, Amylase activities in plasma of cerulein-treated mice. B, The concentration of TC and TGs in plasma before and after FTY720 treatment. Each value is the mean T SEM for n = 6. *P G 0.05 or **P G 0.01 compared with control group. ##P G 0.01 compared with control group before FTY720 treatment. ApoCIII-Tg indicates ApoCIII transgenic mice; non-Tg, nontransgenic mice.

decreased (Fig. 4, B and D). Immunohistochemically (Fig. 4, EYH), macrophage infiltration is more visible in transgenic mice after induction of AP, and FTY720 significantly decreased macrophages in pancreatic tissues in transgenic mice. By quantifying these changes, the total pathological score of ApoCIII transgenic mice is significantly higher than that of nontransgenic mice; moreover, the total scores of FTY720

administration groups significantly deceased compared with control groups both in ApoCIII transgenic mice and nontransgenic mice (Table 2). FTY720 decreased MCP-1 expression in the pancreas

Acute pancreatitis is a kind of acute inflammatory response in the pancreas. We measured the expressions of many inflammatory

FIG. 4. The representative photographs of the pancreatic sections from each group after induction of cerulein. Less injury was observed in the pancreatic sections from the groups with FTY720 administration in both non-Tg and ApoCIII-Tg. AYD, Sections with HE staining, and the photographs below are the amplified part of the box in above photographs. EYH, Immunohistochemical staining with MAC-2 antibody. A and E, Non-Tg control group. B and F, FTY720treated non-Tg group. C and G, ApoCIII-Tg control group. D and H, FTY720-treated ApoCIII-Tg group. ApoCIII-Tg indicates ApoCIII transgenic mice; non-Tg, nontransgenic mice.

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TABLE 2. The pathological scores for pancreatic injury Non-Tg (Ctrl)

Non-Tg (1.5 mg/kg)

ApoCIII-Tg (Control)

ApoCIII-Tg (1.5 mg/kg)

Edema

3.0 T 0.13

2.4 T 0.15*

3.8 T 0.25*

3.0 T 0.13†

Vacuolization

1.9 T 0.24

1.8 T 0.28

2.3 T 0.17

2.0 T 0.43

Necrosis

1.9 T 0.35

1.8 T 0.10

2.8 T 0.17*

2.3 T 0.11†

Inflammatory infiltration

3.1 T 0.15

2.6 T 0.08*

3.8 T 0.25*

2.7 T 0.17†

10.0 T 0.30

8. 7 T 0.17*

12.6 T 0.15*

9.9 T 0.51†

Total

Results are expressed as mean T SE of six mice. *P G 0.05 compared with control group of nontransgenic mice. † P G 0.05 compared with control group of ApoCIII transgenic mice. ApoCIII-Tg indicates ApoCIII transgenic mice; non-Tg, nontransgenic mice.

factors in the pancreas, including IL-6, IL-1", IL-10, TGF-"1, MCP-1, and TNF-!. We found that only MCP-1 was observed significantly increased in ApoCIII transgenic mice compared with nontransgenic mice after induction of AP, and it significantly decreased after FTY720 administration, especially

nearly fourfold reduction of MCP1 mRNA in the pancreas in transgenic mice (Fig. 5). Monocyte chemoattractant protein 1 has been shown to play a crucial role in migration of inflammatory cells, particularly monocytes and neutrophils (15). Therefore, the decrease in pancreatitis scores was not due to the

FIG. 5. Effects of FTY720 on the expressions of pancreatic inflammatory factors in cerulein-induced AP. IL-6, IL-10, IL-1", TGF-"1, TNF-!, and MCP-1 levels of pancreatic mRNA were quantified by real-time PCR and normalized by 18S mRNA levels shown as the mean T SE of six mice. *P G 0.05 compared with control group of non-Tg. #P G 0.05 compared with control group of ApoCIII-Tg. ApoCIII-Tg indicates ApoCIII transgenic mice; non-Tg, nontransgenic mice.

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reduction of plasma TG levels but to the potential antiinflammatory effect of FTY720, and maybe MCP-1 can suggest the severity of HTGP as a biomarker. DISCUSSION In this study, a severe HTG mice model induced by cerulein was used to mimic the HTGP patients, whose TG levels in plasma are usually higher than 1,000 mg/dL. In some previous studies, HTG was induced in animals by high-fat diets or direct LPL inhibition via intravenous administration of the detergent Triton-WR 1339. These manipulations resulted in either transient or mild to moderate HTG, even though more severe pancreatitis did occur upon chemical induction in comparison with non-HTG control animals (9, 16Y18). This is in sharp contrast to clinical situation, in which only severe HTG with plasma TG exceeding 1,000 mg/dL is considered as a risk factor for attack of HTGP (19). Using cerulein as inducing agent, we can show here that susceptibility to pancreatitis increased substantially in these ApoCIII transgenic mice compared with nontransgenic mice, as evidenced by higher pancreatic pathological scores. The cellular and molecular mechanisms underlying HTGP are still poorly understood, although local release of large quantities of free fatty acids had been proposed as a pathogenic mechanism (3, 9, 16, 20). Triglyceride-lowering drug, insulin and/or heparin treatment, apheresis, and dietary interventions are general management for HTGP patients. However, the HTGP patients who are suffering from recurrent attacks and more severe pancreatitis were usually negatively affected by these treatments (21, 22). Above all, with lifestyle changes, more and more HTGP cases (23) suggest that prophylactic measures to avoid AP attacks are more important in the clinic. Hypertriglyceridemic pancreatitis is an inflammatory response with many immunological events in pathogenesis, and then we carried out the current study to confirm the preventive effects of FTY720. FTY720 can be phosphorylated by sphingosine kinase 2 to become a biologically active form FTY720-P, which shares similar molecular structure with naturally occurring molecule S1P. Thus, as an agonist or antagonist of S1P, it is able to imitate the function of binding sphingosin-1-phosphate receptors (S1PRs) (24). Keul et al (25) suggested that S1PR3 mediates the chemotactic effect of S1P in macrophages in vitro and in vivo and plays a causal role in atherosclerosis by promoting inflammatory monocyte/macrophage recruitment and altering smooth muscle cell behavior. Furthermore, FTY720 causes less digestive tract adverse effect and does not induce a generalized immunesuppressed state (26); thus, extensive studies about FTY720_s protective effect on pancreatitis in high-risk conditions, such as HTG, will give us more insights of FTY720_s indications of clinical applications. In this experiment, our results showed proportional decrease of lymphocyte numbers in blood of mice, which was highly consistent with previous studies (27Y29). At the same time, weight loss of the spleen suggested the FTY720_s effect on lymphocyte migration. Here having excluded the reduction of plasma TG level, FTY720 showed the protective and anti-inflammatory effects both in nontransgenic mice and transgenic mice by decreasing pathological scores and expression of MCP-1 in the pancreas, indicating the potential applications of FTY720 in many types of AP.

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In our experiment, pretreatment with FTY720 did not decrease amylase activity in transgenic mice. It is suggested that amylase activity could not indicate the severity of HTGP. Likewise, in clinical settings, amylase activity is also a highly controversial index (30). Interestingly, our data showed that the levels of MCP-1 in the pancreas and plasma were increased in ApoCIII transgenic mice. And after FTY720 treatment, MCP-1 was also the only decreased inflammatory factor in our screening and dramatically decreased in transgenic mice. It is suggested that MCP-1 as an early proinflammatory mediator probably played a more important role in HTGP, and it may have the prospect of serving as a biomarker in HTGP. In fact, MCP-1 is a prototypic inflammatory chemokine, which targets the cells expressing the C-C chemokine receptor. Remarkably, MCP-1 is involved in the recruitment of monocytes/ macrophages from the bloodstream to the tissue (7). It has been demonstrated that MCP-1 implicates the development of acute or chronic inflammation, including pancreatitis, and upregulated MCP-1 expression has been found in AP both in mice and rat models (31, 32). Previously, it was reported that FTY720 attenuated recruitment of macrophages in vascular wall (25). Our results of MAC-2 staining also supported this phenomenon in the pancreas. Macrophage infiltration significantly reduced in transgenic mice after FTY720 treatment. This evidence suggests that in HTGP FTY720 acted as an anti-inflammatory agent, by decreasing the expression of MCP-1 to ameliorate the degree of pancreatic damage. In conclusion, pretreatment with FTY720 can reduce the susceptibility of AP significantly to mitigate injure of HTGP, especially in an animal model of HTGP through inhibition of the proinflammation in HTG, and MCP-1 may be a distinct biomarker in HTGP. ACKNOWLEDGMENTS The authors thank the Institute of Materia Medica, Chinese Academy of Medical Sciences for the FTY720 agent; Yahan Liu, Yuxuan Liu (Peking University) for expertise and equipment; and Guotao Lu (University of Yangzhou) for advice and suggestions on the manuscript.

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FTY720 Attenuates Acute Pancreatitis in Hypertriglyceridemic Apolipoprotein CIII Transgenic Mice.

Hypertriglyceridemic pancreatitis (HTGP) is often encountered clinically as a common form of recurrent acute pancreatitis (AP). It is important to eva...
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