Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution

2018 ◽  
Vol 132 (6) ◽  
pp. 669-683 ◽  
Author(s):  
Shao-Jung Hsu ◽  
Ming-Hung Tsai ◽  
Ching-Chih Chang ◽  
Yu-Hsin Hsieh ◽  
Hui-Chun Huang ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Treatment Strategies ◽  
Vascular Complications ◽  
Control Group ◽  
No Production ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Window Area

Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague–Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.

Role of thromboxane A2 in early BDL-induced portal hypertension

2003 ◽  
Vol 284 (3) ◽  
pp. G453-G460 ◽  
Author(s):  
Yukihiro Yokoyama ◽  
Hongzhi Xu ◽  
Nicole Kresge ◽  
Steve Keller ◽  
Amir H. Sarmadi ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Bicarbonate Buffer ◽  
Constant Flow Rate ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Cox 2

Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA2 in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B2(TXB2), the stable metabolite of TXA2. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB2 in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 ± 803 vs. 10,210 ± 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB2 release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA2 release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA2 in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA2, which is associated with upregulation of the COX-2 enzyme.

Beneficial effects of combined terlipressin and tetramethylpyrazine administration on portal hypertensive rats

1999 ◽  
Vol 77 (8) ◽  
pp. 618-624 ◽  
Author(s):  
Fang-Chi Chang ◽  
Yi-Tsau Huang ◽  
Han-Chieh Lin ◽  
Chuang-Ye Hong ◽  
Jaung-Geng Lin ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Venous Pressure ◽  
Peripheral Resistance ◽  
Therapeutic Effects ◽  
Portal Vein Ligation ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Beneficial Effects ◽  
Sprague Dawley Rats ◽  
Duct Ligation

The purpose of this study was to investigate the therapeutic effects of terlipressin (TP) alone or in combination with tetramethylpyrazine (TMP) on anesthetized portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL, without cirrhosis) or bile duct ligation (BDL, with cirrhosis) in Sprague-Dawley rats. Each PVL or BDL rat received only one of the two regimens: vehicle for 3 min followed by TP (0.017 mg·kg-1·min-1 for 3 min) or TMP (10 mg·kg-1·min-1 for 3 min) followed by TP. In PVL rats, infusion of vehicle followed by TP induced significant reduction of portal venous pressure (PVP, -15.0 ± 1.0%) and prominent elevation of mean arterial pressure (MAP, 57.3 ± 8.1%) as well as total peripheral resistance (TPR, 113 ± 11%) from baseline, and there was a cardiodepressant response (cardiac index, CI, -26.3 ± 1.1%). Infusion of TMP followed by TP induced significant reduction of PVP (-20.3 ± 0.4%) and CI (-9.9 ± 1.2%) and significant elevation of MAP (31.3 ± 2.5%) and TPR (46.0 ± 4.1%) from baseline. In BDL rats, infusion of vehicle followed by TP also induced significant reduction of PVP (-13.8 ± 1.7%) but an increase in MAP (57.1 ± 2.2%) and TPR (101 ± 6%) from baseline, and there also was a cardiodepressant response (CI, -21.4 ± 2.3%). Infusion of TMP followed by TP induced significant reduction of PVP (-18.9 ± 1.4%) and CI (-11.9 ± 2.1%), but an increase in MAP (36.2 ± 2.5%) and TPR (55.0 ± 5.2%). Compared with vehicle followed by TP, TMP not only significantly enhanced portal hypotensive (PVP reduction) effects of TP but also attenuated the systemic pressor (MAP and TPR elevation) and cardiodepressant (CI reduction) effects of TP in both PVL and BDL rats. Our results suggest that TP, alone or in combination with TMP, induced portal hypotensive effects in two models of portal hypertensive rats. Combination of TP and TMP was beneficial in enhancing portal hypotensive effects of TP and ameliorating the systemic pressor and cardiodepressant effects of TP.Key words: terlipressin, tetramethylpyrazine, cirrhosis, portal hypertension, hemodynamics.

scholarly journals Anti-inflammatory activity of palmitoylethanolamide ameliorates osteoarthritis induced by monosodium iodoacetate in Sprague–Dawley rats

2021 ◽  
Vol 29 (5) ◽  
pp. 1475-1486
Author(s):  
Jae In Jung ◽  
Hyun Sook Lee ◽  
Young Eun Jeon ◽  
So Mi Kim ◽  
Su Hee Hong ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Acid Amide ◽  
Treatment Strategies ◽  
Leukotriene B4 ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Monosodium Iodoacetate ◽  
Anti Inflammatory

AbstractNovel treatment strategies are urgently required for osteoarthritis (OA). Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide with analgesic and anti-inflammatory effects. We aimed to examine its effect on OA and elucidate the molecular mechanism of actions in monosodium iodoacetate (MIA)-induced OA Sprague–Dawley rats. The experimental animals were divided into normal control group (injected with saline + treated with phosphate-buffered saline (PBS), NOR), control group (injected with MIA + treated with PBS, CON), 50 or 100 mg/kg body weight (BW)/day PEA-treated group (injected with MIA + treated with 50 or 100 mg of PEA/kg BW/day, PEA50 or PEA100), and positive control group (injected with MIA + treated with 6 mg of diclofenac/kg BW/day, DiC). The changes in blood parameters, body parameters, gene expression of inflammatory mediators and cytokines, knee thickness, and joint tissue were observed. Oral administration of PEA had no adverse effects on the BW, liver, or kidneys. PEA reduced knee joint swelling and cartilage degradation in MIA-induced OA rats. The serum levels of leukotriene B4, nitric oxide, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and prostaglandin E2 considerably reduced in the PEA100 group compared with those in the CON group. In the synovia of knee joints, the mRNA expression of iNOS, 5-Lox, Cox-2, Il-1β, Tnf-α, and Mmp-2, -3, -9, and -13 apparently increased with MIA administration. Meanwhile, Timp-1 mRNA expression apparently decreased in the CON group but increased to the normal level with PEA treatment. Thus, PEA can be an effective therapeutic agent for OA.

scholarly journals The Effects of L-Arginine on Liver Damage in Experimental Acute Cholestasis an Immunohistochemical Study

HPB Surgery ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Yucel Ozsoy ◽  
Mustafa Ozsoy ◽  
Teoman Coskun ◽  
Kemal Namlı ◽  
Ahmet Var ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Damage ◽  
Biliary Obstruction ◽  
Hepatic Tissue ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
And Control ◽  
Acute Cholestasis

Obstructive jaundice damages critical functions in the liver. Nitric oxide modulation would influence liver damage induced by biliary obstruction, and little is known about it Acute cholestasis was induced by bile duct ligation (BDL) in two groups of male Sprague-Dawley rats. L-Arginine or serum physiologic was administered to treatment and control group. Histopathological and immunohistochemical iNOS expression was investigated in hepatic tissue. Plasma enzyme activities were increased in acute cholestasis, and that L-arginine treatment partially but significantly prevented the elevation of these markers of liver damage (P< .05). Also histopathology scoring showed that the liver injury was prevented and immunohistochemical iNOS activity was increased significantly in L-arginine group (P< .05). This study shows that, after 7 days of biliary obstruction, liver damage is well established and exogenous L-arginine treatment partially but significantly prevented the liver injury in acute cholestasis.

scholarly journals Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats

2021 ◽  
Vol 22 (14) ◽  
pp. 7662
Author(s):  
Chon Kit Pun ◽  
Hui-Chun Huang ◽  
Ching-Chih Chang ◽  
Chiao-Lin Chuang ◽  
Chun-Hsien Yen ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Statistical Significance ◽  
Portal Pressure ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Duct Ligation ◽  
The Impact

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.

Motor Recovery after Chronic Spinal Cord Transection in Rats: A Proof-of-Concept Study Evaluating a Combined Strategy

2019 ◽  
Vol 18 (1) ◽  
pp. 52-62 ◽  
Author(s):  
Antonio Ibarra ◽  
Erika Mendieta-Arbesú ◽  
Paola Suarez-Meade ◽  
Elisa García-Vences ◽  
Susana Martiñón ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Motor Recovery ◽  
Neural Regeneration ◽  
Histological Evaluation ◽  
Control Group ◽  
Proof Of Concept ◽  
Sprague Dawley ◽  
Concept Study

Background: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). Methods: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. Results: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. Conclusion: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

scholarly journals Skeletal Muscle Metabolomic Responses to Endurance and Resistance Training in Rats under Chronic Unpredictable Mild Stress

2021 ◽  
Vol 18 (4) ◽  
pp. 1645
Author(s):  
Xiangyu Liu ◽  
Xiong Xue ◽  
Junsheng Tian ◽  
Xuemei Qin ◽  
Shi Zhou ◽  
...  
Keyword(s):  
Resistance Exercise ◽  
Endurance Exercise ◽  
Field Tests ◽  
Treadmill Running ◽  
Control Group ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Sprague Dawley ◽  
Exercise Interventions ◽  
Sprague Dawley Rats

The objectives of this study were to compare the antidepressant effects between endurance and resistance exercise for optimizing interventions and examine the metabolomic changes in different types of skeletal muscles in response to the exercise, using a rat model of chronic unpredictable mild stress (CUMS)-induced depression. There were 32 male Sprague-Dawley rats randomly divided into a control group (C) and 3 experimental groups: CUMS control (D), endurance exercise (E), and resistance exercise (R). Group E underwent 30 min treadmill running, and group R performed 8 rounds of ladder climbing, 5 sessions per week for 4 weeks. Body weight, sucrose preference, and open field tests were performed pre and post the intervention period for changes in depressant symptoms, and the gastrocnemius and soleus muscles were sampled after the intervention for metabolomic analysis using the 1H-NMR technique. The results showed that both types of exercise effectively improved the depression-like symptoms, and the endurance exercise appeared to have a better effect. The levels of 10 metabolites from the gastrocnemius and 13 metabolites from the soleus of group D were found to be significantly different from that of group C, and both types of exercise had a callback effect on these metabolites, indicating that a number of metabolic pathways were involved in the depression and responded to the exercise interventions.

Ranitidine as an alcohol dehydrogenase inhibitor in acute methanol toxicity in rats

2009 ◽  
Vol 29 (2) ◽  
pp. 93-101 ◽  
Author(s):  
Amal A El-Bakary ◽  
Sahar A El-Dakrory ◽  
Sohayla M Attalla ◽  
Nawal A Hasanein ◽  
Hala A Malek
Keyword(s):  
Alcohol Dehydrogenase ◽  
High Performance ◽  
Negative Control Group ◽  
Positive Control ◽  
Negative Control ◽  
Control Group ◽  
Sprague Dawley ◽  
Blood Samples ◽  
Methanol Poisoning ◽  
Sprague Dawley Rats

Methanol poisoning is a hazardous intoxication characterized by visual impairment and formic acidemia. The therapy for methanol poisoning is alcohol dehydrogenase (ADH) inhibitors to prevent formate accumulation. Ranitidine has been considered to be an inhibitor of both gastric alcohol and hepatic aldehyde dehydrogenase enzymes. This study aimed at testing ranitidine as an antidote for methanol acute toxicity and comparing it with ethanol and 4-methyl pyrazole (4-MP). This study was conducted on 48 Sprague-Dawley rats, divided into 6 groups, with 8 rats in each group (one negative control group [C1], two positive control groups [C2, C3] and three test groups [1, 2 and 3]). C2, C3 and all test groups were exposed to nitrous oxide by inhalation, then, C3 group was given methanol (3 g/kg orally). The three test groups 1, 2 and 3 were given ethanol (0.5 g/kg orally), 4-MP (15 mg/kg intraperitoneally) and ranitidine (30 mg/kg intraperitoneally), respectively, 4 hours after giving methanol. Rats were sacrificed and heparinized, cardiac blood samples were collected for blood pH and bicarbonate. Non-heparinized blood samples were collected for formate levels by high performance liquid chromatography. Eye balls were enucleated for histological examination of the retina. Ranitidine corrected metabolic acidosis (p = .025), decreased formate levels (p = .014) and improved the histological findings in the retina induced by acute methanol toxicity.

Mineralocorticoid Receptor Activation by Aldosterone or Corticosterone Induces Hypertension, Myocardial Infarction and Proteinuria

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 723-723
Author(s):  
Qing-Feng Tao ◽  
Diego Martinez vasquez ◽  
Ricardo Rocha ◽  
Gordon H Williams ◽  
Gail K Adler
Keyword(s):  
Myocardial Infarction ◽  
Drinking Water ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Weight Ratio ◽  
Myocardial Necrosis ◽  
Receptor Activation ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

P165 Aldosterone through its interaction with the mineralocorticoid receptor (MR) plays a critical role in the development of hypertension and cardiovascular injury (CVI). Normally, MR is protected by 11β-hydroxysteroid dehydrogenase (11β-HSD) which inactivates glucocorticoids preventing their binding to MR. We hypothesis that if activation of MR by either aldosterone or glucocorticoids induces hypertension and CVI, then the inhibition of 11β-HSD with glycyrrhizin (GA), a natural inhibitor of 11β-HSD, should induce damage similar to that observed with aldosterone. Sprague-Dawley rats were uninephrectomized, and treated for 4 weeks with 1% NaCl (in drinking water) for the control group, 1% NaCl + aldosterone infusion (0.75 μg/h), or 1% NaCl + GA (3.5 g/l in drinking water). After 4 weeks, aldosterone and GA caused significant increases in blood pressure compared to control rats ([mean ± SEM] 211± 9, 205 ± 12, 120 ± 9 mmHg, respectively, p<0.001). Both aldosterone- and GA-treated rats had a significant increase in proteinuria (152.2 ± 8.7 and 107.7 ± 19.5 mg/d, respectively) versus controls (51.2 ± 9.5 mg/d). There was a significant increase (p<0.001) in heart to body weight ratio in the rats treated with aldosterone or GA compared with control (3.92 ± 0.10, 3.98 ± 0.88, and 3.24 ± 0.92 mg/g, respectively). Hearts of GA and aldosterone treated rats showed similar histological changes consisting of biventricular myocardial necrosis and fibrinoid necrosis of small coronary arteries and arterioles. These data suggests that in rodents activation of MR by either aldosterone or corticosterone leads to severe hypertension, vascular injury, proteinuria and myocardial infarction. Thus, 11β-HSD plays an important role in protecting the organism from injury.

scholarly journals Synergistic suppression of pre-perfusion of donor livers with recipient serum and cobra venom factor treatment on hyperacute rejection following liver xenotransplantation

2012 ◽  
Vol 27 (5) ◽  
pp. 301-305 ◽  
Author(s):  
Baohua Zhu ◽  
Chuanming Tong ◽  
Weitao Guo ◽  
Rong Pu ◽  
Guoping Zhang ◽  
...  
Keyword(s):  
Survival Time ◽  
Hyperacute Rejection ◽  
Cobra Venom ◽  
Control Group ◽  
Sprague Dawley ◽  
Donor Liver ◽  
Cobra Venom Factor ◽  
Sd Rats ◽  
Sprague Dawley Rats ◽  
And Control

PURPOSE: To investigate synergistic suppression of donor liver pre-perfusion with recipient serum (RS) and cobra venom factor (CVF) treatment on hyperacute rejection (HAR) following liver xenotransplantation. METHODS: Guinea-pigs (GP, n=24) and Sprague-Dawley rats (SD, n=24) were recruited. Before transplantation, serum was collected from SD rats and used for preparation of inactivated complements. GP and SD rats were randomly assigned into four groups (n=6), respectively: RS group, CVF group, RS+CVF group and control group. Orthotopic liver xenotransplantation was performed with modified two-cuff technique. The survival time and liver function of recipients, morphological and pathological changes in rat livers were investigated. RESULTS: There was no piebald like change in the recipient livers in all experiment groups. The survival time of recipients in all experiment groups was longer than that in control group (p<0.05). Moreover, the survival time in the RS+CVF group was markedly longer than that in the RS group (p<0.01) and CVF group (p<0.05). The serum ALT level in all experiment groups were lower than that in the control group (p<0.05). Furthermore, the ALT level in the RS+CVF group was significantly lower than that in the CVF group (p<0.05) and RS group (p<0.01). The histological damages were significantly improved when compared with the control group, and the histological damages in the RS+CVF group were milder than those in the remaining groups (p<0.05) CONCLUSION: Pre-perfusion of donor liver with recipient serum and cobra venom factor treatment can exert synergistic suppressive effects on the hyperacute rejection following liver xenotransplantation.

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