Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Mar 13, 2020; 11(1): 1-19
Published online Mar 13, 2020. doi: 10.4291/wjgp.v11.i1.1
Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats
Slaven Gojkovic, Ivan Krezic, Borna Vrdoljak, Dominik Malekinusic, Ivan Barisic, Andreja Petrovic, Katarina Horvat Pavlov, Marijan Kolovrat, Antonija Duzel, Mario Knezevic, Katarina Kasnik Kovac, Domagoj Drmic, Lovorka Batelja Vuletic, Antonio Kokot, Alenka Boban Blagaic, Sven Seiwerth, Predrag Sikiric
Slaven Gojkovic, Ivan Krezic, Borna Vrdoljak, Dominik Malekinusic, Ivan Barisic, Andreja Petrovic, Katarina Horvat Pavlov, Marijan Kolovrat, Antonija Duzel, Mario Knezevic, Katarina Kasnik Kovac, Domagoj Drmic, Lovorka Batelja Vuletic, Antonio Kokot, Alenka Boban Blagaic, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
Author contributions: Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S and Sikiric P performed experiments; Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S and Sikiric P analysed data; Seiwerth S and Sikiric P contributed reagents and analytic tools; Gojkovic S, Drmic D, Seiwerth S and Sikiric P wrote the manuscript.
Institutional review board statement: The study was reviewed and approved by the Department of Veterinary, Ministry of Agriculture, Republic of Croatia, No: UP/I 322-01/07-01/210.
Institutional animal care and use committee statement: Male Albino Wistar, body weight 200 g, 12 weeks old, randomly assigned, used in all of the experiments, 6 rats/group/interval, approved by local Ethic Committee.
Conflict-of-interest statement: The authors state that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Predrag Sikiric, MD, PhD, Professor, Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, POB 916, Zagreb 10000, Croatia. sikiric@mef.hr
Received: October 7, 2019
Peer-review started: October 7, 2019
First decision: November 27, 2019
Revised: December 20, 2019
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: March 13, 2020
Processing time: 157 Days and 14 Hours
ARTICLE HIGHLIGHTS
Research background

Resolving the Budd-Chiari syndrome (BCS) in rats follows the evidence that pentadecapeptide BPC 157 therapy alleviated various vascular occlusion disturbances. Rapid activation of a bypassing loop rescues rats with inferior vena cava infrarenal ligation, relieving a Virchow's triad situation, much like in rats with ischemic/reperfusion colitis, duodenal venous congestion lesions, perforated cecum, bile duct ligation induced liver cirrhosis and portal hypertension. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut-brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing.

Research motivation

Against these obstructions, BPC 157 therapy rapidly activates an azygos/hemiazygos vein bypassing pathway, upgrading an inadequate rescuing inferior-superior vena cava shunt to an adequate one, as well as a portocaval shunt. With BCS in rats, both caval and portal hypertension, and aortal hypertension occurred and were largely eliminated by BPC 157 therapy. Likewise, BPC 157 therapy was shown in counteracting rapid clot formation in the portal vein, superior mesenteric vein, splenic vein, inferior vena cava, hepatic artery, and coronary artery, as well as peaked P waves, significant ST-elevation, tachycardia, gross organ lesions, and liver and spleen weight increases.

Research objectives

Occluding the inferior vena cava cranially to the hepatic veins, regardless of some limitations, was used for the Budd–Chiari syndrome and its manifestation in rat. To make the even more severe circumstances, with the complete occlusion of the suprahepatic inferior caval vein, Budd–Chiari syndrome has abrupt disturbances initiation. Thereby, BPC 157 rapid effect with the organized bypassing of the occlusion and Budd–Chiari syndrome manifestation reversal, may provide pharmacotherapy treatment in the rat BCS.

Research methods

In rats with occluded suprahepatic inferior caval vein, we assessed the activated bypassing pathways (inferior/superior caval veins; portocaval shunt), counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion), hepatomegaly and splenomegaly. Medication (at 1 min, 15 min, 24 h, or 48 h) ligation time consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Furthermore, levels of nitric oxide (NO), malondialdehyde (MDA) in the liver and serum enzymes were determined.

Research results

The bypassing pathways (the inferior vena cava-azygos (hemiazygos) vein-superior vena cava; portocaval shunt) occurred rapidly. BPC 157 antagonized portal/caval hypertension (caval ˃ portal hypertension), and aortal hypotension, refractory ascites and thrombosis (portal vein tributaries, inferior vena cava, hepatic and coronary arteries), pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), increased liver and spleen weight serum and enzymes values, NO- and MDA-levels in the liver. BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion.

Research conclusions

Particular reversal of the regular threatening course otherwise arising in the rats with the occluded suprahepatic inferior caval vein. With application of the stable gastric pentadecapeptide BPC 157, we raised new hypothesis about rapid bypassing of the suprahepatic inferior caval vein occlusion in the BCS in rats, and mitigating its manifestations, along with the active and effective pharmacotherapy treatment. The beneficial BPC 157 effects, noted in the present study, may together counteract a downward spiral in rats with BCS, in acute states, much as in prolonged ischemia. In BCS research, rats studies used occluding the inferior vena cava cranially to the hepatic veins, but bypassing of the occlusion in the rat BCS along with pharmacotherapy treatment was not considered. BPC 157 therapy significance results with the rapidly activated azygos/hemiazygos vein bypassing pathway, upgrading an inadequate rescuing inferior-superior vena cava shunt to an adequate one, as well as a portocaval shunt. Consequently, the BCS-rats presented both caval and portal hypertension, and aortal hypertension, largely eliminated by BPC 157 therapy. Largely attenuated consequent disturbances (rapid clot formation in the portal vein, superior mesenteric vein, splenic vein, inferior vena cava, hepatic artery, and coronary artery, as well as peaked P waves, significant ST-elevation, tachycardia, gross organ lesions, and liver and spleen weight increases) all together support this contention. We used gross (USB camera) and microscopic observations, venography, blood pressure and electrocardiogram assessment, bilirubin and enzyme activity, levels of NO, MDA in the liver and serum enzymes assessment. As combined methods, they are together new methods to determine description of the Budd Chiari syndrome in rats, and the significance of the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion), hepatomegaly and splenomegaly. We should emphasize the rapidly activated azygos/hemiazygos vein bypassing pathway presented as an adequate rescuing inferior-superior vena cava shunt along with a portocaval shunt, both caval and portal hypertension, and aortal hypertension largely eliminated. As mentioned above, largely attenuated consequent disturbances (rapid clot formation in the portal vein, superior mesenteric vein, splenic vein, inferior vena cava, hepatic artery, and coronary artery, as well as peaked P waves, significant ST-elevation, tachycardia, gross organ lesions, and liver and spleen weight increases) all together support this contention. Recently, as a possible therapy resolving solution for Budd Chiari syndrome in rats, pentadecapeptide BPC 157 therapy has been used in alleviating vascular occlusion disturbances. Rapid activation of a bypassing loop occurs in rats with an infrarenal ligation of the inferior vena cava, relieving a Virchow's triad situation, much like in rats with ischemic/reperfusion colitis, duodenal venous congestion lesions, perforated cecum, bile duct ligation induced liver cirrhosis and portal hypertension. BPC 157 therapy (intragastric or abdominal bath, 10 µg/kg and 10 ng/kg dosages), using a previously described protocol, could alleviate suprahepatic occlusion of the inferior caval vein, as model of the BCS in rats, activating bypassing pathways. BPC 157 likely counteracted Virchow's triad, as it did in rats with infrarenal inferior vena cava occlusion. A particular effect on portal hypertension disturbances, by activation of bypassing pathways, might be envisaged that needs further elaboration.

Research perspectives

The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval/portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension. Large extent of the consequent disturbances may verify the significance of the Budd Chiari syndrome in rats for the corresponding human condition. Likewise, the largely attenuated disturbances may indicate that the beneficial BPC 157 effects, noted in the present study, may likely counteract a downward spiral in the rats with the suprahepatic inferior caval vein ligation much like in the patients with BCS, as in prolonged ischemia. To further establish the proposed therapy solution for Budd Chiari syndrome, we continue research in this issue. Gross (USB camera) and microscopic observations, venography, blood pressure and electrocardiogram assessment, bilirubin and enzyme activity, levels of NO, MDA in the liver and serum enzymes as combined methods are best methods to determine description of the Budd Chiari syndrome in rats.