Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2023; 29(27): 4289-4316
Published online Jul 21, 2023. doi: 10.3748/wjg.v29.i27.4289
Stomach perforation-induced general occlusion/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect
Luka Kalogjera, Ivan Krezic, Ivan Maria Smoday, Hrvoje Vranes, Helena Zizek, Haidi Yago, Katarina Oroz, Vlasta Vukovic, Ivana Kavelj, Luka Novosel, Slavica Zubcic, Ivan Barisic, Lidija Beketic Oreskovic, Sanja Strbe, Marko Sever, Ivica Sjekavica, Anita Skrtic, Alenka Boban Blagaic, Sven Seiwerth, Predrag Sikiric
Luka Kalogjera, Ivan Krezic, Ivan Maria Smoday, Hrvoje Vranes, Helena Zizek, Haidi Yago, Katarina Oroz, Vlasta Vukovic, Ivana Kavelj, Luka Novosel, Slavica Zubcic, Ivan Barisic, Sanja Strbe, Marko Sever, Ivica Sjekavica, Alenka Boban Blagaic, Predrag Sikiric, Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
Lidija Beketic Oreskovic, Division of Oncology and Radiotherapy, University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb 10000, Croatia
Anita Skrtic, Sven Seiwerth, Department of Pathology, School of Medicine, Zagreb 10000, Croatia
Author contributions: Kalogjera L and Smoday IM contributed to conceptualization; Zizek H, Vukovic V, and Strbe S contributed to methodology; Sikiric P, Skrtic A, and Seiwerth S contributed to writing-original draft preparation, review, and editing; Boban Blagaic A and Beketic Oreskovic L contributed to visualization; Oroz K, Yago H, and Zubcic S contributed to investigation; Krezic I, Vranes H, and Barisic I contributed to formal analysis; Sjekavica I contributed to resources; Kavelj I, Novosel L, and Sever M contributed to validation.
Institutional animal care and use committee statement: This research was reviewed and approved by the Local Ethic Committee (Approval No. 380-59-10106-17-100/290).
Conflict-of-interest statement: Authors declare no conflict of interest.
Data sharing statement: The data that support the findings of this study are available from the corresponding author, upon reasonable request.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Predrag Sikiric, MD, PhD, Full Professor, Department of Pharmacology, School of Medicine, 11 Salata, Zagreb 10000, Croatia. sikiric@mef.hr
Received: February 19, 2023
Peer-review started: February 19, 2023
First decision: May 23, 2023
Revised: June 1, 2023
Accepted: June 19, 2023
Article in press: June 19, 2023
Published online: July 21, 2023
Processing time: 143 Days and 21.1 Hours
ARTICLE HIGHLIGHTS
Research background

Taking stomach perforation as a prime direct injury regularly used in cytoprotection studies, as a new insight in resolving the full extent of the cytoprotection issue, there is the rapid progression of severe occlusion/occlusion-like syndrome considerably complicating the course following stomach perforation in rats. Otherwise, such occlusion/occlusion-like syndrome may suffer rats with permanent occlusion of the major vessel(s), veins and/or arteries, peripherally and centrally, and rats who underwent similar noxious procedures that all severely affect endothelium function. There were cause-consequence lesions in the brain (intracerebral and intraventricular hemorrhage), heart (congestion), lung (hemorrhage), congestion in the liver, kidney, and gastrointestinal tract, arrhythmias, vessel failure (congested inferior caval and superior mesenteric vein, collapsed azygos vein), and blood pressure disturbances (intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension), and widespread thrombosis, peripherally and centrally.

Research motivation

In occlusion/occlusion-like syndromes, stable gastric pentadecapeptide BPC 157 was recognized as counteracting therapy, and has already presented in recent reviews (Curr Med Chem 2023; 30: 1568-1573; World J Gastroenterol 2022; 28: 23-46). In the rats with perforated stomachs, and subsequent occlusion/occlusion-like syndrome, we emphasized the cytoprotection potential of the stable gastric BPC 157 as native and stable in gastric juice, thought to play the role of cytoprotection mediator maintaining stomach mucosa integrity. As a particular clue recognized also in the counteraction of stomach perforation-induced occlusion/occlusion-like syndromes, there was activation of collateral pathways depending on the injury, locally (raised vessel presentation; less bleeding, defect contraction) and systemically. Accordingly, BPC 157 therapy induced direct blood delivery from the inferior caval vein to the superior caval vein via the azygos vein. Application of the BPC 157 therapy (10 µg/kg and 10 ng/kg) into the perforated defect, induced immediate shrinking and contraction of the whole stomach. Simultaneously, there were attenuated/eliminated intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Thrombosis, peripherally (inferior caval vein, portal vein, abdominal aorta) and centrally (superior sagittal sinus) BPC 157 therapy markedly reduced/annihilated, and the severe lesions in the brain, heart (congestion and arrhythmias), lung (hemorrhage and congestion) and marked congestion in the liver, kidney and gastrointestinal tract markedly reduced. In conclusion, with stomach perforation severe occlusion/occlusion-like syndrome, and rapid progression peripherally and centrally, the rapid counteraction should be by BPC 157 therapy.

Research objectives

The first objective was stomach perforation presentation in rats as severe occlusion/occlusion-like syndrome, peripherally and centrally. The second objective was rapid counteraction by BPC 157 therapy.

Research methods

In deeply anesthetized rats underwent calvariectomy, stomach perforation was performed and rats received BPC 157 therapy or saline into the defect in the stomach. Then, in addition to assessing shrinking and contraction/enlargement of the whole stomach, the assessment (gross and microscopy, volume) was as in the occlusion/occlusion-like studies and included all points regularly analyzed. Assessed were swollen brain, failed peripheral vessels (azygos vein, superior mesenteric vein, portal vein, inferior caval vein) and heart, other organs lesions (i.e., stomach, defect closing or widening); intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension; clots peripherally and centrally; ECGs; and bleeding time from the perforation(s).

Research results

BPC 157 effects accord with the beneficial effect noted before in the healing of the perforated defect (raised vessel presentation; less bleeding, defect contraction) and in the occlusion/occlusion-like syndromes. In rats with perforated stomachs, BPC 157 therapy (10 µg/kg and 10 ng/kg) given into the perforated defect, induced immediate shrinking and contraction of the whole stomach (unlike saline-induced immediate stomach considerable enlargement). There were cause-consequence lesions all eliminated/attenuated by BPC 157 therapy (i.e., direct blood flow delivery via azygos vein). There were eliminated/attenuated lesions in the brain (i.e., swelling, hemorrhage), heart (congestion), lung (hemorrhage), congestion in the liver, kidney, and gastrointestinal tract, arrhythmias, and blood pressure disturbances (intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension). Counteracted was major vessel failure (i.e., reversal of congested inferior caval vein and superior mesenteric vein, collapsed azygos vein), and eliminated widespread thrombosis, peripherally and centrally.

Research conclusions

Stomach perforation occurred as severe occlusion/occlusion-like syndrome, peripherally and centrally. Rapid counteraction was by BPC 157 therapy. Thereby, further BPC 157 therapy may be warranted.

Research perspectives

Stomach perforation as severe occlusion/occlusion-like syndrome needs immediate additional medical attention. There, BPC 157, as a prototype cytoprotective agent, should be also considered as further therapy.