Protective effect of pentadecapeptide BPC 157 on organ damage in abdominal compartment syndrome in a rat model

Abstract

Nedavna istraživanja ukazuju da stabilni želučani pentadekapeptid BPC 157 djeluje protektivno na oštećenja tkiva i organa kod okluzivnih sindroma velikih krvnih žila – bilo da se radi o perifernoj ili centralnoj okluziji na način da aktivira kolateralnu cirkulaciju. U ovom istraživanju po prvi smo puta u svijetu ispitivali utjecaj stabilnog želučanog pentadekapeptida BPC 157 na oštećenje organa u abdominalnom kompartment sindromu na animalnom modelu. Inducirali smo abdominalni komapartment sindrom u štakora koji predstavlja model polikompartment multiokluzivnog sindroma. Istraživali smo oštećenje organa i protektivno djelovanje BPC 157 na modelu ishemije i modelu reperfuzije. Intraabdominalni tlak, kojim je induciran abdominalni kompartment sindrom, i vrijeme trajanja ishemije je za štakore koji su bili anestezirani tiopentalom iznosio je 25 mm Hg (60 min), 30 mm Hg (30 min), 40 mm Hg (30 min) i 50 mm Hg (15 min) te kod štakora koji su bili anestezirani sa esketaminom (25 mm Hg tijekom 120 min). Kod modela reperfuzije prije dekompresije (kalvariektomija, laparotomija) štakori su imali dugotrajnu tešku intraabdominalnu hipertenziju, stupanj III (25 mm Hg/60 min) i stupanj IV (30 mm Hg/30 min; 40 mm Hg/30 min) te tešku okluziju / sindrom sličan okluziji odnosno ishemiju. Daljnje pogoršanje oštećenja organa uzrokovano je reperfuzijom od 60 minuta ili 30 minuta nakon dekompresije. Ozbiljno vaskularno i multiorgansko zatajenje (lezije mozga, srca, jetre, bubrega i probavnog sustava), raširena tromboza (periferno i centralno), teške aritmije, intrakranijalna (gornji sagitalni sinus) hipertenzija, portalna i kavalna hipertenzija te aortalna hipotenzija su se javile umodelu ishemije, a dodatno su se pogoršale u modelu reperfuzije. Štakori s intraabdominalnom hipertenzijom u modelu ishemije (stupanj III, stupanj IV) primili su BPC 157 (10 μg ili 10 ng/kg sc) ili fiziološku otopinu (5 ml) nakon 10 minuta. Kod modela reperfuzije, terapija BPC 157 (10 μg/kg, 10 ng/kg sc) primijenjena je u reperfuzijskim vremenima od 3 minute po dekompresiji i induciranju reperfuzije. Primjena BPC 157 oporavila je venu azygos putem spasonosnog kolateralnog puta gornje i donje šuplje vene. Dodatno, smanjena je intrakranijska (gornji sagitalni sinus), portalna i kavalna hipertenzija te aortalna hipotenzija, kao i izrazita kongestija želuca i velike hemoragijske lezije, oticanje mozga, venska i arterijska tromboza, kongestija donje šuplje vene i gornje mezenterične vene te kolabirana vena azygos; stoga je inače neuspjeli kolateralni put potpuno oporavljen kod primjene BPC 157. Ozbiljni EKG poremećaji (tj. teška bradikardija i ST-elevacija do asistolije) također su bili poništeni. Mikroskopski, transmuralna hiperemija gastrointestinalnog trakta, redukcija resica crijevne sluznice, redukcija kripte s fokalnom denudacijom površinskog epitela i dilatacija debelog crijeva bili su inhibirani. U jetri je BPC 157 smanjio kongestiju i ozbiljno povećanje sinusoida. U plućima je primijećena normalna prezentacija, bez žarišnog zadebljanja alveolarne membrane i bez plućne kongestije ili edema, a izostalo je ozbiljno intraalveolarno krvarenje. Spriječena je teška srčana kongestija, subendokardijalni infarkt, bubrežno krvarenje, edem mozga, krvarenje i neuralna oštećenja. Terapija s BPC 157 u reperfuziji eliminirala je / smanjila je vensku hipertenziju (intrakranijalnu (gornji sagitalni sinus), portalnu i kavalnu) i aortnu hipotenziju i spriječila povećanje lezije organa i vrijednosti malondialdehida (krv ˃ srce, pluća, jetra, bubrezi ˃ mozak, gastrointestinalni trakt). Brzo je došlo do vaskularnog oporavka (tj. začepljene donja šuplja vena i gornja mezenterična vena preokrenute su u normalnu prezentaciju krvnih žila, kolabirana vena azigos preokrenuta je u potpuno funkcionalno stanje, šant donje šuplje vene vene–gornje šuplje vene je oporavljen i vraćena je izravna isporuka krvi). Terapija s BPC 157 gotovo je poništila trombozu i krvarenje (tj. intracerebralno krvarenje) kao dokaz suzbijanja općeg zastoja i okolnosti Virchow trijade i reorganiziranog krvotoka. Poboljšanjem funkcije venskog sustava s BPC 157 preokrenuli smo lanac štetnih događaja u ishemiji i reperfuziji. Terapija s BPC 157 i protektivni učinak na organe mogao bi biti prenesen na pacijente, poništavajući lezije uzrokovane povišenim intraabdominalnim tlakom, potičući tako potpuni oporavak oštećenih organa. U konačnici, terapijska primjena BPC 157 kod pacijenata s abdominalnim kompartment sindromom smanjila bi visoku stopu smrtnosti i potrebom za hitnom dekompresijskom laparotomijom.Recent research indicates that the stable gastric pentadecapeptide BPC 157 has a protective effect on tissue and organ damage in occlusive syndromes of large blood vessels, whether there is a case of peripheral or central occlusion, by activating collateral circulation. In this research, for the first time in the world, we examined the influence of stable gastric pentadecapeptide BPC 157 on organ damage in abdominal compartment syndrome in an animal model. We induced abdominal compartment syndrome in rats, which represents a model of polycompartment multiocclusive syndrome. We investigated organ damage and the protective effect of BPC 157 in ischemia and reperfusion models. The intra-abdominal pressure that induced abdominal compartment syndrome and the duration of ischemia for rats anesthetized with thiopental was 25 mm Hg (60 min), 30 mm Hg (30 min), 40 mm Hg (30 min), and 50 mm Hg (15 min). and in rats anesthetized with esketamine (25 mm Hg for 120 min). In the reperfusion model before decompression (calvariectomy, laparotomy), rats had long-term severe intra-abdominal hypertension, grade III (25 mm Hg/60 min) and grade IV (30 mm Hg/30 min; 40 mm Hg/30 min) and severe occlusion/like syndrome or ischemia. Further worsening of organ damage was caused by reperfusion for 60 minutes or 30 minutes after decompression. Severe vascular and multiorgan failure (lesions of the brain, heart, liver, kidneys, and digestive system), widespread thrombosis (peripheral and central), severe arrhythmias, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortic hypotension occurred in the ischemia model and further worsened in the reperfusion model. Rats with intra-abdominal hypertension in the ischemia model (grade III, grade IV) received BPC 157 (10 μg or 10 ng/kg sc) or saline (5 ml) after 10 minutes. In the reperfusion model, BPC 157 therapy (10 μg/kg, 10 ng/kg sc) was administered at reperfusion times of 3 minutes after decompression and induction of reperfusion. Administration of BPC 157 recovered the azygos vein via the superior and inferior vena cava salvage collateral route. In addition, intracranial (upper sagittal sinus), portal and caval hypertension and aortic hypotension were reduced, as well as pronounced gastric congestion and large hemorrhagic lesions, brain swelling, venous and arterial thrombosis, congestion of the inferior vena cava and superior mesenteric veins and collapsed azygos vein; therefore, the otherwise failed collateral pathway was fully restored with BPC 157 administration. Severe ECG disturbances (ie, severe bradycardia and ST-elevation to asystole) were also reversed. Microscopically, transmural hyperemia of the gastrointestinal tract, villi reduction of the intestinal mucosa, crypt reduction with focal denudation of the surface epithelium, and colon dilatation were inhibited. In the liver, BPC 157 reduced congestion and severe sinusoidal enlargement. A normal presentation was observed in the lungs, without focal thickening of the alveolar membrane and without pulmonary congestion or edema, and severe intraalveolar hemorrhage was absent. Severe cardiac congestion, subendocardial infarction, renal hemorrhage, brain edema, hemorrhage, and neural damage were prevented. Therapy with BPC 157 in reperfusion eliminated/reduced venous hypertension (intracranial (upper sagittal sinus), portal and caval) and aortic hypotension and prevented an increase in organ lesions and malondialdehyde values (blood ˃ heart, lungs, liver, kidneys ˃ brain, gastrointestinal tract). Vascular recovery occurred rapidly (ie, the occluded inferior vena cava and superior mesenteric vein were reversed to a normal presentation of blood vessels, the collapsed azygos vein was reversed to a fully functional state, the inferior vena cava–superior vena cava shunt was repaired and returned direct delivery of blood). BPC 157 therapy almost reversed thrombosis and hemorrhage (ie, intracerebral hemorrhage) as evidenced by suppression of general stasis and circumstances of the Virchow triad and reorganized blood flow. By improving the function of the venous system with BPC 157, we reversed the chain of harmful events in ischemia and reperfusion. Therapy with BPC 157 and the protective effect on the organs could be transferred to the patients, reversing the lesions caused by increased intra-abdominal pressure and thus promoting the full recovery of the damaged organs. Ultimately, the therapeutic use of BPC 157 in patients with abdominal compartment syndrome would reduce the high mortality rate and the need for emergency decompressive laparotomy