Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas’ severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal “heaving”, NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (/kg), alone or combined, BPC 157 therapy (10 µg, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other’s effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, “heaving abdomen”, cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of “heaving abdomen”. BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system.

Cytoprotection provides a conceptual framework for the preservation and restoration of tissue integrity under conditions of noxious injury. In liver disease, however, effective protection may require more than direct limitation of hepatocellular damage, encompassing endothelial function, microcirculation, vascular homeostasis, oxidative stress, inflammation, fibrosis, and portal hemodynamics. This review examines possibilities for cytoprotective liver therapy, with particular emphasis on stable gastric pentadecapeptide BPC 157 and comparison with established or experimentally investigated agents, including N-acetylcysteine, ursodeoxycholic acid, corticosteroids, resveratrol, L-arginine, curcumin, sildenafil, VEGF-related approaches, stem cell therapies, melatonin, simvastatin, prostacyclin analogues, and coenzyme Q10. Evidence is considered across representative experimental models of acetaminophen and carbon tetrachloride hepatotoxicity, bile duct ligation, and alcohol-induced liver injury. The diversity of effective agents indicates that liver injury involves multiple interconnected pathological mechanisms and that preservation of hepatocellular integrity may be achieved through different pharmacological pathways. BPC 157 is distinguished by evidence of beneficial effects across these major models and additional vascular and occlusion/occlusion-like syndromes. In particular, reported findings indicate prevention and reversal of experimentally induced portal hypertension, including prehepatic, intrahepatic, and posthepatic disturbances, together with attenuation of hepatic congestion, thrombosis, oxidative injury, and associated multiorgan dysfunction. These findings support the concept that cytoprotection may extend from hepatoprotection to restoration of vascular and tissue homeostasis. Collectively, the available preclinical evidence supports further investigation of integrated cytoprotective strategies for liver injury. Nevertheless, experimental evidence, however extensive, does not establish clinical efficacy, and appropriately designed clinical studies remain necessary to determine therapeutic applicability in human liver disease.