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Pathophysiology of the Renin-Angiotensin System in Septic Shock and Therapeutic Modulation of the Classical and Alternative Pathways

par Garcia, Bruno
Président du jury Lybaert, Pascale
Promoteur Creteur, Jacques
Publication Non publié, 2024-07-02

Thèse de doctorat

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Résumé :

Background: Recent advances have improved our understanding of alterations in the renin-angiotensin system (RAS) during septic shock, including disturbances in the angiotensin I/angiotensin II ratio and its relation to worse outcomes. The availability of a new vasopressor agent, angiotensin II, for clinical use has increased interest in the RAS. However, other therapeutic strategies can modulate the renin-angiotensin system, including angiotensin-(1-7) or inhibition of dipeptidyl peptidase 3 (DPP3), which degrades RAS components.Objectives: In this work, we aimed to describe the dynamics of the disturbances in the renin-angiotensin system during experimental septic shock and to analyze the effects of its modulation in two different experimental models. We assessed the specific effects of angiotensin II on the myocardium in swine, the effects of angiotensin-(1-7) on the development of septic shock in sheep, and the effects of DPP3 inhibition on hemodynamics in swine.Methods: Randomized, controlled, experimental studies were performed in anesthetized and mechanically ventilated swine and sheep. Septic shock was induced by fecal peritonitis in all animals. Resuscitation was performed according to clinical guidelines, using dynamic parameters of fluid responsiveness, peritoneal lavage, antibiotic therapy, and the use of a vasopressor agent targeting a mean arterial pressure between 65 and 75 mmHg. All animals were fully hemodynamically monitored, and organ failure was assessed. Further analyses were performed according to the objective of each experiment, including the analysis of circulating renin-angiotensin system peptides and angiotensin receptor downregulation in myocardium and vascular samples.Results: Sepsis was associated with activation of the renin-angiotensin system, marked by an increase in plasma renin activity and levels of angiotensin I and II, along with an increase in angiotensin-(1-7) and other RAS peptides. A decrease in angiotensin-converting enzyme (ACE) activity was observed, associated with an increase in the angiotensin I/angiotensin II and angiotensin-(1-7)/angiotensin II ratios. Resuscitation with angiotensin II was associated with similar hemodynamics and organ function, along with reduced myocardial inflammation and injury. Early use of angiotensin-(1-7) was able to prevent the development of septic shock, and DPP3 inhibition was associated with reduced norepinephrine use and myocardial injury, while achieving similar organ perfusion.Conclusions: Both the classical and alternative renin-angiotensin systems are altered during experimental septic shock, and their modulation can be associated with beneficial effects: angiotensin II by reducing myocardial injury while achieving similar resuscitation, angiotensin-(1-7) by preventing the development of septic shock, and DPP3 inhibition by preventing the degradation of angiotensin II and improving hemodynamics.