Novel therapeutic targets for organ injury and dysfunction in systemic inflammation

Abstract

Sepsis is caused by systemic (blood) infection and is a major health concern as it is the primary cause of death from infection. There are no specific effective treatments for sepsis. Diabetes mellitus is a chronic metabolic disorder characterised by hyperglycaemia. In 2025, it is expected that the number of people with diabetes will reach 350 million worldwide. I have investigated the pathophysiology and experimental therapy of the organ injury and dysfunction caused by excessive systemic inflammation in animal models of acute (sepsis) and chronic (diabetes) inflammation. The two models used were: diet-induced model of type-2 diabetes mellitus (T2DM) and a polymicrobial sepsis model (cecal ligation and puncture (CLP)). The antimicrobial peptides, Peptide 19-2.5 and Peptide 19-4LF are designed to bind and neutralise the effects of pathogen-associated molecular patterns including lipopolysaccharide (LPS) (from Gram-negative bacteria) and lipoprotein (from Gram-positive bacteria), which are key drivers of the cytokine response underlying both systemic inflammatory response syndrome (SIRS) and ultimately the cytokine storm in sepsis. Aquaporin-9 (AQP9) is a neutral solute channel expressed in hepatocytes and leukocytes. It plays a role in metabolism and inflammation; therefore, it may also play a role in the progression of sepsis. In this thesis, I report that inhibition of AQP9 and prevention of metabolic endotoxemia with Peptide 19-2.5 attenuated the sepsis-induced cardiac dysfunction and the multiple organ (kidney/liver) failure. Peptide 19-2.5 also attenuated the metabolic alterations (Oral Glucose Tolerace Test, dyslipidaemia) and organ injury/dysfunction (steatosis, NASH, diabetic nephropathy) in a diet-induced model of T2DM (although the cardiac dysfunction was limited to heart failure with preserved ejection fraction). Targeting either the excessive inflammation driven by metabolic endotoxaemia (with an anti-LPS strategy), or activation of AQP9 are novel therapeutic approaches for the prevention of systemic inflammation and organ dysfunction associated with sepsis and diabetes.