Abstract
Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis treatment exists despite decades of research on developing potential therapies. Annexins are molecules that show efficacy in preclinical models of sepsis but have not been investigated as a potential therapy in patients with sepsis. Human annexins play important roles in cell membrane dynamics, as well as mediation of systemic effects. Most notably, annexins are highly involved in anti-inflammatory processes, adaptive immunity, modulation of coagulation and fibrinolysis, as well as protective shielding of cells from phagocytosis. These discoveries led to the development of analogous peptides which mimic their physiological function, and investigation into the potential of using the annexins and their analogous peptides as therapeutic agents in conditions where inflammation and coagulation play a large role in the pathophysiology. In numerous studies, treatment with recombinant human annexins and annexin analogue peptides have consistently found positive outcomes in animal models of sepsis, myocardial infarction, and ischemia reperfusion injury. Annexins A1 and A5 improve organ function and reduce mortality in animal sepsis models, inhibit inflammatory processes, reduce inflammatory mediator release, and protect against ischemic injury. The mechanisms of action and demonstrated efficacy of annexins in animal models support development of annexins and their analogues for the treatment of sepsis. The effects of annexin A5 on inflammation and platelet activation may be particularly beneficial in disease caused by SARS-CoV-2 infection. Safety and efficacy of recombinant human annexin A5 are currently being studied in clinical trials in sepsis and severe COVID-19 patients.
Highlights
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al, 2016)
While most people infected with this coronavirus are asymptomatic or only show mild symptoms, many have developed severe disease that requires hospitalization, of whom about 20–25% with critical COVID-19 have been admitted to intensive care units (ICU) (CanadaA of (2021) Epid, 2021)
We summarize existing knowledge of annexin functions and potential therapeutic applications of annexin A1, A2 and A5 in sepsis and COVID-19
Summary
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al, 2016). Annexin A5 improves nitric oxide signalling and vascular endothelial function through inhibition of inflammation and endothelial activation (Ewing et al, 2011a). These properties make it a promising therapeutic agent to reduce the consequences of endothelial injury in sepsis and COVID-19. Annexin A1 and A2 have been shown to have protective roles in coagulopathy and inflammation Other annexins such as annexin A3, which has been shown to mediate pathogen clearance and its expression is increased in neutrophils in patients with sepsis, their therapeutic potential in sepsis is currently not clear (Toufiq et al 2020). We summarize existing knowledge of annexin functions and potential therapeutic applications of annexin A1, A2 and A5 in sepsis and COVID-19
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