New strategies for treatment of infectious sepsis

Abstract

In this mini review, we describe the molecular mechanisms in polymicrobial sepsis that lead to a series of adverse events including activation of inflammatory and prothrombotic pathways, a faulty innate immune system, and multiorgan dysfunction. Complement activation is a wellestablished feature of sepsis, especially involving generation of C5a and C5b-9, along with engagement of relevant receptors for C5a. Activation of neutrophils by C5a leads to extrusion of DNA, forming neutrophil extracellular traps that contain myeloperoxidase and oxidases, along with extracellular histones. Generation of the distal complement activation product, C5b-9 (known as the membrane attack complex, MAC), also occurs in sepsis. C5b-9 activates the NLRP3 inflammasome, which damages mitochondria, together with appearance in plasma of IL-1 and IL-18.Histones are strongly proinflammatory as well as being prothrombotic, leading to activation of platelets and development of venous thrombosis. Multiorgan dysfunction is also a feature of sepsis. It is well known that septic cardiomyopathy, which if severe, can lead to death. This complication in sepsis is linked to reduced levels in cardiomyocytes of three critical proteins (SERCA2, NCX, Na + /K + -ATPase). The reductions in these three key proteins are complement-and histonedependent. Dysfunction of these ATPases is linked to the cardiomyopathy of sepsis. These data suggest novel targets in the setting of sepsis in humans. K E Y W O R D Scomplement receptors, complement, histones, NLRP3 inflammasome

Neutrophil extracellular traps in COVID-19

“…Elevated levels of blood neutrophils are an early indicator of SARS-CoV-2 infection, predicting severe respiratory disease and worse outcomes (2,3). Over the past decade, our group and many others have revealed a pathogenic role for neutrophil-derived neutrophil extracellular traps (NETs) in various thrombo-inflammatory states including sepsis (4,5), thrombosis (6)(7)(8), and respiratory failure (9,10). NETs are extracellular webs of DNA, histones, microbicidal proteins, and oxidant enzymes that are released by neutrophils to corral infections; however, when not properly regulated, NETs have potential to initiate and propagate inflammation and thrombosis (11,12).…”

Neutrophil extracellular traps and thrombosis in COVID-19

“…In COVID-19, elevated levels of blood neutrophils predict severe respiratory disease and unfavorable outcomes [2,3]. Neutrophil-derived neutrophil extracellular traps (NETs) play a pathogenic role in many thrombo-inflammatory states including sepsis [4,5], thrombosis [6][7][8], and respiratory failure [9,10]. NETs are extracellular webs of chromatin and microbicidal proteins that are an evolutionarily conserved aspect of innate immune host-defense [11]; however, NETs also have potential to initiate and propagate inflammation and thrombosis.…”

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…C5a reacts with its receptor, leading to cytokine storm, lymphocyte apoptosis, neutrophilic innate immune function loss, cardiomyopathy, disseminated intravascular coagulation, etc. Meanwhile, C5a also affects intracellular calcium homeostasis (Fattahi et al, 2018a;Ward and Fattahi, 2019). SCM is associated with decreased levels of three key enzymes (serca2, NCX, and Na+/K+-atpase) in cardiomyocytes, which are complement receptor-dependent (Fattahi et al, 2018a).…”