Journal of Clinical Trials
Open Access

Abstract

Roles of Complement and Extracellular Histones in Infectious Sepsis

Peter A Ward*

In North America, infectious sepsis is associated with bacteria, fungi, protozoa and viruses. It has been well established that age is an important factor. Septic patients of 60 years of age, or greater, are much more susceptible to lethality as compared to patients whose age is around 40 years of age. Recently, there is also evidence that sepsis associated with non-penetrating trauma, drug toxicity of liver, or hemorrhagic shock are associated with similar responses developing in infectious sepsis. Following onset of sepsis (infectious or non-infectious), during the first 2-3 days there is a “cytokine storm,” also involving proinflammatorychemokines.Typically, IL-1β, IL-6, TNF and IL-17A and F rapidly rise in plasma. After day 3-4, this inflammatory cascade related to the innate immune system (involving neutrophils, macrophages and an array of proinflammatory mediators) results in reduced responsiveness of the innate immune system, followed by development of immune suppression. The precise molecular mechanisms for these outcomes are poorly understood. It is well known that sepsis activates the following complement activation pathways: classical, alternative and lectin pathways, resulting in release of two powerful anaphylatoxins: C3a and C5a. Each anaphylatoxin has powerful proinflammatory functions. In the setting of sepsis, C5a reacts with its high affinity receptors (C5aR1, C5aR2), especially on phagocytes (neutrophils, macrophages), resulting in release of proinflammatory factors (proteases, oxygen-derived free-radicals, extracellular histones, etc.). C5a has a molecular weight of approximately 12 kDa and is freely diffusable locally. Histones have only recently been shown to be released with a variety of inflammatory products from phagocytic cells activated by C5a. There is a great deal of work going on to define precisely how histones contribute to the adverse outcomes of sepsis.

Published Date: 2020-06-26; Received Date: 2020-06-06