Pathophysiology of sepsis

Abstract

Purpose of review To provide a current overview of sepsis pathophysiology. Recent findings The emphasis on sepsis pathophysiology has moved away from the pathogen - the initiating factor - and instead is focussed upon the abnormal and exaggerated host response. Instead of targeted eradication of the infection, the host response activates or suppresses multiple downstream pathways, leading to multiple organ dysfunction. Summary Sepsis represents a dysregulated host response to infection leading to organ dysfunction. Here, the pathogen triggers an initial exaggerated inflammatory-immune response that leads to activation or suppression of multiple endothelial, hormonal, bioenergetic, metabolic, immune, and other pathways. These, in turn, produce the circulatory and metabolic perturbations resulting in organ dysfunction. This review will provide an overview of underlying mechanisms and propose that these processes, whereas superficially viewed as dysfunctional, may actually be adaptive/protective in the first instance, though spilling over into maladaptation/harm depending on the magnitude of the host response.

Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction

“…The progressive hepatic impairment with alteration of hemodynamics is additionally accompanied by increasing systemic inflammation ( Praktiknjo et al, 2020a ), which may be complicated by an acute event leading to rapid failure of one or more organs, a situation now coined acute on chronic liver failure (ACLF; Moreau et al, 2013 ; Arroyo et al, 2021 ). During deterioration of disease phenotypic changes of the immune cells occur ( Weiss et al, 2020 ) together with an activation of the inflammasomes ( Praktiknjo et al, 2020b ; Monteiro et al, 2021 ) and increases of different cytokines, e.g., Il-6, Il-17, IL-1: a condition we know from subclinical inflammation and sepsis due to other causes ( Arina and Singer, 2021 ). Recent research has increasingly focused on the gut as a major source and trigger of this stimulation of the immune system.…”

Evaluation of the Molecular Mechanisms of Sepsis Using Proteomics

“…These receptors recognize the structures of pathogenic microorganisms, known as pathogen-associated molecular patterns (PAMPs). The same receptors also recognize endogenous molecules released from injured cells, known as damage-associated molecular patterns (DAMPs), such as histones, extracellular DNA, and heat shock proteins (HSPs) (17)(18)(19). In general, proinflammatory reactions are directed at eliminating invading pathogens, whereas anti-inflammatory responses help to limit the degree of local and systemic tissue injury (20).…”

“…In general, proinflammatory reactions are directed at eliminating invading pathogens, whereas anti-inflammatory responses help to limit the degree of local and systemic tissue injury ( 20 ). Therefore, an imbalance between proinflammatory reactions and anti-inflammatory responses results in a series of uncontrolled host responses, including systemic inflammatory response syndrome, coagulation abnormalities, immunosuppression, neuroendocrine disorders, and metabolic disorders ( 17 , 21 – 23 ).…”

“…In sepsis, the sympathetic adrenomedullary system is excited and produces large amounts of catecholamine neurotransmitters, which further increase the expression and release of proinflammatory factors, thereby aggravating endothelial cell injury ( 17 ). The cholinergic anti-inflammatory pathway associated with the vagus nerve plays a role in antagonizing the inflammatory response ( 20 ).…”

“…The second mechanism involves shock, hypoperfusion, and microcirculatory microthrombosis, which aggravate ischemia and generate a hypoxic environment for the affected organs and tissues. Under such hypoxic conditions or in response to ischemia/reperfusion injury, damaged cells and mitochondria produce large amounts of ROS and reactive nitrogen species (RNS) ( 17 ), which can cause lipid peroxidation, destroy the cell structure, and induce cell death ( 17 , 42 ). Moreover, ROS/RNS can modify the post-transcriptional regulation of proteins, such as nitrosylation and acetylation, resulting in protein dysfunction, which further affects the function of cells and organs ( 43 ).…”