Sepsis - Pro-Inflammatory and Anti-Inflammatory Responses

H. Herwald, A. Egesten

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805597111
• Topic: Medicina
• Subtopic: Microbiología y parasitología médicas

Sepsis is a serious condition that is associated with high mortality despite advanced modern medical treatment. Recent years have witnessed novel paradigms describing host responses in sepsis. In particular, the delicate balance between pro- and anti-inflammatory reactions has been subject to intense research. This volume in the book series 'Contributions to Microbiology' presents the state of the art in this rapidly expanding field of research. Leading international experts have contributed with reviews on the most relevant topics in the field such as clinical aspects, pathways of sepsis and pro- and anti-inflammatory mechanisms as well as their regulation. The book will be a valuable source of up-to-date information for clinicians, microbiologists, immunologists, and students with an interest in the complex regulation of host responses during microbial sepsis.

Herwald H, Egesten A (eds): Sepsis – Pro-Inflammatory and Anti-Inflammatory Responses.
Contrib Microbiol. Basel, Karger, 2011, vol 17, pp 48-85

______________________

Molecular Mechanisms of Sepsis

James A. Russell^a,b · John Boyd^a,b · Taka Nakada^a · Simone Thair^a · Keith R. Walley^a,b

^aHeart and Lung Institute and ^bDivision of Critical Care Medicine, St. Paul's Hospital, Vancouver, BC, Canada

______________________

Abstract

In cancer, therapies are targeted at 6 important pathways. In sepsis, there is ongoing controversy regarding the number and relative roles of pathways that are activated or repressed and which are important in the progression from health to death. Adding to complexity, there is interaction of pathways, there are differences in temporal pattern of up and down-regulation of pathways and there are different responses of pathways to therapies of sepsis. In this review, we define four key pathways of sepsis: (1) inflammation and immunity, (2) coagulation and fibrinolysis, (3) apoptosis, and (4) endocrine. Each of these pathways can impair endothelial function, a unifying aspect of the pathophysiology of sepsis. There are few studies of interactions of pathways except for the interaction of inflammation/immunity with coagulation/fibrinolysis. Successful treatment of cancer requires that cancer therapies interrupt several key pathways of cancer. Accordingly, we suggest that successful treatment of sepsis will require therapies that interrupt several key pathways of sepsis. Perhaps the paucity of approved therapies for sepsis is related in part to the underevaluation of novel pathways, to lack of understanding of interactions of pathways and to lack of interruption of key pathways of sepsis.

Copyright © 2011 S. Karger AG, Basel

Sepsis, severe sepsis and septic shock are syndromes of infection that have progressively increasing severity and mortality. There are about 750,000 new cases of severe sepsis per year in the US. About 50% of those patients are critically ill and cared for in an intensive care unit. The incidence of septic shock is increasing because of ageing of the population, rising frequency of resistant microorganisms, immuno-suppressive diseases and drugs, and increasing high-risk surgery. The mortality of severe sepsis and septic shock ranges from 30 to 70% respectively. However, there is only one approved therapy for severe sepsis and septic shock: activated protein C. Why are there no other approved therapies? How can we interrupt the rapid progression from health to death in so many septic patients?

Sepsis arises because of complex interactions between the infecting micro-organism(s) and the responses of the human host. In this review, we define four key pathways of sepsis: (1) inflammation and immunity, (2) coagulation and fibrinolysis, (3) apoptosis, and (4) endocrine (table 1). Each of these pathways can impair endothelial function, a unifying aspect of the pathophysiology of sepsis. We briefly describe how endothelial dysfunction can increase endothelial permeability, a virtually universal feature of severe sepsis and septic shock. There are few studies of interactions of pathways except for the interaction of immunity with coagulation. We particularly focus on inflammation and immunity and how that intersects with each other section and pathway. We suggest that successful treatment of sepsis will require better understanding of key pathways and specifically designed therapies that interrupt these key pathways.

Table 1. Mediators of sepsis

Pathway	Mediators	Potential treatments
Bacterial molecules	TSST-1	anti-TSST-1
	streptococcal exotoxins	anti-streptococcal exotoxins
	lipopolysaccharide (LPS)	anti-LPS
Innate immunity	TLR-2, TLR-4	TLR agonists and antagonists
	monocytes, macrophages	GM-CSF, interferon-γ
	neutrophils	G-CSF
Adaptive immunity	B cells	IgG
	CD4+Tcells(Th1, Th2)
Proinflammatory pathway	intracellularToll/IL-1 receptor (TIR)	nonfunctional receptors (ST2 and SIGIRR)
	NFkB	NFkBIA and NFkBIE
	TNF-α	anti-TNF-α
	IL-1ß	IL-1ß receptor antagonist
	IL-6	IL-6 antagonist; soluble decoy IL-6 receptor (sIL-6R)
	MyD88	nonfunctional short MyD88 (sMyD88)
	prostaglandins, leukotrienes	ibuprofen, corticosteroids
	bradykinin	bradykinin antagonist
	platelet-activating factor	platelet-activating factor acetyl hydrolase
	proteases (e.g. elastase)	elastase inhibitor
	oxidants	antioxidants (e.g. N-acetylcysteine)
	nitric oxide	nitric oxide synthase inhibitors
	HMGB1	HMGB1 antagonists
	RAGE	RAGE antagonist or inhibitor, soluble RAGE (decoy for RAGE), anti-RAGE antibodies
Procoagulant pathway	decreased protein C	activated protein C
	decreased protein S	protein S
	decreased antithrombin III	antithrombin III
	decreased tissue factor pathway inhibitor (TFPI)	tissue factor pathway inhibitor (TFPI)
	increased tissue factor	tissue factor antagonist
	increased plasminogen-activator inhibitor 1	tissue plasminogen activator
Antiinflammatory pathway	IL-10	IL-10
	TNF-α receptors	soluble TNF-α receptors
Hypoxia	hypoxia-inducing factor-1 α	early goal-directed therapy erythropoietin
	vascular endothelial growth factor	early goal-directed therapy erythropoietin
Immunosuppression or apoptosis	lymphocyte apoptosis	anticaspases
	intestinal epithelial cell apoptosis	anticaspases
Endocrine	adrenal insufficiency	corticosteroids
	vasopressin deficiency	vasopressin, terlipressin, AVPRIa agonist
	growth hormone deficiency	growth hormone
	hyperglycemia	intensive insulin therapy

Inflammation and Immunity

Host immunity is the cornerstone of response to infection. Host immunity may be classified into the innate and adaptive immune responses. The innate immune system is the rapid response system that is ‘hard-wired’ in each individual.

Pathogen Recognition and Toll- Like Receptors

The first step in recognition of micro-organisms is that pattern-recognition receptors (such as the Toll-like receptor family; TLRs) bind to highly conserved molecules called pathogen-associated molecular proteins (PAMPs) (fig. 1). In an example of structure matching function, TLRs which recognize components of the bacterial cell wall look outwards from the cytoplasmic membrane, while TLRs which recognize nucleic acids are located within the host cell. TLR1 recognizes Gram-positive bacteria; TLR2 recognizes the peptidoglycan of Gram-positive bacteria, whereas TLR4 binds lipopolysaccharide of Gram-negative bacilli. CD-14 interacts with TLR-4 in response to Gram-negative infection and LPS [1]. CD14 exists in a membrane bound form (m CD 14) and can be released into the circulation as soluble CD 14 (s CD 14). During sepsis, both m CD 14 and s CD 14 are upregulated to bind PAMPS and modify the inflammatory response.

TLR3 recognizes RNA released from necrotic cells as well as viral infection [2]. TLR5 recognizes flagellin, a molecule present in nearly all bacteria. TLR9 binds unmethylated CpG dinucleotides (i.e. CpG sequences of DNA); CPG sites are rare in human DNA but common in viral and bacterial DNA. The role of TLRs is complex as demonstrated by careful studies showing that preconditioning using TLR2 ligands attenuates myocardial dysfunction in the cecal ligation and perforation model of sepsis [3].

Toll-like receptors recruit adaptor proteins to the cell surface and the adaptor proteins (such as MyD88) then activate a series of cytoplasmic kinases (such as IRAK1, IRAK4, TBK1 and IKKi). Transcription factors activated by the Toll-like receptor signaling pathways include NFĸB, activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF-3).

The binding of PAMPs to TLRs rapidly induces a broad array of genes. These genes prepare the cell to choose one of the following main responses: rapidly undergo apoptosis if overwhelmingly infected, fight the infection with pro-inflammatory molecules and proliferation, or quench the inflammatory reaction if no further danger is detected.

The magnitude of inflammation for a given stimulus depends upon the cell type, tissue and the presence or absence of tolerance.

Many cell types and tissues express TLRs and other pattern recognition receptors, and are therefore involved in the innate immune response. Tissues which interface with the environment such as lung epithelium [4] and gut endothelium express most known TLRs, and are continuously exposed to their ligands. However, through the induction of counter-regulatory molecules which oppose inflammation, these tissues develop a tolerance towards pathogens. Cells and tissues such as leukocytes, vascular endothelium and the heart however, are not routinely exposed to pathogens and therefore produce a significant inflammatory burst upon initial exposure.

Important initial responders are monocytes/macrophages which through induction of early response genes such as TNF and IL-6 rapidly produce inflammatory cytokines and chemokines. These cytokines then amplify the early inflammatory response. Neutrophils are recruited to the infected site via chemokine gradients, are activated to express cell adhesion molecules which result in neutrophil retention in affected ...

Table of contents

• Cover Page
• Front Matter
• Roger C. Bone, MD and the Evolving Paradigms of Sepsis
• Clinical Aspects of Sepsis
• Virulence Factors of Gram-Negative Bacteria in Sepsis with a Focus on Neisseria meningitidis
• Molecular Mechanisms of Sepsis
• Pro-Inflammatory Mechanisms in Sepsis
• Anti-Inflammatory Mechanisms of Sepsis
• Regulation of Pro-and Anti-Inflammatory Host Responses
• Future Perspectives on Regulating Pro-and Anti-Inflammatory Responses in Sepsis
• Author Index
• Subject Index