Sepsis Syndrome

2014 ◽  
pp. 395-402
Author(s):  
Joshua A. Englert ◽  
Rebecca Marlene Baron
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Innate Immune System ◽  
Tissue Injury ◽  
Treatment Strategies ◽  
Sepsis Syndrome ◽  
Clinical Syndrome ◽  
High Morbidity ◽  
Early Management ◽  
Inflammatory State

Sepsis is a clinical syndrome characterized by systemic inflammation leading to tissue injury that arises as a complication of an infection. According to current paradigms, sepsis arises as a result of the infection of a normally sterile body compartment. Infection leads to activation of the innate immune system to produce a systemic inflammatory response. This response is a necessary component of the body's defense against infection under normal conditions, but it is the lack of regulation of this response that is central to the pathogenesis of sepsis. As discussed in more detail below, this dysregulated inflammatory state can lead to tissue injury and dysfunction in organs not involved in the original infectious insult. Although sepsis remains a condition with exceedingly high morbidity and mortality, recent early management and treatment strategies have demonstrated exciting improvements in overall outcomes.

scholarly journals Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

2017 ◽  
Vol 114 (13) ◽  
pp. E2758-E2765 ◽  
Author(s):  
Alexey V. Kostarnoy ◽  
Petya G. Gancheva ◽  
Bernd Lepenies ◽  
Amir I. Tukhvatulin ◽  
Alina S. Dzharullaeva ◽  
...  
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Innate Immune System ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Skin Damage ◽  
Cholesterol Sulfate ◽  
Local Inflammatory Response

Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.

Sepsis Syndrome

2012 ◽  
pp. 274-279
Author(s):  
Andrew D Badley
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Physical Examination ◽  
Supportive Care ◽  
Tissue Injury ◽  
Tissue Perfusion ◽  
Sepsis Syndrome ◽  
Systemic Response ◽  
Immune Mediated ◽  
Patient’S History

Systemic inflammatory response syndrome (SIRS) is the specific host systemic response that may be elicited by various stimuli, including infection, burns, pancreatitis, ischemia, trauma, hemorrhage, immune-mediated tissue injury, and exogenous stimuli. 2. Sepsis is SIRS resulting from infection. Sepsis syndrome is sepsis with altered tissue perfusion of vital organs (resulting in oliguria, hypoxemia, elevated levels of lactate, or altered mentation or any combination of these conditions) When a patient has SIRS, the objective is to define its cause. If SIRS is caused by infection, appropriate antibiotics must be administered and supportive care guided by the patient's history and physical examination.

scholarly journals The Autumn Low Milk Yield Syndrome in High Genetic Merit Dairy Cattle: The Possible Role of a Dysregulated Innate Immune Response

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 388
Author(s):  
Massimo Amadori ◽  
Chiara Spelta
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Dairy Cattle ◽  
Memory Effect ◽  
Milk Yield ◽  
Innate Immune System ◽  
Innate Immune ◽  
Effective Control ◽  
Dry Period ◽  
Genetic Merit

The analysis of milk yield data shows that high genetic merit dairy cows do not express their full production potential in autumn. Therefore, we focused on metabolic stress and inflammatory response in the dry and peripartum periods as possible causes thereof. It was our understanding that some cows could not cope with the stress imposed by their physiological and productive status by means of adequate adaptation strategies. Accordingly, this study highlights the noxious factors with a potential to affect cows in the above transition period: hot summer climate, adverse genetic traits, poor coping with unfavorable environmental conditions, outright production diseases and consequences thereof. In particular, the detrimental effects in the dry period of overcrowding, photoperiod change and heat stress on mammary gland development and milk production are highlighted in the context of the autumn low milk yield syndrome. The latter could be largely accounted for by a “memory” effect on the innate immune system induced in summer by diverse stressors after dry-off, according to strong circumstantial and indirect experimental evidence. The “memory” effect is based on distinct epigenetic changes of innate immunity genes, as already shown in cases of bovine mastitis. Following a primary stimulation, the innate immune system would be able to achieve a state known as “trained immunity”, a sort of “education” which modifies the response to the same or similar stressors upon a subsequent exposure. In our scenario, the “education” of the innate immune system would induce a major shift in the metabolism of inflammatory cells following their reprogramming. This would entail a higher basal consumption of glucose, in competition with the need for the synthesis of milk. Also, there is strong evidence that the inflammatory response generated in the dry period leads to a notable reduction of dry matter intake after calving, and to a reduced efficiency of oxidative phosphorylation in mitochondria. On the whole, an effective control of the stressors in the dry period is badly needed for better disease control and optimal production levels in dairy cattle.

scholarly journals Inhibition of Toll-like Receptor and Cytokine Signaling—A Unifying Theme in Ischemic Tolerance

2004 ◽  
Vol 24 (11) ◽  
pp. 1288-1304 ◽  
Author(s):  
Katalin Karikó ◽  
Drew Weissman ◽  
Frank A. Welsh
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Lipid Rafts ◽  
Inflammatory Cytokines ◽  
Innate Immune System ◽  
Endotoxin Tolerance ◽  
Ischemic Tolerance ◽  
Innate Immune ◽  
Cytokine Signaling ◽  
The Brain

Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. Inflammation occurs through the action of proinflammatory cytokines, such as TNF, IL-1β and IL-6, that alter blood flow and increase vascular permeability, thus leading to secondary ischemia and accumulation of immune cells in the brain. Production of these cytokines is initiated by signaling through Toll-like receptors (TLRs) that recognize host-derived molecules released from injured tissues and cells. Recently, great strides have been made in understanding the regulation of the innate immune system, particularly the signaling mechanisms of TLRs. Negative feedback inhibitors of TLRs and inflammatory cytokines have now been identified and characterized. It is also evident that lipid rafts exist in membranes and play a role in receptor-mediated inflammatory signaling events. In the present review, using this newly available large body of knowledge, we take a fresh look at studies of ischemic tolerance. Based on this analysis, we recognize a striking similarity between ischemic tolerance and endotoxin tolerance, an immune suppressive state characterized by hyporesponsiveness to lipopolysaccharide (LPS). In view of this analogy, and considering recent discoveries related to molecular mechanisms of endotoxin tolerance, we postulate that inhibition of TLR and proinflammatory cytokine signaling contributes critically to ischemic tolerance in the brain and other organs. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Tolerance can be established with two temporal profiles: (i) a rapid form in which the trigger induces tolerance to ischemia within minutes and (ii) a delayed form in which development of protection takes several hours or days and requires de-novo protein synthesis. The rapid form of tolerance is achieved by direct interference with membrane fluidity, causing disruption of lipid rafts leading to inhibition of TLR/cytokine signaling pathways. In the delayed form of tolerance, the preconditioning stimulus first triggers the TLR/cytokine inflammatory pathways, leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors of inflammation. These inhibitors, which include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines, reduce the inflammatory response to a subsequent episode of ischemia. This novel interpretation of the molecular mechanism of ischemic tolerance highlights new avenues for future investigation into the prevention and treatment of stroke and related diseases.

Sepsis begins at the interface of pathogen and host

2001 ◽  
Vol 29 (6) ◽  
pp. 853-859 ◽  
Author(s):  
B. Beutler
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Tissue Injury ◽  
Living Organism ◽  
Life Forms ◽  
Innate Immune ◽  
Host Immune System ◽  
Toxic Substances ◽  
Septic Syndrome ◽  
Modern Mind

To the modern mind, the term ‘sepsis’ conjures up images of microbes. It is easy to forget that the word predates any understanding of the microbial origins of infectious disease. Derived from the Greek ‘sepsios’ (rotten), sepsis denotes decay: a phenomenon that humans once regarded as a mysterious though inevitable natural process. A living organism does not accept decay passively. Virtually all multicellular life forms are capable of resisting infection through the generation of a vigorous immune response. In mammals, the response is so stereotypic that it has come to define sepsis itself: it is often called the ‘septic syndrome’. Our current understanding of the innate immune system is deeply rooted in the study of sepsis. The chain of events linking infection to tissue injury and cardiovascular collapse is not obvious, and affirmation of the concept required three major discoveries. First, the septic syndrome was found to be caused by toxic products of microbes. Secondly, these toxic substances were found to be toxic because of their propensity to activate cells of the innate immune system, prompting cytokine production. Thirdly, the activating events initiated by microbial toxins were traced to members of an ancient family of defensive molecules, versions of which operate in virtually all multicellular life forms. In mammals, proteins of this family are now known as Toll-like receptors. They represent a point of direct contact, and first contact, between a pathogen and the host immune system.

scholarly journals Toll-Like Receptors, Tissue Injury, and Tumourigenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Savvas Ioannou ◽  
Michael Voulgarelis
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Tissue Injury ◽  
Healing Process ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
Innate Immune ◽  
Wound Healing Process ◽  
Toll Like Receptors ◽  
And Function

Toll-like receptors (TLRs) belong to a class of molecules known as pattern recognition receptors, and they are part of the innate immune system, although they modulate mechanisms that impact the development of adaptive immune responses. Several studies have shown that TLRs, and their intracellular signalling components, constitute an important cellular pathway mediating the inflammatory process. Moreover, their critical role in the regulation of tissue injury and wound healing process as well as in the regulation of apoptosis is well established. However, interest in the role of these receptors in cancer development and progression has been increasing over the last years. TLRs are likely candidates to mediate effects of the innate immune system within the tumour microenvironment. A rapidly expanding area of research regarding the expression and function of TLRs in cancer cells and its association with chemoresistance and tumourigenesis, and TLR-based therapy as potential immunotherapy in cancer treatment is taking place over the last years.

scholarly journals Genetic variability associated with OAS1 expression in myeloid cells increases the risk of Alzheimer's disease and severe COVID-19 outcomes

2021 ◽  
Author(s):  
Naciye Magusali ◽  
Andrew C Graham ◽  
Thomas M Piers ◽  
Pantila Panichnantakul ◽  
Umran Yaman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Critical Illness ◽  
Inflammatory Response ◽  
Innate Immune System ◽  
Transcriptional Network ◽  
Innate Immune ◽  
Genome Wide Association Studies ◽  
Oligoadenylate Synthetase

Genome-wide association studies of late-onset Alzheimer's disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes associated with variants that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD, including the interferon-responsive oligoadenylate synthetase 1 (OAS1). However, the function of OAS1 within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD and 1,234 control individuals, we confirm that the OAS1 variant, rs1131454, is associated with increased risk for AD and decreased OAS1 expression. Moreover, we note that the same locus was recently associated with critical illness in response to COVID-19, linking variants that are associated with AD and a severe response to COVID-19. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APPNL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a, providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 by analysing scRNA-seq data from human microglia isolated from individuals with AD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma (IFN-γ), we note that cells with lower OAS1 expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF-α. Collectively, our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19 centred on OAS1 and interferon signalling, a finding with potential implications for future treatments of both AD and COVID-19, and the development of biomarkers to track disease progression.

scholarly journals Effects of mannose-binding lectin on pulmonary gene expression and innate immune inflammatory response to ozone

2016 ◽  
Vol 311 (2) ◽  
pp. L280-L291 ◽  
Author(s):  
Jonathan M. Ciencewicki ◽  
Kirsten C. Verhein ◽  
Kevin Gerrish ◽  
Zachary R. McCaw ◽  
Jianying Li ◽  
...  
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Innate Immune System ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Gene Sets ◽  
Mannose Binding ◽  
Gene Transcripts ◽  
Binding Lectin

Ozone is a common, potent oxidant pollutant in industrialized nations. Ozone exposure causes airway hyperreactivity, lung hyperpermeability, inflammation, and cell damage in humans and laboratory animals, and exposure to ozone has been associated with exacerbation of asthma, altered lung function, and mortality. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose-binding lectin (MBL), an innate immunity serum protein, contributes to the proinflammatory events caused by ozone-mediated activation of the innate immune system. Wild-type ( Mbl+/+) and MBL-deficient ( Mbl−/−) mice were exposed to ozone (0.3 ppm) for up to 72 h, and bronchoalveolar lavage fluid was examined for inflammatory markers. Mean numbers of eosinophils and neutrophils and levels of the neutrophil attractants C-X-C motif chemokines 2 [ Cxcl2 (major intrinsic protein 2)] and 5 [ Cxcl5 (limb expression, LIX)] in the bronchoalveolar lavage fluid were significantly lower in Mbl−/− than Mbl+/+ mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in transcript response profiles and networks at baseline [e.g., nuclear factor erythroid-related factor 2 (NRF2)-mediated oxidative stress response] and after exposure (e.g., humoral immune response) between Mbl+/+ and Mbl−/− mice. The microarray data were further analyzed to discover several informative differential response patterns and subsequent gene sets, including the antimicrobial response and the inflammatory response. We also used the lists of gene transcripts to search the LINCS L1000CDS2 data sets to identify agents that are predicted to perturb ozone-induced changes in gene transcripts and inflammation. These novel findings demonstrate that targeted deletion of Mbl caused differential levels of inflammation-related gene sets at baseline and after exposure to ozone and significantly reduced pulmonary inflammation, thus indicating an important innate immunomodulatory role of the gene in this model.

scholarly journals Modeling Virus-Induced Inflammation in Zebrafish: A Balance Between Infection Control and Excessive Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Con Sullivan ◽  
Brandy-Lee Soos ◽  
Paul J. Millard ◽  
Carol H. Kim ◽  
Benjamin L. King
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Inflammatory Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune System ◽  
Innate Immune ◽  
Zebrafish Model ◽  
Infection Models

The inflammatory response to viral infection in humans is a dynamic process with complex cell interactions that are governed by the immune system and influenced by both host and viral factors. Due to this complexity, the relative contributions of the virus and host factors are best studied in vivo using animal models. In this review, we describe how the zebrafish (Danio rerio) has been used as a powerful model to study host-virus interactions and inflammation by combining robust forward and reverse genetic tools with in vivo imaging of transparent embryos and larvae. The innate immune system has an essential role in the initial inflammatory response to viral infection. Focused studies of the innate immune response to viral infection are possible using the zebrafish model as there is a 4-6 week timeframe during development where they have a functional innate immune system dominated by neutrophils and macrophages. During this timeframe, zebrafish lack a functional adaptive immune system, so it is possible to study the innate immune response in isolation. Sequencing of the zebrafish genome has revealed significant genetic conservation with the human genome, and multiple studies have revealed both functional conservation of genes, including those critical to host cell infection and host cell inflammatory response. In addition to studying several fish viruses, zebrafish infection models have been developed for several human viruses, including influenza A, noroviruses, chikungunya, Zika, dengue, herpes simplex virus type 1, Sindbis, and hepatitis C virus. The development of these diverse viral infection models, coupled with the inherent strengths of the zebrafish model, particularly as it relates to our understanding of macrophage and neutrophil biology, offers opportunities for far more intensive studies aimed at understanding conserved host responses to viral infection. In this context, we review aspects relating to the evolution of innate immunity, including the evolution of viral pattern recognition receptors, interferons and interferon receptors, and non-coding RNAs.

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