The inflammatory response in sepsis.
TL;DR: Recent insights into the signaling pathways in immune and phagocytic cells that underlie sepsis and SIRS are discussed and how these might be targeted for therapeutic interventions to reverse or attenuate pathways that lead to lethality during sepsi are considered.
About: This article is published in Trends in Immunology.The article was published on 2013-03-01 and is currently open access. It has received 382 citations till now. The article focuses on the topics: Systemic inflammatory response syndrome & Septic shock.
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Brighton and Sussex Medical School1, Université libre de Bruxelles2, Sunnybrook Health Sciences Centre3, Federal University of São Paulo4, University of Pittsburgh5, University Hospital of Lausanne6, Brown University7, The Feinstein Institute for Medical Research8, University of Amsterdam9, European Medicines Agency10
TL;DR: The understanding of the clinical epidemiology and management of sepsis is set out and how the present approaches might be challenged to develop a new roadmap for future research is asked.
Abstract: Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research.
774 citations
TL;DR: It is argued that it is time to delineate novel immunometabolic and neurophysiological mechanisms underlying the altered cellular bioenergetics and failure of epithelial and endothelial barriers that produce organ dysfunction and death.
495 citations
Cites background from "The inflammatory response in sepsis..."
...Neural signals can also descend from the brainstem via the sympathetic chain, culminating in the release of adrenergic neurotransmitters in tissues that interact with innate immune cells expressing alpha-adrenergic and beta-adrenergic receptors to modulate cytokine release (Bosmann and Ward, 2013)....
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TL;DR: Efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long‐term sepsis mortality, which alters the innate and adaptive immune responses for sustained periods of time after clinical recovery.
Abstract: Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality
427 citations
TL;DR: These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved.
Abstract: Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after "recovery" from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical "recovery," with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved.
424 citations
TL;DR: This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as a focal point in immunomodulatory strategies for treating inflammatory diseases.
Abstract: Although acute or chronic inflammation is a common component of many clinical disorders, the underlying processes can be highly distinct. In recent years, the complement system has been associated with a growing number of immunological and inflammatory conditions that include degenerative diseases, cancer, and transplant rejection. It becomes evident that excessive activation or insufficient control of complement activation on host cells can cause an immune imbalance that may fuel a vicious cycle between complement, inflammatory cells, and tissue damage that exacerbates clinical complications. Although the exact involvement of complement needs to be carefully investigated for each disease, therapeutic modulation of complement activity emerges as an attractive target for upstream inhibition of inflammatory processes. This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as a focal point in immunomodulatory strategies for treating inflammatory diseases.
399 citations
References
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TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.
12,240 citations
TL;DR: The rate of sepsis due to fungal organisms increased by 207 percent, with gram-positive bacteria becoming the predominant pathogens after 1987, and the total in-hospital mortality rate fell, yet the total number of deaths continued to increase.
Abstract: Background Sepsis represents a substantial health care burden, and there is limited epidemiologic information about the demography of sepsis or about the temporal changes in its incidence and outcome. We investigated the epidemiology of sepsis in the United States, with specific examination of race and sex, causative organisms, the disposition of patients, and the incidence and outcome. Methods We analyzed the occurrence of sepsis from 1979 through 2000 using a nationally representative sample of all nonfederal acute care hospitals in the United States. Data on new cases were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Results Review of discharge data on approximately 750 million hospitalizations in the United States over the 22-year period identified 10,319,418 cases of sepsis. Sepsis was more common among men than among women (mean annual relative risk, 1.28 [95 percent confidence interval, 1.24 to 1.32]...
5,704 citations
TL;DR: Progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors, and on developing novel therapeutics that can facilitate and enhance lung repair.
Abstract: The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
1,506 citations
TL;DR: Standardized procedures for inducing sepsis in mice and rats are defined by applying defined severity grades of sepsi through modulation of the position of cecal ligation.
Abstract: Sepsis remains a prevalent clinical challenge and the underlying pathophysiology is still poorly understood. To investigate the complex molecular mechanisms of sepsis, various animal models have been developed, the most frequently used being the cecal ligation and puncture (CLP) model in rodents. In this model, sepsis originates from a polymicrobial infectious focus within the abdominal cavity, followed by bacterial translocation into the blood compartment, which then triggers a systemic inflammatory response. A requirement of this model is that it is performed with high consistency to obtain reproducible results. Evidence is now emerging that the accompanying inflammatory response varies with the severity grade of sepsis, which is highly dependent on the extent of cecal ligation. In this protocol, we define standardized procedures for inducing sepsis in mice and rats by applying defined severity grades of sepsis through modulation of the position of cecal ligation. The CLP procedure can be performed in as little as 10 min for each animal by an experienced user, with additional time required for subsequent postoperative care and data collection.
1,480 citations
TL;DR: Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression, and targeted immune-enhancing therapy may be a valid approach in selected patients with sepsi.
Abstract: Context Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections. Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.
1,192 citations