Cannabinoid 2 Receptor and GPR55 as Therapeutic Targets in Experimental Sepsis (original) (raw)
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Accepted for publication on September 14, 2007. SEPSIS: FROM BENCH TO BEDSIDE
2014
Sepsis is a syndrome related to severe infections. It is defined as the systemic host response to microorganisms in previously sterile tissues and is characterized by end-organ dysfunction away from the primary site of infection. The normal host response to infection is complex and aims to identify and control pathogen invasion, as well as to start immediate tissue repair. Both the cellular and humoral immune systems are activated, giving rise to both anti-inflammatory and proinflammatory responses. The chain of events that leads to sepsis is derived from the exacerbation of these mechanisms, promoting massive liberation of mediators and the progression of multiple organ dysfunction. Despite increasing knowledge about the pathophysiological pathways and processes involved in sepsis, morbidity and mortality remain unacceptably high. A large number of immunomodulatory agents have been studied in experimental and clinical settings in an attempt to find an efficacious anti-inflammatory ...
Advances in Bioscience and Biotechnology, 2013
Despite the advances in the therapeutic approaches, health care protocols and policies, sepsis continues to be an important problem in clinical medicine. High lethality of sepsis cases calls for a detailed and critically important study of the pathophysiology of sepsis. In this review, we discuss pathomechanisms of sepsis and the role of cytokines that are released in sepsis. We propose that the systemic levels of cytokines are not always reflecting the pathological picture and the immune status of the patient. One of the emerging approaches which may bring an effective treatment strategy exploits the endocannabinoid system for its immunomodulatory properties. Following from that, the research in this particular field is very important as it can bring understanding behind the complicated pathophysiology of sepsis.
Critical Care, 2012
Introduction: Cannabinoid receptor 2 (CB2R) expression is upregulated during sepsis. However, there are conflicting results regarding the effects of CB2R modulation in the hyperinflammatory phase of the disease. The aim of this study was therefore to investigate the effects of CB2R manipulation on leukocyte activation within the intestinal microcirculation in two acute experimental sepsis models. Methods: In the endotoxemia model we studied four groups of Lewis rats: controls, lipopolysaccharide (LPS), LPS + CB2R agonist HU308 (2.5 mg/kg), and LPS + CB2R antagonist AM630 (2.5 mg/kg). In the colon ascendens stent peritonitis (CASP)-induced sepsis model we also studied four groups: sham group, CASP and CASP + CB2R agonist (HU308, 2.5 or 10 mg/kg). Intravital microscopy was performed 2 hours following LPS/placebo administration or 16 hours following CASP/sham surgery to quantify intestinal leukocyte recruitment. Additionally, hemodynamic monitoring, histological examinations and measurements of inflammatory mediators were performed. Results: HU308 administration significantly reduced intestinal leukocyte adhesion in both acute sepsis models. The systemic levels of inflammatory mediators were significantly reduced by 10 mg/kg HU308 treatment in CASP animals. Conclusion: CB2R activation reduces leukocyte activation and systemic release of inflammatory mediators in acute experimental sepsis. Drugs targeting the CB2R pathway may have therapeutic potential in sepsis.
Mechanisms of immunodysregulation in sepsis
Contributions to nephrology, 2004
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents ® and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
BMJ, 2003
Severe sepsis and septic shock are important causes of death in intensive care units. Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated into clinical benefit. Several new treatment approaches have given encouraging results. Evidence suggests that the way forward is to develop pathogen specific regimens rather than assume that one treatment fits all.
The etiology of sepsis: turned inside out
Trends in Molecular Medicine, 2006
The sepsis syndrome is thought to occur when microbial products activate Toll-like receptors stimulating widespread inflammation, in turn causing organ failure, shock and death. However, recent discoveries reveal that: (i) not only microbial substances but also endogenous molecules can trigger Toll-like receptors; (ii) Toll-like receptor-4, the endotoxin receptor, is constitutively suppressed; and (iii) the first step in sepsis could be the release of Toll-like receptor-4 from suppression. These discoveries suggest that endotoxin might not always initiate the sepsis syndrome and they explain why anti-endotoxin therapies fail. The discoveries also suggest new therapeutic targets-endogenous agonists and Toll-like receptor regulators-for treatment of sepsis.
Sepsis: a roadmap for future research
The Lancet Infectious Diseases, 2015
Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specifi c 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 fl uids 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 aff ect the incidence and course of the disease, sepsis has stubbornly resisted all eff orts 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.
Mechanisms of sepsis and insights from clinical trials
Drug discovery today. Disease mechanisms, 2007
Multiple clinical trials of adjunctive therapy for sepsis and septic shock have been conducted to neutralize bacterial components or to modulate host inflammatory responses to infection but with limited success. Many therapies are only beneficial only in patients with a high severity of illness and have minimal or harmful effects in patients that are less severely ill. Improved measures of severity of illness and discovery of biomarkers to help identify these high-risk patients are needed.
Sepsis and Septic Shock: Updates
2015
Sepsis, severe sepsis and septic shock are a spectrum which occurs in response to an infection. They are associated with a high degree of morbidity and mortality. This article reviews the definitions, pathophysiology and management of sepsis. In particular, measures to achieve adequate tissue perfusion and oxygenation, as outlined by the updated 2012 Surviving Sepsis Campaign, are discussed. INTRODUCTION: Sepsis is a common disease condition. It occurs when an infection causes a generalized inflammatory response in the host. Sepsis is potentially fatal and should be treated as a medical emergency. It is one of the leading causes of death across the world. It is estimated that 750,000 cases of sepsis occur in the United States annually and that about 1/3 rd to ½ of these die 1, 2. Despite advances in medical care, its incidence continues to rise. Developing countries, like Pakistan, especially suffer due to sepsis. An estimated 60-80% of deaths in these countries occur due to sepsis 3. Poor hygiene, low standards of living, malnutrition and a paucity of healthcare facilities and resources contribute to the disproportionately high morbidity and mortality from sepsis in these nations 4. Early, aggressive therapy of sepsis improves the chance of survival 5. This article reviews the pathophysiology and management of sepsis. DEFINITIONS: The systemic inflammatory response syndrome (SIRS) is a deleterious reaction of the immune system to a variety of clinical insults. (See Table I). When SIRS occurs in the setting of an infection, the overall syndrome is referred to as sepsis. Severe sepsis occurs when there is evidence of acute end organ dysfunction in the setting of sepsis, whereas septic shock refers to sepsis associated with arterial hypotension that is refractory to adequate fluid resuscitation 6. Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate, or oliguria 6. PATHOPHYSIOLOGY OF SEPSIS: Bacteremia or infection at any site of the body, by any microorganismbacteria, fungi, parasites or virusescan lead to sepsis. Microbial molecules (e.g. bacterial cell wall componentslipopolysaccharide A, endotoxin for Gram negatives, peptidoglycans, exotoxins for Gram positive organismsbacterial DNA, viral RNA) trigger the inflammatory cascade, via trans-membrane receptors, e.g. toll-like Receptors or T-cell antigen receptors. Pro-inflammatory cytokines, TNF alpha and IL-1, are released via signal transduction molecules (nuclear factor kappa B) and are part of a complex metabolic milieu in which, besides the inflammatory cascade (comprising prostaglandins, leukotrienes platelet activating factor, phospholipase A 2 , adhesion molecules), the complement and coagulation systems, along with anti-inflammatory cytokines (IL-10), also play a role.
Sepsis: Current Dogma and New Perspectives
Immunity, 2014
Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity and mortality worldwide. Current immunological mechanisms do not explain the basis of cellular dysfunction and organ failure, the ultimate cause of death. Here we review current dogma and argue 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. These mechanisms might hold the key to future therapeutic strategies.