Sepsis inflammatory mediators

Discuss the pathophysiology of sepsis as it relates to endotoxin, peptidoglycan, and pro-and anti-inflammatory mediators. 

Inflammation is the key factor in the development of sepsis. Patients with severe infections, trauma, debilitating conditions, or an immunocompromised status may experience an imbalance between inflammatory mediators that progresses to sepsis. 

The development of sepsis is complex and multifactorial. The normal host response to infection is designed to localize and control bacterial invasion and initiate repair of injured tissue through phagocytic cells and inflammatory mediators.1 Sepsis... 

The key factor in the development of sepsis is inflammation. Inflammation is intended to be a local and contained response to infection or injury. Infection or injury is controlled through pro- and anti-inflammatory mediators. Pro-inflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue.1,13-16 In order to control the intensity and duration of the inflammatory response, antiinflammatory mediators are released that act to regulate pro-inflammatory mediators.15-16 The balance between pro- and anti-inflammatory mediators localizes infection/injury of host tissue.13-16 However, systemic responses ensue when equilibrium in the inflammatory process is lost. 

The inflammatory process in sepsis is linked to the coagulation system. Pro-inflammatory mediators maybe procoagulant and antifibrinolytic, whereas anti-inflammatory mediators may be fibrinolytic. A key factor in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Protein C levels are decreased in septic patients. 

Thus, inflammatory mediators of humoral and cellular origin are largely implicated in the development of sepsis and SIRS. These mediators, together with the inflammatory cells themselves, activate and damage the endothelial cells, which... 

B26. Billiau, A., and Vandekerckhove, F., Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock. Eur. J. Clin. Invest. 21, 559-573 (1991). 

Sepsis, or SIRS, is a maladaptive reaction to severe infection in which a variety of inflammatory mediators are released. Some of these mediators are bacterial... 

The bead-based technology works not only for inflammatory mediators that have diagnostic/prognostic valne, bnt also for others (e.g., C-reactive protein, IL-6). This can make bead-based systems even more powerful. Kofoed et al. combined in-house and commercially available kits and used bead-based Luminex systems to assay biomarkers of potential interest in EDTA-plasma samples (70). A 3-plex assay for suPAR, sTREM-1, MIF was added to a commercially available human cytokine panel, IL-1P, IL-6, IL-8, GM-CSF, and TNF-a. Compared to healthy controls, all eight analytes were significantly higher in plasma from bacterial sepsis patients. 

With one exception sepsis therapy focusing primarily on the pro-inflammatory mediators has not produced positive results (Zeni et al., 1997). Hence, targeting the sepsis cascade at earlier steps may yield better outcomes. 

Kanesaka, S., Sasaki, J., Kuzume, M., Narihara, K., Takahashi, Y. Effect of direct hemoperfusion using polymyxin B immobilized fiber on inflammatory mediators in patients with severe sepsis and septic shock. Int J Artif Organs 31 (2008) 891-897. 

Sepsis involves activation of inflammatory pathways, and a complex interaction between proinflammatory and anti-inflammatory mediators plays a major role in the pathogenesis of sepsis. The key proinflammatory mediators include tumor necrosis factor-a (TNF-a), interleukin 1/3 (IL-1/3), and interleukin 6 (IL-6), which are released by activated macrophages. Other mediators that may be important for the pathogenesis of sepsis include interleukin 8 (IL-8), platelet-activating factor (PAF), leukotrienes, and thromboxane A2. " The significant anti-inflammatory mediators include IL-1 receptor antagonist (IL-lra), IL-4, and IL-10. These anti-inflammatory cytokines inhibit the production of the proinflammatory cytokines and down-regulate some inflammatory cells. 

The specific cellular and biochemical mechanisms mediating septic shock and ARDS are undefined. Current concepts favour inflammatory mediators, a number of which have been implicated in experimentally induced sepsis and ARDS. These include oxygen free radicals, endogenous opiates, kinins, angiotensin, histamine, serotonin and catecholamines . ... 

Indications for renal replacement therapy in the acute setting and for other disease processes are different from those for ESRD. A common mode of ESRD therapy in the outpatient setting is intermittent hemodialysis (IHD) where a patient receives intense treatment over the course of a few hours several times a week. Acute renal failure in the inpatient setting is often treated with continuous renal replacement therapy (CRRT), which is applied for the entire duration of the patient s clinical need and relies upon hemofiltration to a higher degree than IHD (Meyer, 2000). Other nonrenal indications for CRRT are based on the theoretical removal of inflammatory mediators or toxins and elimination of excess fluid (Schetz, 1999). These illnesses include sepsis and systemic inflammatory response syndrome, acute respiratory distress syndrome, congestive heart failure with volume overload, tumor lysis syndrome, crush injury, and genetic metabolic disturbances (Schetz, 1999). 

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