Pathophysiology

Sepsis is caused by the invasion of intact pathogenic or commensal bacteria or bacterial cell wall constituents, especially lipopolysaccharides (LPS), in particular li-poid A = endotoxin of the outer membrane of Gramnegative bacteria, or peptidoglycan, teichoic and lipo-teichoic acids of Gram-positive bacteria, or toxins, e.g., toxic-shock-syndrome-toxin 1 and Staphylococcus au-reus toxin A. They bind to cellular receptors and co-receptors, e.g., CD14, toll-like receptors TLR2 and TLR4, CD18 (|32 integrins), and selectins, on the surfaces of monocytes/macrophages, neutrophils, and endothelial cells. Via intracellular signaling molecules, e.g., NF-kB and protein kinase C, they activate the transcription of mediator genes to induce the synthesis and release of numerous endogenous mediators, i.e., cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF), and platelet-activating factor (PAF). These pro-inflammatory and anti-inflammatory mediators often originate in an inflammed local site. They are formed and released with various kinetics. They act in part synergistically and in part antagonistically, mainly via additional mediators (chemokines, prostaglandins, thromboxanes, leukotrienes, and endogenous vasodilators nitric oxide [NO]), on target organs, and are responsible for a plethora of local and systemic effects in the host organism (Bernard et al. 2001; Dellinger 2003; Gerard 2003; Gogos et al. 2000; Hotchkiss and Karl 2003; Russell 2006; Van Amersfoort et al. 2003; Wilson et al. 1998).

TNF-a and IL-1 are the primary pro-inflammatory cytokines and have similar biological activities (Camus-si et al. 1991; Dinarello 1984). They alter the temperature regulation center in the hypothalamus, thus inducing fever. They act on the formatio reticularis in the brain stem (sleeping-waking center), the patient becomes somnolent or comatose. They stimulate the liberation of ACTH in the hypophysis. Via hematopoietic growth factors, they act on the bone marrow to stimulate the synthesis of neutrophils and liberate reserve neutrophils, causing peripheral leukocytosis and increased numbers of immature neutrophils (bands). They activate the neutrophils to rapid phagocytosis and production of bactericidal agents, i.e., proteases and oxygen radicals. They stimulate B and T lymphocytes and synthesis of antibodies and cellular immune reactions are increased; however, as sepsis persists, there is a shift to an anti-inflammatory immunosuppressive state (transient immune paralysis) because of apoptosis of B cells, CD4 helper T cells, and follicular dendritic cells (Liles 1997). In the liver, they stimulate the synthesis of acute-phase proteins, e.g., C-reactive protein (CRP), complement factors, and 1-antitrypsin. They stimulate the decay of muscle proteins (increased protein catabolism), and liberated amino acids are used for antibody synthesis. They activate vascular endothelial cells to produce cytokines such as PAF and NO, and promote increased vascular permeability by vascular endothelial injury and endo-thelial detachment. They up-regulate the synthesis of cell-surface molecules that enhance neutrophil-endo-thelial cell adhesion. They increase pro-coagulatory activity on endothelial cells and the synthesis of plasminogen activator inhibitor, and activate the complement and blood coagulation systems, which may result in micro-circulatory failure, tissue hypoxia, organ ischemia, and organ failure (Dellinger 2003; Dinarello 1984; Gogos et al. 2000; Hotchkiss and Karl 2003). On the other hand, IL-4 and IL-10 are anti-inflammatory cytokines since they inhibit the production of IL-1 and TNF (Gogos et al. 2000; Hotchkiss and Karl 2003; Russell 2006).

In summary, the pathophysiological phenomena and consequences of sepsis, severe sepsis, and septic shock result in:

• Poor perfusion of skin and internal organs with reduced arterial-venous oxygen gradient by by-passing the capillaries via multiple shunts, accumulation of lactate (metabolic acidosis), anoxia

• Activation of the complement and blood coagulation cascades

• Activation of B and T lymphocytes

• Activation of neutrophils, thus increasing their chemotaxis and adhesiveness

• Increased capillary permeability (capillary leak syndrome), hemoconcentration, decreased circulating blood volume

• Accumulation of neutrophils in the lungs where they release proteases and oxygen radicals which alter alveolar-capillary permeability to increased transudation of liquid, ions, and proteins into the interstitial space, which finally results in acute respiratory distress syndrome (ARDS, shock lung)

• Myocardial depression, hypotension

• Accelerated apoptosis of lymphocytes and gastrointestinal epithelial cells

• Disseminated intravascular coagulation (DIC)

• Impairment and finally failure of hepatic, renal, and pulmonary functions

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