There is now compelling evidence that septic shock and its morbid consequences are the direct result of endogenous proteins and phospholipid mediators secreted by the infected individual. Molecular pathophysiology of sepsis can be divided into 3 phases: induction of cytokine synthesis, cytokine synthesis and secretion, and cascade phase of sepsis.
The induction of cytokine synthesis involves the interaction of certain microbial molecules that, when recognized by the host, results in the production of mediators that amplify and transmit the microbial signal to other cells and tissues.
Of currently available models, the pathophysiology of gram-negative infection is best understood. An individual suffering from a gram-negative infection is not only exposed to membrane bound lipopolysaccharides (LPS) at the site of infection, but is also systemically exposed to the free endotoxin on fragments of bacterial outer membrane commonly shed during bacterial growth and replication. LPS binds to LPS-binding protein forming an LPS-LPS-binding protein complex. This complex is
1000-fold more potent than LPS alone in inducing TNF production by macrophages. The receptor for this complex is known to be the CD14 molecule that is found on monocytes, macrophages, and neutrophils. The peptidoglycan and lipoteichoic acids of gram-positive bacteria, certain polysaccharides, extracellular enzymes, and toxins induce cytokine synthesis in animals similar to those of LPS.
The phase of cytokine synthesis and secretion involves several regulated steps. These steps include transcription (synthesis of messenger RNA from the DNA template), translation of mRNA into protein, post-translational processing, and secretion of protein. An example is when LPS-LPS-binding protein complex interacts with the CD14, transcription of TNF gene in vitro increases threefold with levels of TNF mRNA increasing 100-fold. Biosynthesis and secretion of TNF, however, increase over 10,000-fold; this is primarily due to increased translational efficiency of preformed TNF mRNA as well as efficient translation of newly transcribed TNF mRNA.
The cascade portion of sepsis results from the activation and release of a central mediator (TNF, IL-1), which results in the secretion of various secondary mediators (IL-1, IL-6, IL-8, PAF, prostaglandins, leukotrienes); the activation of neutrophils, the complement system, and vascular endothelial cells; and synthesis of acute phase reactants. LPS and TNF probably promote intravascular coagulation initially by inducing blood monocytes to express tissue factor, by initiating the release of plasminogen activator inhibitor-1 (PAI-1) and inhibiting the expression of thrombomodulin and plasminogen activator by vascular endothelial cells. TNF, IL-1, and IL-6 are cytokines that have been detected in increased concentrations in the serum of patients with septic shock. The physiologic outcome of this complex cascade comprises the SIRS.
Parallel to SIRS is the body's intrinsic anti-inflammatory response. This response "compensatory anti-inflammatory response syndrome (CARS)" attempts to downregulate the SIRS response. Agents identified as participating in CARS include interleukins (IL-4, -10, -11, -13), transforming growth factor-b (TGF-b), colony-stimulating factor (CSF), soluble receptors to tumor necrosis factor (sTNFR), and antagonists to tumor necrosis factor (TNFra) and IL-1 (IL-1ra) receptors. These mediators inhibit T and B lymphocyte activity, as well as decrease antigen-presenting activity on the monocyte. The body normally maintains a delicate balance between SIRS and CARS. Uncontrolled sepsis and SIRS lead to profound hypotension, inadequate perfusion, and death. If the CARS reaction is severe, it will manifest clinically as anergy and increase susceptibility to infection.
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