Septic And Traumatic Shock

In the initial response to a localised infection, the release of endotoxins or exotoxins by a bacterial infection induces tissue macrophages, as well as other cells, to generate inflammatory cytokines. Although these early-response cytokines play an important role in host defence (see above) by attracting activated neutrophils to the site of infection, the entry of these cytokines and bacterial products into the systemic circulation can induce widespread microvascular injury. Systemic alterations observed in patients affected by disseminated sepsis are identified as systemic inflammatory response syndrome. All the clinical features of this syndrome are due to the effects of cytokines expressed in response to PAMPs. They may include fever and haematic increase of neutrophils and acute phase-proteins in patients with a moderate clinical expression. In contrast, a massive septic process induces a marked systemic inflammatory response syndrome caused by high levels of circulating cytokines induced by large quantities of PAMPs released by pathogens, resulting in disseminated intravascular coagulation (DIC). Thrombosis and inflammation are responsible for the damage to tissues and organs and lead to functional collapse and septic shock. Additional damage is caused by neutrophil activation before their migration out of the vascular system, with consequent endothelial damage and slowing of the haematic flux, that affect particularly lungs and liver, leading to an inadequate hepatic gluco-neogenesis and respiratory distress syndrome due to plasma outflow into interstitial pulmonary space. Kidney and gut are also damaged by reduced perfusion. Excessive amounts of nitric oxide (NO) produced by myocardial cells and vasal muscular cells upon cytokine stimulation lead to cardiac decompensation, pressure collapse and cardiovascular shock. TNF-a, IL-1P and NO seem to play an important role in sepsis-induced myocardial dysfunction [146], Disseminated intravascular coagulation, hypoglycaemia and cardiovascular decompensation are the clinical expression of septic shock that is mostly lethal.

TNF-a, produced by LPS-activated macrophages, is the main mediator responsible for this syndrome. In fact TNF-a plasma levels are elevated during experimental and clinical sepsis and increasing concentrations of TNF-a during sepsis are associated with increasing mortality [147,148]; exogenous TNF-a administration in humans and animals leads to multiorgan failure simulating sepsis and LPS effects, moreover TNF-a neutralization often leads to amelioration of sepsis syndrome and improves survival [149,150].

Also traumatic shock, such as acute hypovolemic hemorragic shock, initiates a similar inflam matory response characterized by the up-regulation of cytokine expression [151] and accumulation of neutrophils in various tissues [ 152] with consequent multiple organ failure. The mechanism by which this type of shock triggers the inflammatory response still remains to be elucidated. Elevated adrenergic activity [153] and systemic release of proinflammatory agents from the gut [154], have been hypothesized to contribute to organ injury. In addition, reactive oxygen species are implicated in various signal transduction pathways [155], Acute hemorragic shock is characterized by severe hypotension, increased levels of TNF-a and vascular failure due to the loss of vascular activity after stimulation with vasoconstrictive stimuli. The early activation of NFkB in the liver induced by blood loss in turn activates an inflammatory cascade, leading to the expression of TNF-a, finally culminating in the fatal outcome for the host [156],

The possible therapeutic use of inhibitors of TLR or complement components to abrogate or minimize the effects of uncontrolled inflammatory response and sepsis is at present under investigation. Basing on the experimental and clinical evidence reported in this Chapter, a number of studies on molecules able to inhibit the function of complement components Clq and MBL [157] or the signaling of TLR4 [158] or CD 14 [159] are ongoing to exploit this possibility.

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