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 Alterations in the activity of the innate host immune
system can be responsible for both the development of
shock, and the pathophysiologic sequelae of shock such
as the proinflammatory changes seen following
hemorrhage or multisystem trauma.

 When these predominantly paracrine mediators gain

access to the systemic circulation, they can induce a
variety of metabolic changes that are collectively
referred to as the á
 




    
 
 ultiple humoral mediators are activated during shock and
tissue injury
 The complement cascade
 Activation of the coagulation cascade
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 activated through both the classic and alternate pathways,

generates the anaphylatoxins C3a and C5a

 Direct complement fixation to injured tissues can progress to

the C5-C9 attack complex, causing further cell damage
 The complement cascade can be activated by injury,
shock, and severe infection, and contributes to host
defense and proflammatory activation.
 Significant complement consumption occurs after
hemorrhagic shock.
 In trauma patients, the degree of complement
activation is proportional to the magnitude of injury
and may serve as a marker for severity of injury.
 ½atients in septic shock also demonstrate activation of the
complement pathway, with elevations of the activated
complement proteins C3a and C5a.
 Activation of the complement cascade can contribute to the
development of organ dysfunction.
 ^ 
 icrovascular thrombosis
 with subsequent fibrinolysis leading to repeated episodes of
ischemia and reperfusion

 Components of the coagulation system, e.g. thrombin

 potent proinflammatory mediators that cause expression of
adhesion molecules on endothelial cells and activation of
neutrophils
 leading to microvascular injury

 Coagulation also activates the kallikrein-kininogen cascade

 contributing to hypotension
èicosanoids
 are vasoactive and immunomodulatory products of
arachidonic acid metabolism that include cyclooxygenase-
derived ½ s and thromboxane A2 as well as lipoxygenase-
derived leukotrienes and lipoxins.
Thromboxane A2
 a potent vasoconstrictor that contributes to the pulmonary
hypertension and acute tubular necrosis of shock.
½ I2 and ½ è2
 potent vasodilators that enhance capillary permeability and
edema formation.
The cysteinyl leukotrienes LTC4 and LTD4
 pivotal mediators of the vascular sequelae of anaphylaxis as
well as of shock states resulting from sepsis or tissue injury.
LTB4
 a potent neutrophil chemoattractant and secretagogue that
stimulates the formation of reactive oxygen species.
½latelet-activating factor
 an ether-linked, arachidonyl-containing phospholipid
mediator
 causes pulmonary vasoconstriction,
bronchoconstriction, systemic vasodilation, increased
capillary permeability, and the priming of macrophages
and neutrophils to produce enhanced levels of
inflammatory mediators
Tumor necrosis factor (TNF-Î)
 produced by activated macrophages, reproduces many
components of the shock state, including hypotension, lactic acidosis,
and respiratory failure.

Interleukin 1 (IL-1)
 produced by tissue-fixed macrophages, is critical to the
inflammatory response

Both are significantly elevated immediately following trauma and

shock.
IL-6
 also produced predominantly by the macrophage, has a
slightly delayed peak response but is the best predictor of
prolonged recovery and development of multiple organ
failure following shock.
IL-8
 chemokine
 potent neutrophil chemoattractants and activators that
upregulate adhesion molecules on the neutrophil to enhance
aggregation, adherence, and damage to the vascular
endothelium.
Inducible isoform of NO synthase (iNOS)
 stimulated by the inflammatory response
 is overexpressed and produces toxic nitrosyl- and oxygen-
derived free radicals that
 contribute to the hyperdynamic cardiovascular response in
sepsis.
 ultiple inflammatory cells, including neutrophils,
macrophages, and platelets, are a major contributor to
inflammation-induced injury.
 argination of activated neutrophils in the microcirculation
is a common pathologic finding in shock
 Causing secondary injury due to the release of
 Toxic oxygen radicals
 Lipases
 ½roteases
 Tissue-fixed macrophages
 produce virtually all major components of the inflammatory
response
 orchestrate the progression and duration of the inflammatory
response
 Activation of the monocyte/macrophage
 through the highly conserved membrane Toll-like receptors
(TLRs)
 recognize damage-associated molecular patterns (DA½s)
 released following tissue injury
 recognize pathogen-associated molecular patterns (½A½s)
 released by pathogenic microbial organisms
 TLRs also appear important for the chronic inflammation
seen in
 Crohn's disease
 ulcerative colitis
 transplant rejection