inflammatory responses

8/8/2019 Inflammatory Responses

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Inflammatory Responses

in Shock


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y Alterations in the activity of the innate host immunesystem can be responsible for both the development ofshock, and the pathophysiologic sequelae of shock suchas the proinflammatory changes seen followinghemorrhage or multisystem trauma.

y When these predominantly paracrine mediators gainaccess to the systemic circulation, they can induce avariety of metabolic changes that are collectively

referred to as the host inflammatory response.


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Schwartzs Principles of Surgery 8/ed


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y Multiple humoral mediators are activated during shock and

tissue injury

y The complement cascade

y

Activation of the coagulation cascade


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The complement cascade

y activated through both the classic and alternate pathways,

generates the anaphylatoxins C3a and C5a

yDirect complement fixation to injured tissues can progress tothe C5-C9 attack complex, causing further cell damage


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y The complement cascade can be activated by injury,shock, and severe infection, and contributes to hostdefense and proflammatory activation.

y

Significant complement consumption occurs afterhemorrhagic shock.

y In trauma patients, the degree of complementactivation is proportional to the magnitude of injury

and may serve as a marker for severity of injury.


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y Patients in septic shock also demonstrate activation of the

complement pathway, with elevations of the activated

complement proteins C3a and C5a.

y

Activation of the complement cascade can contribute to thedevelopment of organ dysfunction.


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Coagulation cascade

y Microvascular thrombosisy with subsequent fibrinolysis leading to repeated episodes of

ischemia and reperfusion

y

Components of the coagulation system, e.g. thrombiny potent proinflammatory mediators that cause expression ofadhesion molecules on endothelial cells and activation ofneutrophilsy leading to microvascular injury

y Coagulation also activates the kallikrein-kininogen cascadey contributing to hypotension


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Eicosanoids

y are vasoactive and immunomodulatory products of

arachidonic acid metabolism that include cyclooxygenase-

derived PGs and thromboxane A2 as well as lipoxygenase-derived leukotrienes and lipoxins.


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ThromboxaneA2y a potent vasoconstrictor that contributes to the pulmonary

hypertension and acute tubular necrosis of shock.


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PGI2 and PGE2y potent vasodilators that enhance capillary permeability and

edema formation.


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The cysteinyl leukotrienes LTC4 and LTD4y pivotal mediators of the vascular sequelae of anaphylaxis as

well as of shock states resulting from sepsis or tissue injury.


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LTB4y a potent neutrophil chemoattractant and secretagogue that

stimulates the formation of reactive oxygen species.


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Platelet-activating factor

y an ether-linked, arachidonyl-containing phospholipid

mediator

y causes pulmonary vasoconstriction,bronchoconstriction, systemic vasodilation, increased

capillary permeability, and the priming of macrophages

and neutrophils to produce enhanced levels ofinflammatory mediators


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Tumor necrosis factor (TNF-)

y produced by activated macrophages, reproduces many

components of the shock state, including hypotension, lactic acidosis,

and respiratory failure.

Interleukin 1 (IL-1)

y produced by tissue-fixed macrophages, is critical to the

inflammatory response

Both are significantly elevated immediately following trauma and

shock.


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IL-6

y also produced predominantly by the macrophage, has a

slightly delayed peak response but is the best predictor of

prolonged recovery and development of multiple organfailure following shock.


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IL-8

y chemokine

y potent neutrophil chemoattractants and activators that

upregulate adhesion molecules on the neutrophil to enhanceaggregation, adherence, and damage to the vascular

endothelium.


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Inducible isoform of NO synthase (iNOS)

y stimulated by the inflammatory response

y is overexpressed and produces toxic nitrosyl- and oxygen-derived free radicals that

y contribute to the hyperdynamic cardiovascular response in

sepsis.


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y Multiple inflammatory cells, including neutrophils,

macrophages, and platelets, are a major contributor to

inflammation-induced injury.


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y Margination of activated neutrophils in the microcirculation

is a common pathologic finding in shock

y Causing secondary injury due to the release of

y Toxic oxygen radicals

y Lipases

y Proteases


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y Tissue-fixed macrophages

y produce virtually all major components of the inflammatory

response

y orchestrate the progression and duration of the inflammatory

response


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y Activation of the monocyte/macrophage

y through the highly conserved membrane Toll-like receptors

(TLRs)

y recognize damage-associated molecular patterns (DAMPs)

y released following tissue injury

y recognize pathogen-associated molecular patterns (PAMPs)

y released by pathogenic microbial organisms


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y TLRs also appear important for the chronic inflammation

seen in

y Crohn's disease

y ulcerative colitis

y transplant rejection


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inflammatory responses

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