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upregulation of cell adhesion molecules such as P-selectin, and inhibits vasorelaxation and perfusion.298

Low oxygen tension induces the conversion of xanthine dehydrogenase to xanthine oxidase. Reperfusion

and reoxygenation yield the formation of superoxide anion and H2O2 and induce oxidant injury.

Neutrophils and other cellular effectors are progressively recruited and activated, releasing ROS,

cytokines, and NO, further contributing to increased vascular permeability and tissue injury. PAF

released by neutrophils activates circulating platelets and promotes vascular plugging. Platelets also

release factors that enhance platelet–neutrophil adhesion. Both cell types also release vasoconstricting

agents that can further exacerbate no-reflow. Capillary plugging by neutrophils and platelets can impair

local blood flow and cause the “no-reflow phenomenon.”39

Neutrophils mediate direct toxicity to the surrounding tissue through the elaboration of ROS and

granule contents. Peroxynitrite formed by the reaction of NO and superoxide can contribute directly to

tissue injury during reperfusion. Neutrophil granule proteases such as elastase, collagenase, and

gelatinase alter the vascular permeability and are highly destructive to local tissue. The significance of

the neutrophil in mediating these effects are apparent in neutrophil depletion studies demonstrating

attenuated tissue injury when compared to subjects with normal numbers of neutrophils.299 Animal

studies using blocking monoclonal antibodies to selectins and β2

integrins show improved organ

function ischemia/reperfusion.300

The mechanism by which complement is activated with reperfusion is not completely understood.

Ischemia may alter the cell’s plasma membrane or through the exposure of basement membrane or

subcellular organelle components, creating a complement-activating surface. Alternatively, binding of

natural antibody may lead to induction of these cascades.172 Complement activation has been shown to

occur in the setting of therapeutic thrombolysis. The generation of plasmin-dependent fibrinolytic

agents and plasmin after tissue plasminogen activator administration has been associated with

complement activation.301

Anaphylatoxins are important effectors of complement-mediated injury. They alter vascular

permeability, induce smooth muscle cell contraction, and stimulate the release of histamine from mast

cells and basophils. C3a and C5a are potent chemoattractants especially for neutrophils. C5 can be

activated by an abundance of oxygen free radicals. The subsequent generation of the MAC perturbs the

maintenance of vital ion gradients, induces cell lysis, and facilitates neutrophil recruitment. In addition

it can induce the expression of numerous inflammatory mediators, including cytokines (TNFα, IL-1, IL8), ROS, prostaglandins, LTs, and cell surface adhesion molecules.302

Systemic Inflammatory Response Syndrome

The inability of host defenses to control a localized inflammatory process or an unchecked inflammatory

response can result in SIRS. A recent consensus conference defined SIRS as the presence of any two of

the following physiologic parameters: (1) a temperature greater than 38°C or less than 36°C; (2)

leukocytosis (>12,000), leukopenia (<4,000), of more than 10% bands; (3) pulse greater than 90 beats

per minute; (4) tachypnea (respiratory rate greater than 20 or PaCO2 < 32 mm Hg).303 Infection

underlies a significant minority of cases as only a third of patients with SIRS will have a documented

infection and meet the criteria for sepsis. There is a continuum from the development of SIRS to sepsis,

to severe sepsis, septic shock, and MODS.304 The outcome depends on the balance between SIRS and

host compensatory mechanisms. In one prospective study, 26% of patients with SIRS developed sepsis

and 7% died.305

SIRS may be initiated by infectious or noninfectious causes, such as trauma, autoimmune reactions, or

pancreatitis. Gram-negative organisms, rich in LPS, induce a potent inflammatory response mediated

through the CD14/TLR4/MyD88 pathway previously described and account for the majority of

infectious SIRS cases. Gram-positive organisms can generate a similarly impressive degree of

inflammation either through TLR2 or alternative mechanisms. Streptococcal superantigen may induce a

global and nonspecific activation of T cells that culminates in massive systemic elaboration of cytokines

and cardiovascular collapse termed TSS. Trauma, either through tissue injury (HMGB1-RAGE, HSPCD91) or the ischemia/reperfusion consequent to hemorrhage can culminate in inflammatory

pathophysiology indistinguishable from that accompanying these other inflammatory states. As the

growing evidence continues to support the promiscuity of TLR and other signaling pathways, we are

replacing the former concept distinct receptor-signaling mechanisms for each stimulus with one that

emphasizes the similarities, overlap and integration. Though there are clearly mechanisms by which

host distinguishes normal self from endogenous (trauma) and exogenous (infection) dangers, there is

considerable overlap, and all stimuli appear to converge upon similar signaling mechanisms in attaining

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the goal of preserving the host.

The development of SIRS has been described as progressing through three stages: Stage I – local

cytokine production recruits inflammatory cells to the injured site; Stage II – an acute-phase response is

initiated and small quantities of cytokines are released into the circulation to enhance the local

response; and Stage III – homeostasis cannot be reestablished.306 Enhanced levels of CRP, the major

acute-phase protein in humans, occur in SIRS/sepsis, and clinical resolution is preceded by a drop in

CRP levels.

The elaboration of proinflammatory cytokines (IL-1, TNFα, and IL-6) is central to the pathogenesis of

SIRS regardless of the initiating stimulus. Their release triggers increased expression of adhesion

molecules, leukocyte recruitment, and the production of secondary proinflammatory mediators, such as

chemokines. Endotoxin is one of the most powerful triggers of SIRS. LPS activates the complement and

coagulation cascades, induces endothelial cell activation, and increases TNFα and IL-1 synthesis, and the

late release of HMGB1. However, noninfectious tissue injury induces a similar inflammatory response.

LPS, TNFα, and IL-1 also induce increased production of NO by iNOS. PGI2 and arachidonic acid,

together with NO contribute to decreased systemic vascular resistance and hypotension. Autocrine and

paracrine NO production also results in myocardial depression. Increased vascular permeability

promotes extravasation of fluid and edema formation. Activated endothelial cells express tissue factor,

PECAM, and TXA2

, which promote a procoagulant local environment that predisposes to microthrombi

formation. Adherent leukocytes further exacerbate organ injury by mechanically impeding

microvascular blood flow and by damaging the endothelial cells and surrounding connective tissue. The

results are end-organ hypoperfusion, inadequate oxygen delivery, initiation of anaerobic metabolism,

and organ failure. The metabolic and nutritional sequelae of this activated cytokine milieu includes

fever, catabolism, cachexia, and altered fat, glucose, and trace mineral metabolism.

SIRS is counteracted by the concomitant induction of an anti-inflammatory response termed the

compensatory anti-inflammatory response syndrome (CARS).306 Many of the proinflammatory

mediators that participate in SIRS modulate the immune function of lymphocytes and mononuclear cells.

Proinflammatory mediators can inhibit their own synthesis or enhance the synthesis of natural

antagonists by negative feedback mechanisms. Thus, at any given time, the clinical manifestation is

SIRS, CARS, or an intermediate, mixed inflammatory response syndrome. The spectrum of features that

characterizes these syndromes has been termed CHAOS (cardiovascular shock, homeostasis, apoptosis,

organ dysfunction, and immune suppression). Studies employing a variety of specific anticytokine

agents have failed to observe an improvement in the outcome of patients with SIRS or sepsis.

Chronic Inflammation

There are no clear boundaries between an acute and a chronic inflammatory response. In general, if the

source of an acute inflammatory process is incompletely eliminated, a state of chronic inflammation

eventually ensues. Chronicity is usually not characterized by the signs classically associated with acute

responses, such as swelling, heat, or redness. Pain is minimal if not absent. Microscopically, a

mononuclear cell infiltrate predominates (lymphocytes, monocytes, plasma cells) with proliferation of

fibroblasts and vascular elements.

Many agents can create a state of chronic inflammation, including persistent infectious agents,

remnants of dead organisms, foreign bodies, and metabolic byproducts. Ultimately, chronicity of

inflammation is a result of the immune response to a persistent antigen. Furthermore, a chronic

inflammatory response can develop in the absence of a preceding acute response, such as infections with

agents of low toxicity such as mycobacterium and treponema. CD4+ T cells and macrophages are the

primary cellular orchestrators of chronic inflammatory response.307 TH1 cell–mediated immune

responses are protective against most microbes and usually result in the elimination of the pathogen. If

the microbe persists, the ongoing TH1 response results in inflammatory tissue injury. Cytokines and

growth factors released by T lymphocytes and macrophages stimulate proliferative responses.

Neutrophils and eosinophils contribute to the release of proteolytic enzymes and oxygen derivatives.

Eosinophilia occurs with chronic parasitic infections and hypersensitivity conditions. Fibroblasts are

actively recruited by chemoattractants such as fibrin, collagens, and cytokines. Local IL-1 stimulates

fibroblast proliferation and collagen production. Irreversible tissue damage can occur through the

replacement of normal parenchyma with fibrous connective tissue. Fibroblasts can release

metalloproteinases that degrade normal tissue, further contributing to tissue destruction. Mast cells are

elevated in chronic conditions and may play a part in cell-mediated immune responses. Inflammatory

cyst formation may occur as a result of epithelial hyperplasia.

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