These substances originate primarily in the activation of the complement and coagulation-fibrinolytic cascades. The endotoxins, the acute phase reactant proteins (characteristic of the inflammatory reaction), the proteases released from damaged organs, and some peptides, proteins, and protein fragments (which appear in the blood during shock and inflammatory states) could also be added to this list. Complement degradation products, particularly C5a, are found in high concentrations in various pathological states associated with the development of ARDS, such as infections, extracorporeal circulation (used for cardiac surgery), acute pancreatitis, burns, and multiple trauma. Activation of the complement cascade, by either the classical or the alternative pathways, can occur early after trauma and infection. This system triggers the coagulation cascade and attracts and activates polymorphonuclear neutrophils (and thus spreads and amplifies the inflammatory reaction), but it is not the cause of ARDS; complement-split products are not specific markers of ARDS.
In ARDS, particularly in the presence of infection, the activation of the coagulation-fibrinolytic cascades is caused by complement fragments, endotoxins, and the original inciting trauma. Several elements tend to prove the activation of these systems, including demonstration of pulmonary sequestration of microthrombi, platelet aggregates, and fibrinogen, the presence of DIC, and unusually high plasma concentrations of active enzymes (thrombin, plasmin) and of abnormal kininogen and fibrin-split products.
Excessive proteolytic activity is responsible for the increased plasma concentrations of peptides with various activities (including immunosuppression) commonly seen in ARDS. These proteases also originate from the activation of various humoral cascades, but also from activated cells and damaged organs (particularly the pancreas) after lesions produced by hypoperfusion and the onset of the multiple organ failure syndrome. They rapidly saturate available endogenous antiproteases, such as antithrombin III and a2-macroglobulin, and lead to an imbalance between active proteases and antiprotease defenses.
The presence of endotoxin in the bloodstream is related not only to infection, but also to translocation across an intestinal mucosal barrier altered by ischemia. However, this mechanism is controversial. Endotoxins activate not only monocytes and macrophages (with consequent production of cytokines), but also polymorphonuclear neutrophils and endothelial cells via complexes formed with binding proteins that are recognized by cellular receptors.
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