Mechanisms involved in indirect pulmonary insults

The primary mechanism responsible for causing ARDS after extrathoracic injuries is the delivery to the lung of activated cells, inflammatory mediators, and microaggregates originating from a remote site. This form of ARDS constitutes a specific expression of a generalized inflammatory reaction, in which blood-borne cells (monocytes, polymorphonuclear neutrophils, platelets, erythrocytes) and vascular endothelial cells are the principal actors. After severe trauma, infection, or shock states with ischemia followed by reperfusion, cellular functions are activated in situ, initiating a localized inflammatory reaction. Phagocytic cells are stimulated by the trauma itself or by bacterial toxins, while endothelial cells are activated by both the initial lesion and the stimulated leukocytes. Under these circumstances, the usually antiaggregant and anticoagulant activity of the endothelium (via production of prostacyclin, thrombomodulin, etc.) becomes predominantly procoagulant (decreased production of thrombomodulin, and secretion of thromboplastin, plasminogen activator-inhibitor, and platelet activating factor). This activity predisposes to the development of disseminated intravascular coagulation (DIC), platelet consumption, and fibrin deposits. These cells release inflammatory mediators, such as cytokines and prostaglandins, as well as substances capable of modulating vascular tone (prostacyclin, endothelin, and nitric oxide (NO)). They activate the complement cascade by binding immune complexes, and express increasing numbers of adhesion receptors either by migration of preformed receptors to the cell surface or by de novo synthesis. These receptors facilitate neutrophil binding, allowing them to act locally on the surface of the endothelium, to migrate into the extravascular space, and to maintain and amplify the inflammatory reaction. Localized activation of endothelial-bound neutrophils damages the vascular lining, alters capillary permeability, and leads to formation of cellular and tissue edema with passage of fluid and mediators into the alveoli. It also leads to modifications of the normal metabolic functions of the endothelium, such as decreased production of converting enzyme. The metabolism of active products is also decreased, leading to longer intravascular persistence of bradykinin (which causes vasodilation and increases vascular permeability), serotonin, prostaglandins E 1, E2, and F2a (which increase vascular permeability, modulate vascular tone, and cause platelet aggregation and bronchospasm), and norepinephrine (noradrenaline) which causes vasoconstriction.

Neutrophils are the second category of cells intimately involved in the development of ARDS after extrathoracic injury. Mediators derived from polymorphonuclear neutrophils and activated cells themselves are transported by the bloodstream from the damaged area or organ to the pulmonary capillaries. It should be remembered that these cells are found in large numbers in the lung under ordinary circumstances; three times as many are localized, but not activated, in the pulmonary circulation as are found in the general circulation. The transient peripheral neutropenia described early in the course of ARDS is believed to be due to sequestration of these cells in the lung, where they are slowed, trapped, and bound to endothelial adhesion receptors. This is followed by diapedesis into the interstitial and alveolar spaces, where they induce reactions identical to those seen with ARDS of thoracic origin. The demonstration of the existence of activated forms of oxygen in the bloodstream is difficult, but increased levels of protective enzymes such as superoxide dismutase and catalase are noted in infected patients who go on to develop ARDS.

Platelets also participate in the series of reactions leading to the development of ARDS. These cells are activated by endotoxins, complement fragments, and other mediators, such as platelet activating factor. They liberate mediators which include platelet activating factor itself, serotonin, platelet factor 4, etc. All of these probably contribute to amplification of the inflammatory reaction and the coagulation cascade, and participate in the formation of microaggregates; these aggregates can subsequently cause or worsen hypoxemia and DIC.

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