Cellular mediators

Most cellular mediators are produced by monocyte-macrophages, polymorphonuclear neutrophils, and endothelial cells, but they can also be derived from lymphocytes, platelets, alveolar cells, and fibroblasts.

Cytokines, secreted by macrophages and monocytes after stimulation by endotoxins, constitute a class of peptide molecules with effects on either the cells that produced them (autocrine effect) or more distant target cells (paracrine effect). These molecules are tumor necrosis factor-a and interleukins 1, 6, and 8 (IL-1, IL-6, and IL-8). The sequential release of the interleukins is consecutive to that of tumor necrosis factor-a. Their effects are mainly exerted on polymorphonuclear neutrophils, endothelial cells, and certain target organs such as the liver (where they stimulate production of acute phase reactant proteins). IL-8, which is produced by numerous cell types, is a chemoattractant, stimulates adhesion, and powerfully activates polymorphonuclear neutrophils. IL-12, which has recently been implicated in the pathogenesis of ARDS, acts by stimulating lymphocytes. High levels of tumor necrosis factor-a, IL-1, IL-6, and IL-8 are found in the plasma and bronchoalveolar lavage fluid during ARDS. Levels of tumor necrosis factor-a have been found to correlate with the incidence and intensity of the syndrome. A genetically determined variability in the capacity to produce cytokines, and therefore to develop ARDS, has also been invoked.

Among the lipid substances (prostanoids, leukotrienes, platelet activating factor) formed from phospholipids de-esterified by phospholipase A 2, thromboxane A2 has been considered to be an early mediator with a role in the development of ARDS. In effect, its liberation precedes that of prostacyclin and the leukotrienes. None of the lipid mediators found in plasma or bronchoalveolar lavage fluid is considered to be specific to ARDS, but their varied actions (vasoconstriction, vasodilation, bronchoconstriction, chemotaxis, cellular activation) appear to confirm a key position in the generalization and maintenance of the inflammatory reaction seen during the syndrome.

Active oxygen species and free radicals (superoxide anion, hydrogen peroxide, the hydroxyl radical, hypochlorous acid, singlet oxygen) are produced by stimulated phagocytic cells. They are responsible for lipid peroxidation reactions and for molecular and tissue damage. They are also believed to be at the origin of oxidative stress and are considered to play an important role in the intracellular activation of nuclear transcription regulatory factors (such as NF _B), the synthesis of messenger RNA, the induction of protein synthesis, and the triggering of apoptosis. Other sources of activated oxygen species are the mitochondria, the ischemic organs (by the action of xanthine oxidase), and free plasma hemoglobin. Their short half-lives make direct detection of these species difficult, but the time course of plasma concentrations of antioxidant molecules and specific antiradical enzymes (such as superoxide dismutase, catalase, and glutathione peroxidase) indirectly suggests their presence.

The adhesion receptors found on cell surfaces play an important role by favoring cellular interactions. They belong to the family of the selectins and the integrins, and the immunoglobulin superfamily. Their expression is modulated during the inflammatory reaction by the influence of endotoxins and cytokines; it is increased by the action of stimulated polymorphonuclear neutrophils and by numerous signal molecules such as platelet activating factor and IL-8.

During shock states and inflammatory reactions, cells produce heat shock proteins. These peptides are chemotactic and immunosuppressive, and as yet their role is poorly characterized (protection from or propagation of the inflammatory reaction).

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