Lung injury eicosanoids

Treatment of acute respiratory distress syndrome (ARDS) or acute lung injury may be defined as a condition involving impaired oxygenation. The nonpharmacologic therapies include mechanical ventilation. The pharmacologic therapies include the use of exogenous surfactant, corticosteroids, acetylcysteine (antioxidant), ketoconazole, nitric oxide, eicosanoids and their inhibitors, sodium nitroprus-side (vasodilator), pentoxifylline, antiendotoxin, and anticytokine therapy and antibiotics. 

IS THERE A ROLE FOR EICOSANOIDS IN THE PATHOGENESIS OF LUNG INJURY ... 

A recent report by Parsons et a/." presented evidence for simultaneous elevation of complement fragments and measurable levels of endotoxin in plasma from patients with ARDS. Because complement activation by toxins and by other mechanisms" is thought to cause neutrophil and platelet activation" and subsequent generation of toxic oxygen species and eico-sanoids various strategies known to activate intravascular complement have been used to examine the role of eicosanoids in lung injury . To... 

There is consensus that arachidonic acid metabolites are produced by the lung in the course of endotoxin-triggered lung injury, and at least some of the cyclo-oxygenase metabolites have been incriminated in the pulmonary vasomotor response to endotoxin. However, whether eicosanoids are causative for lung injury remains unclear. Recently, platelet activating factor has been suggested as an important mediator of endotoxic shock The evidence is as follows ... 

At this time, it is difficult to reconcile the results from all the studies in the literature regarding the role of specific eicosanoids or PAF in the development of endotoxin-induced lung injury. The differences in results may be due to the use of inadequate or ineffective inhibitors, different doses and preparation of endotoxin, variable sensitivity of different species of animals to endotoxin effect and differences in eicosanoid metabolism in different species . A final possibility is that perhaps none of the metabolites alone is adequate to cause injury, but mediator chain reactions and synergistic actions of several mediators are important. This might explain why interventions targeting a single mediator (thromboxane or leukotrienes) have so far met with limited success. 

TREATMENT OF HUMAN LUNG INJURY BASED ON MANIPULATIONS OF THE EICOSANOID METABOLISM... 

Meaningful interpretation of eicosanoid levels in plasma or pulmonary oedema fluid during clinical sepsis or ARDS is complicated by the large number of uncontrolled variables compared with experimental sepsis or models of acute lung injury. These include diverse etiological factors precipitating sepsis and ARDS, variation in the stage of severity of these inflammatory conditions... 

Panos RJ, Voelkel NF, Cott GR, Mason RJ, Westcott JY. Alterations in eicosanoid production by rat alveolar type It cells isolated after silica-induced lung injury. Am J Respir Cell Mol Biol 1992 6 430 38. 

Other enzyme systems may also be directly or indirectly involved in the generation of ROS in the lung, including those of the eicosanoid pathway, the mitochondrial electron transport system, and aldehyde, glucose and xanthine oxidases (Parks and Granger, 1986). These systems may also be relevant to lung damage. For example, the oedematous pulmonary injury that results from cessation of blood flow for a period followed by reinstatement of... 

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