Thromboxane Synthase And 5lipoxygenase Inhibitors

Thromboxane and leukotrienes are in part responsible for the pulmonary hypertension and hypoxaemia of ARDS. Pulmonary vascular smooth muscle cells, endothelial cells, platelets, and neutrophils all release TXA2 on stimulation. TXA2 can initiate microvascular thromboses consisting of neutrophil and platelet aggregates that are responsible for perfusion abnormalities and recurrent ischaemia-reperfusion injury to the lung. The vasoconstrictive effect of TXA2 similarly contributes to impaired gas exchange.47 In animal models of lung injury thromboxane synthase inhibition reduced pulmonary oedema formation and inhibited microembolism, but pulmonary hypertension was only partially relieved.48 Similarly, improved oxygenation and reduced pulmonary hypertension have been found in small trials of a thromboxane receptor antagonist in patients with ARDS.

Leukotrienes (LT) are derived from arachidonic acid by 5-lipoxygenase. LTB4 is a potent neutrophil chemokine while LTC4 and LTD4 cause pulmonary vasoconstriction, capillary leak, and pulmonary oedema. The role of leukotrienes in ARDS has been less well researched but bronchoalveolar lavage fluid from patients with ARDS contains increased concentrations of LTB4, LTC4 and LTD4, which may be markers for developing ARDS.49 Ketoconazole is an imidazole antifungal agent that inhibits thromboxane synthase and 5-lipoxygenase without inhibiting CoX. Ketoconazole may therefore have a dual anti-inflammatory action in ARDS by inhibiting inflammatory eicosanoid synthesis and directing COX products down other less inflammatory metabolic paths such as those synthesising prostacyclin or PGE2.50 Four trials have used enteral ketoconazole in patients at risk of or with ARDS. The incidence of acute respiratory failure was reduced in high risk surgical patients and other critically ill patients.51-53 However, an ARDS Network trial (http://hedwig.mgh.harvard.edu/ ardsnet) in patients with established ARDS of medical and surgical aetiology found no differences in in-hospital mortality, ventilator free days at day 28, organ failure-free days, or markers of gas exchange between patients given ketoconazole or placebo.54 This trial achieved plasma levels of ketoconazole higher than targeted previously but could not demonstrate a reduction in thromboxane production in vivo. The effect of decreasing thromboxane synthesis in ARDS is therefore still unknown. It is still possible that ketoconazole in surgical and trauma patients at risk of or with incipient pulmonary injury may be beneficial.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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