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J Thorac Cardiovasc Surg 2004;128:949-950
© 2004 The American Association for Thoracic Surgery
Letter to the Editor |
Bristol Heart Institute, University of Bristol, Bristol, United Kingdom
To the Editor:
We read with interest the elegant article by De Wet and associates,1 who demonstrated that inhaled prostacyclin (PGI2) prevents pulmonary hypertension, right-heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. We would like to add some observations regarding the mechanisms of action that might be of interest and of possible value in the further clinical implementation of inhalational PGI2.
First, pulmonary hypertension is associated with increased superoxide (O2·-) formation that is largely mediated by an upregulation of intravascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.2-5 O2·- reacts with endogenous nitric oxide (NO) to form reactive nitrogen species, which effectively reduces NO bioavailability.2 Because NO is a vasodilator and an inhibitor of inflammation, the reduction of NO formation is considered axiomatic in pulmonary hypertension.2
O2·- also reduces endogenous vascular PGI2 formation.3 We recently demonstrated that the PGI2 analogue iloprost is a potent inhibitor of NADPH oxidase expression and activity in porcine pulmonary arteries and therefore of O2·- formation.3 Therefore by reducing O2·- formation, PGI2 protects and enhances NO formation, which itself inhibits NADPH oxidase.4 The reduction of O2·- also prevents the formation of isoprostanes, which are vaconstrictors and promoters of NADPH oxidase expression.3
One interesting facet of the effect of inhalational PGI2 reported by De Wet and associates1 was that it prevented refractory hypoxemia. We found that hypoxia promotes the expression of NADPH oxidase in porcine pulmonary arteries.5 Hypoxemia, by promoting O2·- formation, would create a self-perpetuating cascade that would worsen hypertension and further augment hypoxemia. PGI2, by blocking the expression of NAPDH oxidase, might break this cycle and protect the pulmonary vasculature during surgical intervention through this antioxidant mechanism. Inhalational PGI2 might also prevent perioperative and postoperative intrapulmonary inflammation because PGI2 prevents the adhesion of leukocytes and platelets to vascular walls.6 Similarly, the preservation of intrapulmonary NO-forming capacity would also afford protection against inflammation because NO has similar anti-inflammatory properties to PGI2.7 This is of importance because leukocytes and platelets release vasoconstrictors and inflammogens, including thromboxane A2 and cytokines, all of which upregulate the expression of NADPH oxidase and the formation of O2·-.2-4
The beneficial effect of inhalational PGI2 on left ventricular function reported by De Wet and associates1 could be related to its antioxidative effect on the lungs. There is substantial evidence that reactive oxygen species, including O2· and peroxynitrite, impair left ventricular function.8 Thus it is reasonable to suggest that the suppression of intrapulmonary oxygen free radical formation by PGI2 might contribute to the beneficial downstream protective effect of the prostanoid on the left ventricle.
Finally, in a broader context the administration of the stable analogue iloprost in cardiac surgery might be indicated for other more long-term conditions. In particular, PGI2 has been shown to inhibit vascular smooth muscle cell proliferation and migration, platelet and leukocyte adhesion, and metalloproteinase expression,6 all key components of vein graft disease. As such, iloprost might be useful in preventing vein graft failure.
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in cultured porcine pulmonary artery vascular smooth muscle cells. Br J Pharmacol 2004;141:488-496.[Medline]This article has been cited by other articles:
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  M. Winterhalter, S. Fischer, R. Tessmann, A. Goerler, S. Piepenbrock, A. Haverich, and M. Strueber Using inhaled iloprost to wean from cardiopulmonary bypass after implanting a left ventricular assist device. Anesth. Analg., August 1, 2006; 103(2): 515 - 516. [Full Text] [PDF]
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