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Introduction

Department of Pediatrics, University of Virginia, School of Medicine, Charlottesville, Virginia

Correspondence and requests for reprints should be addressed to Benjamin Gaston, M.D., Department of Pediatrics, University of Virginia School of Medicine, Box 800386 Uva HSC, Charlottesville, VA 22908. E-mail: bmg3g{at}virginia.edu

Inhaled nitric oxide (iNO) has been a life-saving therapy for acute pulmonary hypertension, particularly in the newborn. Its mechanism of action is often presented as following a straightforward paradigm: NO diffuses from the airway into pulmonary vascular smooth muscle, where it activates guanylate cyclase to cause acute pulmonary arterial vasodilatation; it is inactivated by reactions with other molecules in the lung, particularly including oxyhemoglobin.

As useful as this paradigm has been, recent evidence suggests that our understanding of this "path of the wind" [Ecclesiastes 11:5] is too simple and falls short in two important areas. First, it obscures several mechanisms by which NO regulates lung biology. Second, it fails to explain data regarding extrapulmonary effects of iNO therapy. The first of these issues has recently been reviewed elsewhere; this symposium in the Proceedings focuses primarily on the second.

Specifically, a simplified understanding of iNO metabolism does not explain (1) the association of iNO with increased extrapulmonary morbidity—and the failure of iNO to improve outcomes—in adult respiratory distress syndrome; (2) the observation that reperfusion of ischemic extrapulmonary vascular beds is enhanced by iNO therapy in animal models; (3) evidence that neurodevelopment is improved in infants treated with iNO therapy for pulmonary hypertension, an effect partly independent of gas exchange and hemodynamic parameters; and (4) evidence for extrapulmonary immunomodulatory effects of iNO therapy.

To foster improved understanding of these issues, INO Therapeutics sponsored—through an unrestricted grant—a symposium on the systemic effects of iNO therapy at the 2005 ATS International Conference, held in San Diego, California. The monographs in this issue of the Proceedings summarize data presented at this symposium. I believe that the reader will be encouraged to learn that iNO therapy for neonatal pulmonary hypertension is not the end of the road for applied NO biology; indeed, that the therapeutic possibilities have only just begun to be discovered.

FOOTNOTES

Conflict of Interest Statement: B.G. is a consultant for and minor shareholder in Nitrox, LLC.

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