Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

No abstract

Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-beta is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-beta in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-beta in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O(2)-induced injury of the maturing lung is associated with TGF-beta-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-beta-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-beta signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-beta activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-beta antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-beta signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-beta antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

Studies in vitro have underestimated the importance of cGMP-dependent protein kinase (PKG) in the modulation of vascular smooth muscle cell (SMC) proliferation and apoptosis in vivo. This is attributable, in part, to a rapid decline in PKG levels as vascular SMC are passaged in culture. We used a recombinant adenovirus encoding PKG (Ad.PKG) to augment kinase activity in cultured rat pulmonary artery SMC (RPaSMC). Incubation of Ad.PKG-infected RPaSMC (multiplicity of infection ‫؍‬ 200) with 8-Br-cGMP decreased serum-stimulated DNA synthesis by 85% and cell proliferation at day 5 by 74%. The effect of 8-Br-cGMP on DNA synthesis in Ad.PKG-infected RPaSMC was blocked by KT5823 (PKG inhibitor), but not by KT5720 (cAMP-dependent protein kinase inhibitor). A nitric oxide (NO) donor compound, S-nitrosoglutathione, at concentrations as low as 100 nM, inhibited DNA synthesis in Ad.PKG-infected RPaSMC, but not in uninfected cells or in cells infected with a control adenovirus. In addition, 8-Br-cGMP and S-nitrosoglutathione induced apoptosis in serum-deprived RPaSMC infected with Ad.PKG, but not in uninfected cells or in cells infected with a control adenovirus. These results demonstrate that modulation of PKG levels in vascular SMC can alter the sensitivity of these cells to NO and cGMP. Moreover, these observations suggest an important role for PKG in the regulation of vascular SMC proliferation and apoptosis by NO and cGMP.The endothelium plays a pivotal role in the regulation of vascular tone, the prevention of thrombosis, and the modulation of adhesive interactions between inflammatory cells and the vessel wall. The endothelium modulates the functions of the subjacent vascular smooth muscle, in part, by producing active effector molecules, including angiotensin II, heparinoids, and nitric oxide (NO) 1 (1, 2). Endothelial dysfunction is a shared process in the pathogenesis of vascular disorders, including atherosclerosis, neointima formation after angioplasty, and vascular remodeling associated with pulmonary or systemic hypertension (3). This dysfunction is associated with an alteration of the balance between cell growth and apoptosis and with dysregulation of cell-cell as well as cell-matrix interactions (1).In addition to its role as an endothelium-derived relaxing factor (4), NO regulates platelet adhesion and aggregation (5, 6), leukocyte recruitment and activation (7), and cytokine-induced endothelial cell activation (8) as well as vascular smooth muscle cell (SMC) apoptosis (9 -11), proliferation (12-14), and migration (15,16). NO acts, in part, by stimulating soluble guanylate cyclase to produce the intracellular second messenger cGMP (17). cGMP activates cGMP-dependent protein kinase (PKG), leading to many of the effects of NO (18). The two isoforms of PKG detected in vascular smooth muscle (I␣ and I␤) share substrate-binding/catalytic domains, but differ in cGMP affinity (19,20).The effects of NO on vascular SMC proliferation have been extensively investigated. Although several studies established that NO dec...

Since the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991. 1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension.Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases. Pharmacology and Physiology of Inhaled NO Chemistry of NO GasNO is a colorless, odorless gas that is only slightly soluble in water. 3 NO and its oxidative byproducts (eg, NO 2 and N 2 O 4 ) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams 4 provides a review of the chemistry of NO. Therapeutic Versus Endogenous NO Concentrations in the AirwayAlthough early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations Ͼ20 ppm provide little additional hemodynamic benefit in most patients. In some adults with acute respiratory failure, the effective concentrations of inhaled NO required to improve oxygenation can be as low as 10 ppb. 5,6 Of note, NO has been detected in exhaled human breath. The majority of exhaled NO in normal humans appears to be derived from nasal bacterial flora (25 to 64 ppb), with lower concentrations measured in the mouth, trachea, and distal airway (1 to 6 ppb). 5,7 Mechanism of ActionAfter inhalation, NO diffuses rapidly across the alveolarcapillary membrane into the subjacent smooth muscle of pulmonary vessels to activate soluble guanylate cyclase (Figure 1). This enzyme mediates many of the biological effects of NO and is responsible for the conversion of GTP to cGMP. Increased intracellular concentrations of cGMP relax smooth muscle via several mechanisms. The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell. Of the 11 reported...