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Nitric Oxide Synthesis in the Lung Regulation by Oxygen through a Kinetic Mechanism

Nitric Oxide Synthesis in the Lung Regulation by Oxygen through a Kinetic Mechanism,Raed A. Dweik,Daniel Laskowski,Husam M. Abu-Soud,F. Takao Kaneko,R

Nitric Oxide Synthesis in the Lung Regulation by Oxygen through a Kinetic Mechanism   (Citations: 56)
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In this study, we show that oxygen regulates nitric oxide (NO) levels through effects on NO synthase (NOS) enzyme kinetics. Initially, NO synthesis in the static lung was mea- sured in bronchiolar gases during an expiratory breath-hold in normal individuals. NO accumulated exponentially to a plateau, indicating balance between NO production and con- sumption in the lung. Detection of NO 2 2 , NO 3 2 , and S- nitro- sothiols in lung epithelial lining fluids confirmed NO con- sumption by chemical reactions in the lung. Interestingly, alveolar gas NO (estimated from bronchiolar gases at end- expiration) was near zero, suggesting NO in exhaled gases is not derived from circulatory/systemic sources. Dynamic NO levels during tidal breathing in different airway regions (mouth, trachea, bronchus, and bronchiole) were similar. However, in individuals breathing varying levels of inspired oxygen, dynamic NO levels were notably dependent on O 2 concentration in the hypoxic range ( K m O 2 190 m M). Purified NOS type II enzyme activity in vitro was similarly depen- dent on molecular oxygen levels ( K m O 2 135 m M), revealing a means by which oxygen concentration affects NO levels in vivo. Based upon these results, we propose that NOS II is a mediator of the vascular response to oxygen in the lung, be- cause its K m O 2 allows generation of NO in proportion to the inspired oxygen concentration throughout the physiologic range. ( J. Clin. Invest. 1998. 101:660-666.) Key words: ni- tric oxidenitric oxide synthaseoxygenventilation-per- fusion ratiokinetics
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    • ...On the other hand, exhaled NO output is reduced by hypoxia exposure in the human lower airways (6) and in isolated perfused rabbit lungs (11, 21, 29)...
    • ...It has been clearly demonstrated that NO production is regulated by ambient O2 tension through a mechanism that obeys Michaelis-Menten kinetics in the human lower airways (6) and in isolated perfused rabbit lungs (11, 29)...
    • ...In contrast to these values, Dweik et al. (6) estimated the Km value to be 190 M in the human lower airways...
    • ...Indeed, it has been shown that exhaled NO from the lower airways is reduced by hypoxic gas inhalation in humans (6) and in isolated perfused rabbit lungs (11, 21, 29)...

    Patrick M. Kelleyet al. nose Ambient oxygen regulates epithelial metabolism and nitric oxide p...

    • ...Other investigators have measured nitrite and nitrate in the bronchoalveolar lavage fluid of healthy subjects. Notably, the back-calculated concentrations in the extracellular lining fluid were at a micromolar range for nitrite and >100 μM for nitrate [...

    Jirina Chladkovaet al. Validation of Nitrite and Nitrate Measurements in Exhaled Breath Conde...

    • ...Studies in the mature airway indicate that the epithelium is the primary source of NO (14) and that NO mediates neurotransmission, smooth muscle relaxation, bacteriostasis, ciliary motility, mucin secretion, and plasma exudation (5, 19, 23, 35)...

    Donald C. McCurninet al. Inhaled NO improves early pulmonary function and modifies lung growth ...

    • ...In healthy adults, a range of 1.0–5.6 ppb for CANO has been reported, which is consistent with the direct bronchoscopic measurements of the lower airways (8, 9). Although direct measurement of the alveolar maximum fl ux, JalvNO ,i s not possible, an estimate can be made by using reports of the alveolar diffusing capacity, DalvNO (also reported as DLNO), and the simple relationship at steady state, JalvNO DalvNO CANO...

    Steven C. Georgeet al. Modeling pulmonary nitric oxide exchange

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