Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness

1 Physiology Program, Department of Environmental Health, Harvard School of Public Health, 2 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, and 3 Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; an...

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Published in:Journal of applied physiology (1985) 2004-07, Vol.97 (1), p.249-259
Main Authors: Hjoberg, Josephine, Shore, Stephanie, Kobzik, Lester, Okinaga, Shoji, Hallock, Arlene, Vallone, Joseph, Subramaniam, Venkat, De Sanctis, George T, Elias, Jack A, Drazen, Jeffrey M, Silverman, Eric S
Format: Article
Language:English
Subjects:
Airway Resistance - genetics
Airway Resistance - physiology
Animals
Asthma
Asthma - enzymology
Asthma - metabolism
Biological and medical sciences
Blotting, Northern
Blotting, Western
Bronchoalveolar Lavage Fluid - cytology
Bronchodilator Agents - pharmacology
Cells
DNA, Complementary - biosynthesis
DNA, Complementary - genetics
Doxycycline - metabolism
Enzymes
Fundamental and applied biological sciences. Psychology
Gene expression
Immunohistochemistry
Lung - enzymology
Lung - physiology
Lungs
Methacholine Chloride - pharmacology
Mice
Mice, Transgenic
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide - physiology
Nitric Oxide Synthase - antagonists & inhibitors
Nitric Oxide Synthase - biosynthesis
Nitric Oxide Synthase Type II
Respiratory Mechanics - genetics
Respiratory Mechanics - physiology
Respiratory Mucosa - metabolism
Respiratory Mucosa - physiology
Reverse Transcriptase Polymerase Chain Reaction
Rodents
Tetracycline - metabolism
Trans-Activators - genetics
Trans-Activators - metabolism
Transgenes
Transgenic animals
Uteroglobin - genetics
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Summary:1 Physiology Program, Department of Environmental Health, Harvard School of Public Health, 2 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, and 3 Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and 4 Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520 Submitted 23 December 2003 ; accepted in final form 11 March 2004 Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from 10 parts per billion to a plateau of 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function. asthma; inducible transgene; mouse; epithelial cell; methacholine Address for reprint requests and other correspondence: E. S. Silverman, Physiology Program, Dept. of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115-6021 (E-mail: esilverm{at}hsph.harvard.edu ).
ISSN:8750-7587
1522-1601
DOI:10.1152/japplphysiol.01389.2003