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J. Exp. Med.,
Volume 189, Number 10, May 17, 1999 1621-1630
By



From the * Pulmonary and Critical Care Divisions, Department of Medicine, Brigham and Women's
Hospital and Harvard Medical School, Boston, Massachusetts 02115; the Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model
of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the
lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and
was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and
NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and
neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed
in similarly treated NOS2 and WT groups. These findings demonstrate an important function for
the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of
allergic asthma.
Department of Allergy
and Clinical Immunology, Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts 02114; the § Physiology Program, Harvard School of Public Health, Boston,
Massachusetts 02115; the
Pulmonary Division, Departments of Medicine and Pharmacology,
London Health Sciences Centre, University of Western Ontario, London, Ontario N6A 4G5,
Canada; ¶ Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877; and the ** Cardiac
Unit and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical
School, Boston, Massachusetts 02114
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