Airway hyperresponsiveness in transgenic mice overexpressing platelet activating factor receptor is mediated by an atropine-sensitive pathway.
Platelet activating factor (PAF) is a potent mediator potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. Recently, transgenic mice overexpressing the PAF receptor (PAFR) gene have been established, and exhibit bronchial hyperresponsiveness, one of the cardinal features of asthma. To elucidate the molecular and pathophysiologic mechanisms underlying PAF-associated bronchial hyperreactivity, we studied airway responsiveness to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT) in PAFR-transgenic mice. In addition, we examined the role of the muscarinic receptor in PAF-induced responses and the binding activities of the muscarinic receptor. The PAFR-transgenic mice exhibited hyperresponsiveness to MCh and PAF; however, no significant differences in 5-HT responsiveness were observed between the control and PAFR-transgenic mice. The administration of atropine significantly blocked PAF-induced responses in PAFR-transgenic mice. There were no differences between the two phenotypes in the binding activities of muscarinic receptor. Morphometric analyses demonstrated that PAFR overexpression did not affect airway structure. These findings suggest that the muscarinic pathway may have a key role in airway hyperresponsiveness associated with PAFR gene overexpression. More generally, PAFR-transgenic mice may provide appropriate models for study of the molecular mechanisms underlying PAF-associated diseases.
Nagase
Takahide
T
Departments of Geriatric Medicine and Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. takahide-tky@umin.ac.jp
Ishii
Satishi
S
Shindou
Hideo
H
Ouchi
Yasuyoshi
Y
Shimizu
Takao
T
D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001982:Bronchial Diseases / Q000503:physiopathology*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010972:Platelet Activating Factor / Q000187:drug effects / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016166:Free Radical Scavengers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; C039351:platelet activating factor receptor; D016210:Methacholine Chloride; D012701:Serotonin; D001285:Atropine