Published ahead of print on April 13, 2006, doi:10.1165/rcmb.2005-0468OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 3, September 2006, 320-326 A more recent version of this article appeared on September 1, 2006
Submitted on December 20, 2005 Pulmonary Neuroendocrine Cells, Airway Innervation and Smooth Muscle are Altered in Cftr Null MiceJie Pan1,1 Division of Pathology, Deparment of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada, 2 Research Institute, The Hospital for Sick children, Toronto, Ontario, Canada, 3 Animal Care and Veterinary Services, University of Western Ontario, London, Ontario, Canada, 4 Division of Pathology, Deparment of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Research Institute, The Hospital for Sick children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada * To whom correspondence should be addressed. E-mail: hermie{at}sickkids.ca.
The amine and peptide producing Pulmonary Neuroendocrine Cells (PNEC) are widely distributed within the airway mucosa of mammalian lung as solitary cells and innervated clusters, Neuroepithelial Bodies (NEB), that function as airway O2 sensors. These cells express Cftr and hence could play a role in the pathophysiology of Cystic Fibrosis (CF) lung disease. We performed confocal microscopy and morphometric analysis on lung sections from Cftr-/- (null), Cftr +/+ and Cftr +/- (controls) mice at developmental stages E20, P5, P9, and P30 to determine the distribution, frequency and innervation of PNEC/NEB, innervation and cell mass of airway smooth muscle, and neuromuscular junctions, using synaptic vesicle protein 2, smooth muscle actin and synaptophysin markers, respectively. The mean number of PNEC/NEB in Cftr-/- mice was significantly reduced compared to controls at E20 while comparable or increased numbers were observed postnataly. NEB cells in Cftr null mice showed a significant reduction in intracorpuscular nerve endings compared to controls consistent with an intrinsic abnormality of PNEC system. The airways of Cftr-/- mice showed reduced density (~20-30%) of smooth muscle innervation, decreased mean airway smooth muscle mass (~35%) and reduced density (~20%) of nerve endings compared to controls. We conclude that airways of Cftr-/- mice exhibit heretofore unappreciated structural alterations affecting both cellular and neural components of PNEC system as well as airway smooth muscle and its innervation resulting in blunted O2 sensing and reduced airway tonus. Thus Cftr could play a role in the development of PNEC system, lung innervation and airway smooth muscle.
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