MW Leigh, JE Kylander, JR Yankaskas and RC Boucher
Department of Pediatrics, University of North Carolina at Chapel Hill 27599-7220, USA.

Integrative gene therapy typically requires dividing cells. This requirement has been perceived as an impediment for gene transfer to mature, uninjured airways where proliferation rates are very low. In diseases such as cystic fibrosis (CF) that may be candidates for integrative gene therapy, airway cell turnover is not known but may be increased as a result of chronic inflammation. To determine if cells in airway surface epithelium and submucosal glands of CF patients proliferate at an increased rate, paraffin sections of bronchial segments removed from CF patients (n = 6) at the time of lung transplantation or rapid autopsy and from non-CF patients (n = 4) undergoing lung resection or transplantation were immunostained with PC10, a monoclonal antibody to proliferating cell nuclear antigen (PCNA), a marker of proliferating cells. The PCNA index (percentage of nuclei immunostaining for PCNA) in CF bronchial surface epithelium was 17.0 +/- 4.6% (mean +/- SEM), substantially greater than in non-CF airways (less than 0.2%). Within submucosal glands, PCNA-positive cells were more prevalent in the collecting ducts of CF patients than in those of normal subjects, but only rare mucous or serous cells were PCNA positive. These studies show that airway epithelial cell proliferation rates can be very high in inflamed CF airways. This prevalence of proliferating cells suggests that CF airway epithelium and submucosal gland ducts may be amenable to gene transfer using vectors, such as retroviruses, that require cell replication for stable integrative expression. Further studies are needed to evaluate cell proliferation in CF airways with less extensive airway injury.

This article has been cited by other articles:

				C. Coraux, J. Roux, T. Jolly, and P. Birembaut Epithelial Cell-Extracellular Matrix Interactions and Stem Cells in Airway Epithelial Regeneration Proceedings of the ATS, August 15, 2008; 5(6): 689 - 694. [Abstract] [Full Text] [PDF]

				T. N. Hilliard, J. Zhu, R. Farley, S. Escudero-Garcia, B. J. Wainwright, P. K. Jeffery, U. Griesenbach, A. Bush, J. C. Davies, and E. W. F. W. Alton Nasal Abnormalities in Cystic Fibrosis Mice Independent of Infection and Inflammation Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 19 - 25. [Abstract] [Full Text] [PDF]

				M. P. Limberis and J. M. Wilson Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered PNAS, August 29, 2006; 103(35): 12993 - 12998. [Abstract] [Full Text] [PDF]

				J. A. Voynow, B. M. Fischer, B. C. Roberts, and A. D. Proia Basal-like Cells Constitute the Proliferating Cell Population in Cystic Fibrosis Airways Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 1013 - 1018. [Abstract] [Full Text] [PDF]

				P. A. de Jong, N. L. Muller, P. D. Pare, and H. O. Coxson Computed tomographic imaging of the airways: relationship to structure and function Eur. Respir. J., July 1, 2005; 26(1): 140 - 152. [Abstract] [Full Text] [PDF]

				M. O. Henke, A. Renner, R. M. Huber, M. C. Seeds, and B. K. Rubin MUC5AC and MUC5B Mucins Are Decreased in Cystic Fibrosis Airway Secretions Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 86 - 91. [Abstract] [Full Text] [PDF]

				A. M. Gallagher and R. A. Gottlieb Proliferation, not apoptosis, alters epithelial cell migration in small intestine of CFTR null mice Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G681 - G687. [Abstract] [Full Text] [PDF]

				H. Yeger, J. Pan, X. W. Fu, C. Bear, and E. Cutz Expression of CFTR and Cl{-} conductances in cells of pulmonary neuroepithelial bodies Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L713 - L721. [Abstract] [Full Text] [PDF]

				S. Rajan, G. Cacalano, R. Bryan, A. J. Ratner, C. U. Sontich, A. van Heerckeren, P. Davis, and A. Prince Pseudomonas aeruginosa Induction of Apoptosis in Respiratory Epithelial Cells . Analysis of the Effects of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction and Bacterial Virulence Factors Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 304 - 312. [Abstract] [Full Text]

				J.-C. Allo, P. Midoux, M. Merten, E. Souil, J. Lipecka, C. Figarella, M. Monsigny, P. Briand, and I. Fajac Efficient Gene Transfer into Human Normal and Cystic Fibrosis Tracheal Gland Serous Cells with Synthetic Vectors Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 166 - 175. [Abstract] [Full Text]

				M. Sena-Esteves, Y. Saeki, S. M. Camp, E. A. Chiocca, and X. O. Breakefield Single-Step Conversion of Cells to Retrovirus Vector Producers with Herpes Simplex Virus-Epstein-Barr Virus Hybrid Amplicons J. Virol., December 1, 1999; 73(12): 10426 - 10439. [Abstract] [Full Text]

				S. E. Beck, L. A. Jones, K. Chesnut, S. M. Walsh, T. C. Reynolds, B. J. Carter, F. B. Askin, T. R. Flotte, and W. B. Guggino Repeated Delivery of Adeno-Associated Virus Vectors to the Rabbit Airway J. Virol., November 1, 1999; 73(11): 9446 - 9455. [Abstract] [Full Text] [PDF]

				G. Wang, B. L. Davidson, P. Melchert, V. A. Slepushkin, H. H. G. van Es, M. Bodner, D. J. Jolly, and P. B. McCray Jr. Influence of Cell Polarity on Retrovirus-Mediated Gene Transfer to Differentiated Human Airway Epithelia J. Virol., December 1, 1998; 72(12): 9818 - 9826. [Abstract] [Full Text] [PDF]

				L. G. Johnson, J. P. Mewshaw, H. Ni, T. Friedmann, R. C. Boucher, and J. C. Olsen Effect of Host Modification and Age on Airway Epithelial Gene Transfer Mediated by a Murine Leukemia Virus-Derived Vector J. Virol., November 1, 1998; 72(11): 8861 - 8872. [Abstract] [Full Text] [PDF]