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1 Clinical Research Group "Chronic Airway Diseases", Philipps-University, Marburg, 2 Center of Anatomy, University Clinics, Georg-August-University, Göttingen, and 4 Institute of Anatomy, University Clinics "Carl Gustav Carus", Technical University of Dresden, Dresden, Germany. 3 National Jewish Medical and Research Center, Denver, CO, USA
CORRESPONDENCE: H. Fehrenbach, Clinical Research Group "Chronic Airway Diseases", Philipps-University, Baldingerstrasse, D-35033, Marburg, Germany. Fax: 49 64212868987. E-mail: heinz.fehrenbach@mailer.uni-marburg.de
Keywords: airway epithelium, Clara cells, keratinocyte growth factor, neuroepithelial cells, progenitor cells, proliferation
Received: April 20, 2002
Accepted June 12, 2002
This work was supported by a grant from the National Institutes of Health, USA (HL-56556), and by the Bundesministerium für Bildung und Forschung, Germany (01ZZ5904).
Keratinocyte growth factor (KGF) is a potent mitogen of pulmonary bronchial and alveolar epithelial cells. However, it is unclear which type(s) of airway epithelial cells (AEC) proliferate(s) in response to KGF.
AEC proliferation was induced in rats by either endobronchial instillation of 5 mg recombinant human (rHu) KGF per kg body weight or by adenoviral transfer of the human KGF gene (Ad5-HuKGF). Alterations in terminal airway AEC were followed for up to 7 days after rHuKGF, and for up to 28 days after Ad5-HuKGF.
Cell proliferation, as assessed by immunohistochemistry (IHC) for incorporated 5-bromo-2'-deoxyuridine (BrdU) and quantified by stereology, peaked at days 1–2 and was resolved by day 7 after rHuKGF and by day 21 after Ad5-HuKGF. Double immunofluorescence labelling for BrdU or Ki-67 on the one hand, and for Clara cell specific protein 10 (CC10) and calcitonin-gene related peptide on the other hand, demonstrated that Clara cells, not pulmonary neuroendocrine cells, proliferated in response to human KGF. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling) method in conjunction with IHC for MNF116 failed to detect significant numbers of apoptotic AEC. IHC in conjunction with stereology revealed transient phenotypic alterations with a decrease in CC10, an increase in surfactant protein D and an increase in CD44v6 in AEC.
The authors conclude that Clara cells responded to human keratinocyte growth factor in vivo by proliferation as well as by changes in protein expression, whereas no significant response was observed in pulmonary neuroendocrine cells. As Clara cells are intimately involved in airway epithelial repair, ion and fluid transport, and modulate lung inflammation, the potential of human keratinocyte growth factor to protect the lung may in part rely on the response of Clara cells.
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