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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/L1230    most recent 00460.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Plantier, L. Articles by Crestani, B. Search for Related Content PubMed PubMed Citation Articles by Plantier, L. Articles by Crestani, B.

Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice

¹Institut National de la Santé et de la Recherche Médicale, U700, Faculté Xavier Bichat, ²Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bichat, and ³Université Paris 7, Unité de Formation et de Recherche Médicale Denis Diderot, Faculté Bichat, Paris, France; ⁴Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Buenos Aires, Argentina; ⁵Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and ⁶Assistance Publique-Hôpitaux de Paris, CIC 07, Hôpital Bichat, Paris, France

Submitted 21 November 2006 ; accepted in final form 24 August 2007

Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg·kg^–1·day^–1 KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice.

inflammation; chronic obstructive pulmonary disease

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