Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice.
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 x kg(-1) x 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-2alpha) 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.
Plantier
Laurent
L
Institut National de la Santé et de la Recherche Médicale, U700, Faculté Xavier Bichat, Paris, France.
Marchand-Adam
Sylvain
S
Antico Arciuch
Valeria G
VG
Antico
Valeria G
VG
Boyer
Laurent
L
De Coster
Cécile
C
Marchal
Joëlle
J
Bachoual
Rafik
R
Mailleux
Arnaud
A
Boczkowski
Jorge
J
Crestani
Bruno
B
D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
C499706:CXCL2 protein, human; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D051523:Fibroblast Growth Factor 7; D018799:Intercellular Adhesion Molecule-1; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2