Increased local levels of granulocyte colony-stimulating factor are associated with the beneficial effect of pre-elafin (SKALP/trappin-2/WAP3) in experimental emphysema.
Few therapeutic options are offered to treat inflammation and alveolar wall destruction in emphysema. The effect of recombinant human pre-elafin, an elastase inhibitor, was evaluated in porcine pancreatic elastase (PPE)-induced emphysema in C57BL/6 mice. In a first protocol, mice received a single instillation of pre-elafin (17.5 pmol/mouse) at 1 h post-PPE and were sacrificed up to 72 h post-PPE. A single instillation of pre-elafin significantly reduced PPE-induced neutrophil accumulation in lungs, as assessed by bronchoalveolar lavage (BAL), by 51%, 71% and 67% at 24, 48 and 72 h, respectively. In a second protocol, mice also received a single dose of PPE, but pre-elafin three times a week for 2 weeks. After 2 weeks, pre-elafin significantly reduced the PPE-induced increase in BAL macrophage numbers, airspace dimensions and lung hysteresivity by 74%, 62% and 52%, respectively. Since G-CSF was previously shown to reduce emphysematous changes in mice, the BAL levels of this mediator were measured 6 h post-PPE in animals treated as described in the first protocol. Pre-elafin significantly increased G-CSF levels in PPE-exposed mice compared to sham- and PPE only-exposed animals. This suggests that the beneficial effects of pre-elafin could be mediated, at least in part, by its ability to increase G-CSF levels in the lung.
Janelle
Marie France
MF
Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Sainte-Foy G1V 4G5, Canada.
Doucet
Alain
A
Bouchard
Dominique
D
Bourbonnais
Yves
Y
Tremblay
Guy M
GM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D053492:Elafin; D004646:Emphysema / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D011498:Protein Precursors / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use
D053492:Elafin; C506806:PI3 protein, human; D011498:Protein Precursors; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase