Elastin fragments drive disease progression in a murine model of emphysema.
Mice lacking macrophage elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from macrophage elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both macrophage accumulation and airspace enlargement.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. mhoughton@rics.bwh.harvard.edu
A McGarry
AM
Houghton
Pablo A
PA
Quintero
David L
DL
Perkins
Dale K
DK
Kobayashi
Diane G
DG
Kelley
Luiz A
LA
Marconcini
Robert P
RP
Mecham
Robert M
RM
Senior
Steven D
SD
Shapiro
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000502:physiology*; D004646:Emphysema / Q000378:metabolism* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D012907:Smoking
D010446:Peptide Fragments; D004549:Elastin; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12