Elastin fragments drive disease progression in a murine model of emphysema
A. McGarry Houghton, … , obert M. Senior,, Steven D. Shapiro
A. McGarry Houghton, … , obert M. Senior,, Steven D. Shapiro
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):753-759. https://doi.org/10.1172/JCI25617.
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Elastin fragments drive disease progression in a murine model of emphysema

Abstract

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.

Authors

A. McGarry Houghton, Pablo A. Quintero, David L. Perkins, Dale K. Kobayashi, Diane G. Kelley, Luiz A. Marconcini, Robert P. Mecham, obert M. Senior,, Steven D. Shapiro

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Figure 3

Effects of PPE and EF antagonism on lung macrophage content in vivo.

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Effects of PPE and EF antagonism on lung macrophage content in vivo. PPE...
PPE (1 U = 7.4 μg) or PBS control was administered into the lungs of WT mice. BAL was performed before the lungs were inflated and fixed with 10% buffered formalin at days 1, 3, 7, 14, and 21. (A and B) BAL macrophage (A) and BAL neutrophil (B) counts were tabulated using a hemocytometer and HEMA 3–stained cytospins. (C) Lung macrophage counts are expressed as macrophages per high-powered field adjusted for tissue density on mac-3–stained sections. n = 4 mice per group. Bars represent SEM. #P < 0.05 vs. control. (D) To determine the effect of EF antagonism on monocyte recruitment, PPE-recipient mice received 10 μg BA4 (n = 9), 10 μg anti–collagen type I (col) antibody (n = 4), 10 μg anti–laminin-5 (lam) antibody (n = 4), or 10 μg IgG1 isotype control antibody (n = 8) over the course of the 3-day experiment; and either BA4 or IgG1 isotype control over the course of 21 days. The macrophage counts are expressed as above. Bars represent SEM. *P < 0.01 vs. control; **P < 0.01 vs. PPE/IgG1. (E–G) Representative mac-3–stained sections are shown for PBS (E), PPE/IgG1 (F), and PPE/BA4 (G) at the 3-day time point. Magnification, ×40.