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.

[1]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[2]  Jiangang Gao,et al.  Elastic fiber homeostasis requires lysyl oxidase–like 1 protein , 2004, Nature Genetics.

[3]  A. M. Houghton,et al.  Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. , 2003, The American journal of pathology.

[4]  R. Mecham,et al.  A Site on Laminin α5, AQARSAASKVKVSMKF, Induces Inflammatory Cell Production of Matrix Metalloproteinase-9 and Chemotaxis1 , 2003, The Journal of Immunology.

[5]  Jin Dai,et al.  Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown. , 2002, American journal of respiratory and critical care medicine.

[6]  A. Churg,et al.  Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice. , 2002, American journal of respiratory cell and molecular biology.

[7]  Robert W. Thompson,et al.  Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor. , 2002, Journal of vascular surgery.

[8]  J. Keane,et al.  Severity of Elastase-Induced Emphysema Is Decreased in Tumor Necrosis Factor-α and Interleukin-1β Receptor-Deficient Mice , 2002, Laboratory Investigation.

[9]  P. Paré,et al.  Amplification of inflammation in emphysema and its association with latent adenoviral infection. , 2001, American journal of respiratory and critical care medicine.

[10]  P. Fuchs,et al.  Conformational Dependence of Collagenase (Matrix Metalloproteinase-1) Up-regulation by Elastin Peptides in Cultured Fibroblasts* , 2001, The Journal of Biological Chemistry.

[11]  B. Gilks,et al.  Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. , 2000, American journal of respiratory cell and molecular biology.

[12]  M. Ko,et al.  Effects of depletion of neutrophils or macrophages on development of cigarette smoke-induced emphysema. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[13]  R. Peto,et al.  Tobacco—the growing epidemic , 1999, Nature Medicine.

[14]  D. Hansell,et al.  Bronchoalveolar lavage cellularity: lone cryptogenic fibrosing alveolitis compared with the fibrosing alveolitis of systemic sclerosis. , 1998, American journal of respiratory and critical care medicine.

[15]  J. Callahan,et al.  The 67-kDa Enzymatically Inactive Alternatively Spliced Variant of β-Galactosidase Is Identical to the Elastin/Laminin-binding Protein* , 1998, The Journal of Biological Chemistry.

[16]  L. Fabbri,et al.  CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[17]  M. A. Castiglione Morelli,et al.  Structure-activity relationships for some elastin-derived peptide chemoattractants. , 2009, The journal of peptide research : official journal of the American Peptide Society.

[18]  S. Shapiro,et al.  Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. , 1997, Science.

[19]  R. Mecham,et al.  Elastin Degradation by Matrix Metalloproteinases , 1997, The Journal of Biological Chemistry.

[20]  T. Ley,et al.  Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Mecham,et al.  Identification of an Elastin Cross-linking Domain That Joins Three Peptide Chains , 1995, The Journal of Biological Chemistry.

[22]  M. De Biasi,et al.  Migration of monocytes in the presence of elastolytic fragments of elastin and in synthetic derivates. Structure-activity relationships. , 2009, International journal of peptide and protein research.

[23]  L. Grosso,et al.  Peptide sequences selected by BA4, a tropoelastin-specific monoclonal antibody, are ligands for the 67-kilodalton bovine elastin receptor. , 1993, Biochemistry.

[24]  R. Clark,et al.  Cryptic chemotactic activity of fibronectin for human monocytes resides in the 120-kDa fibroblastic cell-binding fragment. , 1988, The Journal of biological chemistry.

[25]  R. Mecham,et al.  Val-Gly-Val-Ala-Pro-Gly, a repeating peptide in elastin, is chemotactic for fibroblasts and monocytes , 1984, The Journal of cell biology.

[26]  R. Crystal,et al.  Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. , 1981, Science.

[27]  R. Mecham,et al.  Chemotactic activity of elastin-derived peptides. , 1980, The Journal of clinical investigation.

[28]  E. Levine,et al.  Elastase release from human alveolar macrophages: comparison between smokers and nonsmokers. , 1977, Science.

[29]  A. Kang,et al.  Collagen-and collagen peptide-induced chemotaxis of human blood monocytes , 1976, The Journal of experimental medicine.