title: ADAM9 is a novel product of polymorphonuclear neutrophils: regulation of expression and contributions to extracellular matrix protein degradation during acute lung injury.
abstract: A disintegrin and a metalloproteinase domain (ADAM) 9 is known to be expressed by monocytes and macrophages. In this study, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein is stored in the gelatinase and specific granules and the secretory vesicles of human PMNs. Unstimulated PMNs express minimal quantities of surface ADAM9, but activation of PMNs with degranulating agonists rapidly (within 15 min) increases PMN surface ADAM9 levels. Human PMNs produce small quantities of soluble forms of ADAM9. Surprisingly, ADAM9 degrades several extracellular matrix (ECM) proteins, including fibronectin, entactin, laminin, and insoluble elastin, as potently as matrix metalloproteinase-9. However, ADAM9 does not degrade types I, III, or IV collagen or denatured collagens in vitro. To determine whether Adam9 regulates PMN recruitment or ECM protein turnover during inflammatory responses, we compared wild-type and Adam9(-/-) mice in bacterial LPS- and bleomycin-mediated acute lung injury (ALI). Adam9 lung levels increase 10-fold during LPS-mediated ALI in wild-type mice (due to increases in leukocyte-derived Adam9), but Adam9 does not regulate lung PMN (or macrophage) counts during ALI. Adam9 increases mortality, promotes lung injury, reduces lung compliance, and increases degradation of lung elastin during LPS- and/or bleomycin-mediated ALI. Adam9 does not regulate collagen accumulation in the bleomycin-treated lung. Thus, ADAM9 is expressed in an inducible fashion on PMN surfaces where it degrades some ECM proteins, and it promotes alveolar-capillary barrier injury during ALI in mice.
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115;
authors: Robin
authors: R
authors: Roychaudhuri
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115;
authors: Anja H
authors: AH
authors: Hergrueter
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115; Lovelace Respiratory Research Institute, Albuquerque, NM 87108; Pulmonary Department, University of Parma, 43100 Parma, Italy; and.
authors: Francesca
authors: F
authors: Polverino
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115;
authors: Maria E
authors: ME
authors: Laucho-Contreras
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115;
authors: Kushagra
authors: K
authors: Gupta
authors: Granulocyte Research Laboratory, Department of Hematology, University of Copenhagen, 2100 Copenhagen, Denmark.
authors: Niels
authors: N
authors: Borregaard
authors: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115; Lovelace Respiratory Research Institute, Albuquerque, NM 87108; cowen@rics.bwh.harvard.edu.
authors: Caroline A
authors: CA
authors: Owen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology*; D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D015824:Blood-Air Barrier / Q000276:immunology / Q000473:pathology; D003094:Collagen / Q000235:genetics / Q000276:immunology; D004549:Elastin / Q000235:genetics / Q000276:immunology; D005109:Extracellular Matrix / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D059748:Proteolysis
chemical_list: D000903:Antibiotics, Antineoplastic; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D001761:Bleomycin; D003094:Collagen; D004549:Elastin; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse