title: Shedding of low-density lipoprotein receptor–related protein-1 in acute respiratory distress syndrome.
abstract: BACKGROUND
  Low-density lipoprotein receptor–related protein-1 (LRP-1) mediates the endocytic clearance of various proteinases, including matrix metalloproteinases (MMPs). The ectodomain of LRP-1 can be shed from the cell surface, releasing a soluble form of this receptor (sLRP-1), which antagonizes ligand endocytosis by cellular LRP-1.
  
  
  OBJECTIVE
  To assess if increased LRP-1 shedding occurs in the lungs of patients with acute respiratory distress syndrome (ARDS) and may lead to the accumulation of MMPs and subsequent tissue injury.
  
  
  METHODS
  We determined sLRP-1 levels in bronchoalveolar lavage fluids (BALF) from 46 patients with ARDS and their correlation with MMP concentration and disease severity. In complementary in vitro studies, we investigated the mechanisms underlying the LRP-1 release from the cell surface and its impact on MMP cellular uptake.
  
  
  RESULTS
  sLRP-1 levels were significantly elevated in BALF but not in plasma from patients with ARDS compared with control subjects and further increased in the later course of the disease. Baseline BALF sLRP-1 concentration was positively correlated with disease severity and significantly higher in nonsurvivors compared with survivors. The presence of ARDS BALF enhanced LRP-1 shedding from cultured lung fibroblasts but not from alveolar type II cells or macrophages. This process was blocked when ARDS BALF was supplemented with metalloproteinase inhibitor resulting in enhanced cellular uptake and degradation of MMP-2 and -9. Accordingly, sLRP-1 BALF concentration in patients with ARDS was positively correlated with MMP levels and laminin, a marker of basement membrane disruption.
  
  
  CONCLUSIONS
  Increased LRP-1 shedding prevents the cellular clearance of MMPs and might thereby contribute to tissue destruction in ARDS lungs.
authors.affiliation: Department of Biochemistry, University of Giessen Lung Center, Giessen, Germany
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Ewa
authors.initials: E
authors.lastname: Jablonska
authors.forename: Dariusz
authors.initials: D
authors.lastname: Zakrzewicz
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D009994:Osmolar Concentration; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D017741:Survivors; D055815:Young Adult
chemical_list: D007797:Laminin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9