title: A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs.
abstract: OBJECTIVE
  To gain knowledge of lung clearance mechanisms of inhaled tissue plasminogen activator (tPA).
  
  
  METHODS
  Using an in vivo mouse model and ex vivo murine whole organ cell suspensions, we examined the capability of the lungs to utilize LRP1 receptor-mediated endocytosis (RME) for the uptake of exogenous tPA with and without an LRP1 inhibitor, receptor associated protein (RAP), and quantitatively compared it to the liver. We also used a novel imaging technique to assess the amount LRP1 in sections of mouse liver and lung.
  
  
  RESULTS
  Following intratracheal administration, tPA concentrations in the bronchoalveolar lavage fluid (BALF) declined over time following two-compartment pharmacokinetics suggestive of a RME clearance mechanism. Ex vivo studies showed that lung and liver cells are similarly capable of tPA uptake via LRP1 RME which was reduced by ~50% by RAP. The comparable lung and liver uptake of tPA is likely due to equivalent amounts of LRP1 of which there was an abundance in the alveolar epithelium.
  
  
  CONCLUSIONS
  Our findings indicate that LRP1 RME is a candidate clearance mechanism for inhaled tPA which has implications for the development of safe and effective dosing regimens of inhaled tPA for the treatment of plastic bronchitis and other fibrin-inflammatory airway diseases in which inhaled tPA may have utility.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Swan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Racz
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Melissa F
authors.initials: MF
authors.lastname: Tai
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Brooks
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Rzeczycki
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Heath
authors.affiliation: Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.affiliation: Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gus R
authors.initials: GR
authors.lastname: Rosania
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. stringek@umich.edu.
authors.forename: Kathleen A
authors.identifier: http://orcid.org/0000-0003-0238-7774
authors.initials: KA
authors.lastname: Stringer
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004705:Endocytosis; D004848:Epithelium / Q000378:metabolism; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D010959:Tissue Plasminogen Activator
keywords: plastic bronchitis; receptor mediated endocytosis; therapeutic proteins