Swan Lin1, Jennifer Racz1, Melissa F Tai1, Kristina M Brooks1, Phillip Rzeczycki2, Lauren J Heath1, Michael W Newstead3, Theodore J Standiford3, Gus R Rosania2, Kathleen A Stringer4. 1. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. 3. Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA. 4. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. stringek@umich.edu.
Abstract
PURPOSE: 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.
PURPOSE: 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 LRP1RME 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 LRP1RME 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.
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Authors: Y Imoto; A Kato; T Takabayashi; M Sakashita; J E Norton; L A Suh; R G Carter; A R Weibman; K E Hulse; W Stevens; K E Harris; A T Peters; L C Grammer; B K Tan; K Welch; D B Conley; R C Kern; S Fujieda; R P Schleimer Journal: Clin Exp Allergy Date: 2018-03-24 Impact factor: 5.018