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A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs

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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.

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Abbreviations

PB:

Plastic bronchitis

tPA:

Tissue plasminogen activator

RME:

Receptor mediated endocytosis

RAP:

Receptor associated protein

LRP1:

Low density lipoprotein receptor-related protein 1

MI:

Myocardial infarction

AIS:

Acute ischemic stroke

IT:

Intratracheal

BALF:

Bronchoalveolar lavage fluid

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported, in part, by a grant (HD065594 to KAS) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), a grant (HL071439 to KAS) from the National Heart, Lung and Blood Institute (NHLBI), and a grant (GM078200 to GRR) from the National Institute of General Medical Sciences (NIGMS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD, NHLBI, NIGMS or the National Institutes of Health.

We would like to acknowledge and thank Dr. Katherine Eichinger (Benz) and Nicholas Lackowski for their help with the in vivo mouse work and Dr. Ingrid Bergin of the University of Michigan Laboratory Animal Medicine Pathology core for her invaluable help and guidance with the LRP1 staining.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

    Swan Lin, Jennifer Racz, Melissa F. Tai, Kristina M. Brooks, Lauren J. Heath & Kathleen A. Stringer

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

    Phillip Rzeczycki & Gus R. Rosania

  3. Division of Pulmonary and Critical Care Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Michael W. Newstead & Theodore J. Standiford

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  1. Swan Lin
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  2. Jennifer Racz
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  10. Kathleen A. Stringer
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Correspondence to Kathleen A. Stringer.

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Lin, S., Racz, J., Tai, M.F. et al. A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs. Pharm Res 33, 72–82 (2016). https://doi.org/10.1007/s11095-015-1763-6

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  • DOI: https://doi.org/10.1007/s11095-015-1763-6

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