A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs.
Pharm Res
; 33(1): 72-82, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26231141
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Receptores de LDL
/
Ativador de Plasminogênio Tecidual
/
Proteínas Supressoras de Tumor
/
Pulmão
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article