Attenuation of murine acute lung injury by PF-573,228, an inhibitor of focal adhesion kinase

Paul A. Lederer, Tingting Zhou, Weiguo Chen, Yulia Epshtein, Huashan Wang, Biji Mathew, Jeffrey R. Jacobson

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Acute lung injury (ALI) is characterized by endothelial barrier disruption resulting in increased vascular permeability. As focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, is involved in endothelial cell (EC) barrier regulation, we hypothesized that FAK inhibition could attenuate agonist-induced EC barrier disruption relevant to ALI. Human lung EC were pretreated with one of three pharmacologic FAK inhibitors, PF-573,228 (PF-228, 10 μM), PF-562,271 (PF-271, 5 μM) or NVP-TAE226 (TAE226, 5 μM) for 30 min prior to treatment with thrombin (1 U/ml, 30 min). Western blotting confirmed attenuated thrombin-induced FAK phosphorylation associated with all three inhibitors. Subsequently, EC were pretreated with either PF-228 (10 μM), TAE226 (5 μM) or PF-271 (5 μM) for 30 min prior to thrombin stimulation (1 U/ml) followed by measurements of barrier integrity by transendothelial electrical resistance (TER). Separately, EC grown in transwell inserts prior to thrombin (1 U/ml) with measurements of FITC-dextran flux after 30 min confirmed a significant attenuation of thrombin-induced EC barrier disruption by PF-228 alone. Finally, in a murine ALI model induced by LPS (1.25 mg/ml, IT), rescue treatment with PF-228 was associated with significantly reduced lung injury. Our findings PF-228, currently being studied in clinical trials, may serve as a novel and effective therapeutic agent for ALI.

Original languageEnglish (US)
Pages (from-to)16-23
Number of pages8
JournalVascular Pharmacology
Volume110
DOIs
StatePublished - Nov 2018
Externally publishedYes

Keywords

  • Acute lung injury
  • Endothelial permeability
  • FAK

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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