Arg mediates LPS-induced disruption of the pulmonary endothelial barrier

Alicia N. Rizzo, Patrick Belvitch, Regaina Demeritte, Joe G.N. Garcia, Eleftheria Letsiou, Steven M. Dudek

Research output: Contribution to journalArticle

Abstract

Acute Respiratory Distress Syndrome (ARDS) is a devastating disease process that involves dysregulated inflammation and decreased alveolar-capillary barrier function. Despite increased understanding of the pathophysiology, no effective targeted therapies exist to treat ARDS. Recent preclinical studies suggest that the multi-tyrosine kinase inhibitor, imatinib, which targets the Abl kinases c-Abl and Arg, has the potential to restore endothelial dysfunction caused by inflammatory agonists. Prior work demonstrates that imatinib attenuates LPS (lipopolysaccharide)-induced vascular leak and inflammation; however, the mechanisms underlying these effects remain incompletely understood. In the current study, we demonstrate that imatinib inhibits LPS-induced increase in the phosphorylation of CrkL, a specific substrate of Abl kinases, in human pulmonary endothelial cells. Specific silencing of Arg, and not c-Abl, attenuated LPS-induced pulmonary vascular permeability as measured by electrical cellular impedance sensing (ECIS) and gap formation assays. In addition, direct activation of Abl family kinases with the small molecule activator DPH resulted in endothelial barrier disruption that was attenuated by Arg siRNA. In complementary studies to characterize the mechanisms by which Arg mediates endothelial barrier function, Arg silencing was found to inhibit LPS-induced disruption of adherens junctions and phosphorylation of myosin light chains (MLC). Overall, these results characterize the mechanisms by which imatinib protects against LPS-induced endothelial barrier disruption and suggest that Arg inhibition may represent a novel strategy to enhance endothelial barrier function.

Original languageEnglish (US)
Article number106677
JournalVascular Pharmacology
Volume128-129
DOIs
StatePublished - May 1 2020

Keywords

  • ARDS
  • Acute lung injury
  • Arg
  • C-Abl
  • Endothelium
  • Imatinib
  • LPS
  • Vascular permeability

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Arg mediates LPS-induced disruption of the pulmonary endothelial barrier'. Together they form a unique fingerprint.

  • Cite this

    Rizzo, A. N., Belvitch, P., Demeritte, R., Garcia, J. G. N., Letsiou, E., & Dudek, S. M. (2020). Arg mediates LPS-induced disruption of the pulmonary endothelial barrier. Vascular Pharmacology, 128-129, [106677]. https://doi.org/10.1016/j.vph.2020.106677