Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury

PLoS One. 2015 Dec 28;10(12):e0145607. doi: 10.1371/journal.pone.0145607. eCollection 2015.

Abstract

Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC) apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1) induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control) nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / enzymology
  • Acute Lung Injury / etiology*
  • Acute Lung Injury / pathology
  • Apoptosis / drug effects
  • Caspase 1 / administration & dosage
  • Caspase 1 / metabolism*
  • Caspase Inhibitors / pharmacology
  • Cell Line
  • Cell-Derived Microparticles / enzymology
  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Endothelial Cells / pathology*
  • Humans
  • Lipopolysaccharides / toxicity
  • Lung / blood supply
  • Monocytes / enzymology*

Substances

  • Caspase Inhibitors
  • Lipopolysaccharides
  • Caspase 1