Unfolded protein response suppression potentiates LPS-induced barrier dysfunction and inflammation in bovine pulmonary artery endothelial cells

Abstract

The development of novel strategies to counteract diseases related to barrier dysfunction is a priority, since sepsis and acute respiratory distress syndrome are still associated with high mortality rates. In the present study, we focus on the effects of the unfolded protein response suppressor (UPR) 4-Phenylbutyrate (4-PBA) in Lipopolysaccharides (LPS)-induced endothelial injury, to investigate the effects of that compound in the corresponding damage. 4-PBA suppressed binding immunoglobulin protein (BiP) – a UPR activation marker – and potentiated LPS – induced signal transducer and activator of transcription 3 (STAT3) and extracellular signal‑regulated protein kinase (ERK) 1/2 activation. In addition to those effects, 4-PBA enhanced paracellular hyperpermeability in inflamed bovine pulmonary endothelial cells, and did not affect cell viability in moderate concentrations. Our observations suggest that UPR suppression due to 4-PBA augments LPS-induced endothelial injury, as well as the corresponding barrier disruption.

Heat shock protein 90 inhibition in the endothelium

“…It is involved in endothelial barrier function. Recent studies suggest that UPR activation increases barrier integrity and reduces endothelial permeability, whereas its suppression is associated to impaired barrier function (21)(22)(23)(24)(25). Hsp90 inhibitors were shown to activate UPR sensors, as well as their downstream targets, in endothelial cells and mouse lungs (26,27).…”