ARDS is characterized by sudden, life-threatening lung failure with diffuse alveolar infiltrate, reduced arterial oxygenation, and pulmonary edema. Acute lung injury (ALI) is the end result of common pathways initiated by a variety of local or systemic insults. Polyethylene glycol (PEG) compounds are inert and nontoxic polymers that act as a surrogate mucin lining providing protection against bacterial infections on intestinal epithelial cells. We hypothesized that PEG may provide similar protective effects on lung endothelium by attenuating endothelial cell (EC) activation that results in barrier dysfunction. This study examines the effects of a high-molecular-weight PEG (PEG15-20) on cultured human pulmonary microvessel EC from barrier disruptive agents. EC were cultured on microelectrodes and changes in transendothelial electrical resistances (TER) were measured to assess alterations in paracellular permeability. PEG induced a rapid, dose-dependent increase in TER similar to barrier-enhancing lipid such as sphingosine 1-phosphate (S1P). Optimal concentration of 7.5-9% PEG induced a robust increase in TER from 2,500 to 5,000 ohm, which was sustained for 40 hours. In comparison to S1P, which induced a 40% increase in resistance in 10-15 minutes, the maximum barrier enhancing effect of PEG was achieved in about 45 minutes, but with 100% increase in resistance. With a 2-fold increase in resistance, PEG is one of the most potent barrier-enhancing agents tested among all the barrier-enhancing agents, such as S1P, FTY720, phospho-FTY720, and HGF. Immunofluorescence data revealed that PEG altered the EC actin cytoskeleton to form a defined cortical actin ring that may help strengthen cell-cell junctional adhesion. PEG rapidly induced dephosphorylation of ERK and MLC as early as 1 minute and completely inhibited thrombin-induced ERK and MLC phosphorylation. More importantly, pretreatment with PEG for 1 hour attenuated thrombin-induced endothelial barrier dysfunction. In summary, PEG activates a rapid, actin-associated, barrier-enhancing signal transduction pathway in EC, which may have therapeutic potential to prevent and reverse pulmonary edema.
Funded by HL058064 and GM062344.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.