Pro-inflammatory endothelial cell dysfunction is associated with intersectin-1s down-regulation.
Sunit Singla1, Dan Predescu, Cristina Bardita
1Pulmonary and Critical Care Medicine, Rush University Medical Center, 1750 W, Harrison Street, 297 Jelke, Chicago, IL 60612, USA. sanda_predescu@rush.edu
Respiratory Research
|April 14, 2011
Summary
Lipopolysaccharide (LPS) causes lung endothelial cell (EC) dysfunction by decreasing intersectin-1s (ITSN-1s). Restoring ITSN-1s function protects ECs from LPS-induced inflammation and apoptosis, highlighting its crucial role in lung injury.
Area of Science:
- Cell Biology
- Pulmonary Medicine
- Immunology
Background:
- Lung microvascular endothelial cells (ECs) exhibit a dual response to lipopolysaccharide (LPS), involving both pro-inflammatory and cyto-protective mechanisms.
- Previous studies showed that Bcl-XL overexpression protects ECs from apoptosis induced by intersectin-1s (ITSN-1s) knockdown.
- This study further investigates the cyto-protective EC response to LPS and associated pro-inflammatory dysfunction.
Purpose of the Study:
- To characterize the cyto-protective endothelial cell response to lipopolysaccharide (LPS).
- To investigate the role of intersectin-1s (ITSN-1s) in LPS-induced endothelial cell dysfunction and inflammation.
- To explore potential therapeutic strategies targeting ITSN-1s for lung injury.
Main Methods:
- Electron microscopy (EM) and biotin assays were used to analyze EC phenotype and caveolae internalization after LPS exposure.
- Quantitative PCR and Western blotting assessed mRNA and protein expression of apoptosis regulators, including ITSN-1s.
- TUNEL assays, cytochrome c efflux measurements, and nitric oxide synthase (NOS) activity assays evaluated apoptosis and NO production.
Main Results:
- LPS exposure induced an activated/dysfunctional EC phenotype, inhibiting caveolae internalization by 40%.
- LPS decreased ITSN-1s expression, but Bcl-XL and survivin upregulation, along with Bim downregulation, prevented apoptosis.
- LPS induced iNOS and mtNOS, increasing mitochondrial NO production; ITSN-1s re-expression reversed these effects and restored caveolae endocytosis.
Conclusions:
- ITSN-1s deficiency is implicated in the pro-inflammatory endothelial cell dysfunction induced by LPS.
- Restoring ITSN-1s expression can mitigate LPS-induced EC dysfunction, suggesting a therapeutic target for lung injury.
- The findings elucidate the complex interplay between ITSN-1s, apoptosis, and inflammation in LPS-challenged lung ECs.
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