Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model

Biomed Res. 2011 Feb;32(1):9-17. doi: 10.2220/biomedres.32.9.


Endothelin (ET)-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of a number of diseases, and some studies suggest that circulating ET-1 is elevated in sepsis. The present study investigated whether ET plays a role in sepsis-mediated acute lung injury and whether its expression could be down regulated by blockade of TNF-α in septic lung. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) at different time points (1, 3, 6 and 10 h) and various tests were then performed. The features of acute lung injury were observed at 1 h after LPS administration, which gradually became severe with time. Systolic and diastolic pressures were reduced just about one hour after LPS administration, whereas pulmonary TNF-α levels were significantly increased at various time points after LPS administration. LPS induced a time-dependent expression of ET-1 and ET(A) receptor in the lungs compared to control, peaking and increasing by 3 fold at 6 h after induction of endotoxemia, whereas levels of ET(B) receptor, which has vasodilating effects, were remarkably down regulated time-dependently. We conclude that time-dependent increase of ET-1 and ET(A) receptor with the down regulation of ET(B) receptor may play a role in the pathogenesis of acute lung injury in endotoxemia. Finally, treatment of LPS-administered rats with TNF-α blocking peptide for three hours significantly suppressed levels of pulmonary ET-1. These data taken together, led us to conclude that differential alteration in ET expression and its receptors may be mediated by TNF-α and may, in part, account for the pathogenesis of acute lung injury in endotoxemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / etiology
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / physiopathology
  • Animals
  • Blood Gas Analysis
  • Blood Pressure / drug effects
  • Endothelin-1 / metabolism*
  • Endotoxemia / complications
  • Endotoxemia / metabolism*
  • Endotoxemia / physiopathology
  • Lactic Acid / blood
  • Lipopolysaccharides / pharmacology*
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology
  • Male
  • Organ Size / drug effects
  • Peptides / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Endothelin / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism


  • Endothelin-1
  • Lipopolysaccharides
  • Peptides
  • Receptors, Endothelin
  • Tumor Necrosis Factor-alpha
  • Lactic Acid