Estrogen ameliorates trauma-hemorrhage-induced lung injury via endothelial nitric oxide synthase-dependent activation of protein kinase G.

Abstract

OBJECTIVE:

In this study, we tested the hypothesis that 17beta-estradiol (E2) administration after trauma-hemorrhage reduces lung injury through a mechanism involving estrogen receptor (ER)-dependent activation of the endothelial nitric oxide (NO) synthase (eNOS)/protein kinase G (PKG)/vasodilator-stimulated phosphoprotein (VASP) pathway.

BACKGROUND:

Estrogen provides protection after injury via activation of multiple signaling cascades, including the cyclic GMP-dependent PKG pathway. Phosphorylation of VASP at Ser239 (p-VASP) can be used to assess PKG signaling activity.

METHODS:

Male Sprague-Dawley rats (275-325 g) underwent soft tissue trauma (midline laparotomy) and hemorrhagic shock (mean blood pressure 35-40 mm Hg for 90 minutes) followed by fluid resuscitation. Animals were pretreated with a nonselective NOS inhibitor (N(omega)-nitro-L-arginine methyl ester; 30 mg/kg), a soluble guanylyl cyclase (sGC) inhibitor [1H-(1, 2, 4) oxadiazolo (3, 4-alpha) quinoxalin-1-one; 10 mg/kg] or an ER antagonist (ICI 182,780; 3 mg/kg) 30 minutes before E2 (100 microg/kg) or vehicle administration. Animals were killed at 2 hours after resuscitation.

RESULTS:

Lung injury induced by trauma-hemorrhage is evidenced by edema (wet/dry ratio), neutrophil infiltration (myeloperoxidase activity), and with an increased expression of cytokines, chemokines, and adhesion molecules. E2 treatment after trauma-hemorrhage resulted in an increase in eNOS expression/phosphorylation, PKG-I activation, and VASP/p-VASP expression, which paralleled a decrease in lung injury. Inhibition of NOS and sGC abolished the E2-induced increase in PKG-I activity, VASP/p-VASP expression. Blockade of eNOS, PKG-I, and ER exacerbated lung inflammation and injury.

CONCLUSIONS:

These results collectively suggest that activation of the eNOS-PKG/VASP pathway by E2 protects against trauma-hemorrhage-induced lung injury.

• Authors: Wen-Hong Kan, Jun-Te Hsu, Martin G Schwacha, Mashkoor A Choudhry, Kirby I Bland, Irshad H Chaudry
• Journal: Annals of surgery (Ann Surg) Vol. 248 Issue 2 Pg. 294-302 (Aug 2008) ISSN: 1528-1140 [Electronic] United States
• PMID: 18650641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cell Adhesion Molecules
• Chemokines
• Cytokines
• Estrogen Antagonists
• Inflammation Mediators
• Microfilament Proteins
• Phosphoproteins
• vasodilator-stimulated phosphoprotein
• Nitric Oxide Synthase Type III
• Cyclic GMP-Dependent Protein Kinases

Topics

• Analysis of Variance
• Animals
• Blotting, Western
• Cell Adhesion Molecules (drug effects, metabolism)
• Chemokines (analysis, metabolism)
• Cyclic GMP-Dependent Protein Kinases (drug effects, metabolism)
• Cytokines (analysis, metabolism)
• Disease Models, Animal
• Estrogen Antagonists (pharmacology)
• Inflammation Mediators (metabolism)
• Lung Diseases (prevention & control)
• Lung Injury
• Male
• Microfilament Proteins (drug effects, metabolism)
• Nitric Oxide Synthase Type III (drug effects, metabolism)
• Phosphoproteins (drug effects, metabolism)
• Probability
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Sensitivity and Specificity
• Shock, Hemorrhagic (complications)
• Signal Transduction
• Wounds and Injuries (complications)