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

Academic Article

Abstract

  • OBJECTIVE:: In this study, we tested the hypothesis that 17β-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-nitro-l-arginine methyl ester; 30 mg/kg), a soluble guanylyl cyclase (sGC) inhibitor [1H-(1, 2, 4) oxadiazolo (3, 4-α) quinoxalin-1-one; 10 mg/kg] or an ER antagonist (ICI 182,780; 3 mg/kg) 30 minutes before E2 (100 μg/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. © 2008 by Lippincott Williams & Wilkins.
  • Published In

  • Annals of Surgery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Kan WH; Hsu JT; Schwacha MG; Choudhry MA; Bland KI; Chaudry IH
  • Start Page

  • 294
  • End Page

  • 302
  • Volume

  • 248
  • Issue

  • 2