Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1

Jun Te Hsu, Wen Hong Kan, Chi Hsun Hsieh, Mashkoor A. Choudhry, Martin G. Schwacha, Kirby I. Bland, Irshad H. Chaudry

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

p38 MAPK has been reported to regulate the inflammatory response in various cell types via extracellular stimuli. p38 MAPK activation also results in the induction of heme oxygenase (HO)-1, which exerts potent anti-inflammatory effects. Although studies have shown that 17β-estradiol (E2) prevented organ dysfunction following trauma-hemorrhage, it remains unknown whether p38 MAPK/HO-1 plays any role in E2-mediated attenuation of intestinal injury under those conditions. To study this, male rats underwent trauma-hemorrhage (mean blood pressure ∼40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body wt), the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt) or E2 plus SB-203580. Two hours thereafter, intestinal myeloperoxidase (MPO) activity and lactate, TNF-α, IL-6, ICAM-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein (MIP)-2 levels were measured. Intestinal p38 MAPK and HO-1 protein levels were also determined. Trauma-hemorrhage led to an increase in intestinal MPO activity and lactate, TNF-α, IL-6, ICAM-1, CINC-1, and MIP-2 levels. This was accompanied with a decrease in intestinal p38 MAPK activity and increase in HO-1 expression. Administration of E2 normalized all the above parameters except HO-1, which was further increased following trauma-hemorrhage. Administration of SB-203580 with E2 abolished the E2-mediated restoration of the above parameters as well as the increase in intestinal HO-1 expression following trauma-hemorrhage. These results suggest that the p38 MAPK/HO-1 pathway plays a critical role in mediating the salutary effects of E2 on shock-induced intestinal injury.

Original languageEnglish (US)
Pages (from-to)R1825-R1831
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Keywords

  • CINC-1
  • MIP-2
  • MPO
  • p38 MAPK inhibitor

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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