gw9662 and Hemorrhage

Studies have shown that administration of 17β-estradiol prevents trauma-hemorrhage-induced increase in proinflammatory cytokine production by Kupffer cells and associated multiple organ injury. Since activation of peroxisome proliferator-activated receptor γ (PPARγ) following ischemic conditions has been shown to be protective, we examined if PPARγ plays any role in the salutary effects of 17β-estradiol on Kupffer cell cytokine production following trauma-hemorrhage. Male mice underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). 17β-estradiol (50 µg/kg) or vehicle with or without PPARγ antagonist GW9662 was injected subcutaneously at the middle of resuscitation. At 2 h after trauma-hemorrhage, plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels, Kupffer cell IL-6 and TNF-α production and mRNA expression, and PPARγ, nuclear factor (NF)-κB and activator protein (AP)-1 DNA binding activity were determined. Kupffer cell IL-6 and TNF-α production, as well as plasma IL-6 and TNF-α levels, increased following trauma-hemorrhage. Moreover, NF-κB and AP-1 DNA binding activity and IL-6 and TNF-α mRNA expression were also enhanced under such conditions. However, 17β-estradiol administration normalized all these parameters. Although PPARγ activity decreased after trauma-hemorrhage, administration of 17β-estradiol following trauma-hemorrhage elevated PPARγ activity above the normal level. Inhibition of PPARγ by co-administration of GW9662, however, abolished the salutary effects of 17β-estradiol on plasma cytokine and Kupffer cells. Thus, activation of PPARγ appears to play an important role in mediating the salutary effects of 17β-estradiol on plasma cytokine levels and Kupffer cell cytokine production after trauma-hemorrhage, which are likely mediated via NF-κB and AP-1.

Topics: Anilides; Animals; Cells, Cultured; Cytokines; Estradiol; Gene Expression Regulation; Hemorrhage; Kupffer Cells; Male; Mice; Mice, Inbred C3H; PPAR gamma; RNA, Messenger; Wounds and Injuries

A recent study suggested that administration of androstenediol (Adiol) after trauma-hemorrhage (T-H) improves hepatic functions; however, the mechanism responsible for the salutary effect of Adiol remains unknown. Although studies indicate similarities and association between the anti-inflammatory properties of Adiol and peroxisome proliferator-activated receptor gamma (PPARgamma), whether the salutary effects of Adiol are mediated via upregulation of PPARgamma remains unclear.. Male Sprague-Dawley rats underwent laparotomy and approximately 90 minutes of hemorrhagic shock (40 mm Hg), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Adiol (1 mg per kilogram of body weight, iv) was administered at the end of resuscitation. An additional group of rats were treated with PPARgamma antagonist (GW9662, 1 mg/kg ip) along with Adiol and the rats were sacrificed 5 hours thereafter.. Hepatic functions were markedly depressed and plasma tumor necrosis factor-alpha, C-reactive protein and endothelin-1 were markedly increased after T-H. DNA-binding activity of nuclear factor kappa B and AP-1, and gene expressions of inducible nitric oxide synthase and endothelin-1 in the liver also increased significantly. These parameters were attenuated by Adiol treatment. These effects were accompanied an increased DNA-binding activity of PPARgamma in T-H-Adiol-treated rats. Treatment of rats with GW9662 prevented the salutary effects of Adiol after T-H.. Since blockade of PPARgamma prevented the salutary effects of Adiol on hepatic functions and proinflammatory factors, this finding suggests that Adiol mediated its salutary effects after T-H via the PPARgamma-related pathways.

Topics: Anabolic Agents; Androstenediol; Anilides; Animals; C-Reactive Protein; Endothelin-1; Gene Expression; Hemorrhage; Liver; Male; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; PPAR gamma; Rats; Rats, Sprague-Dawley; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Wounds and Injuries