Salutary effects of androstenediol on hepatic function after trauma-hemorrhage are mediated via peroxisome proliferators-activated receptor gamma.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Shimizu
Tomoharu
T
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 35294-0019, USA.
Szalay
Laszlo
L
Hsieh
Ya-Ching
YC
Choudhry
Mashkoor A
MA
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D045930:Anabolic Agents / Q000494:pharmacology*; D015114:Androstenediol / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006470:Hemorrhage / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014947:Wounds and Injuries / Q000188:drug therapy
C457499:2-chloro-5-nitrobenzanilide; D045930:Anabolic Agents; D000813:Anilides; D019332:Endothelin-1; D016328:NF-kappa B; D047495:PPAR gamma; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D015114:Androstenediol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat