Pharmacologic resuscitation promotes survival and attenuates hemorrhage-induced activation of extracellular signal-regulated kinase 1/2.
BACKGROUND
Hemorrhage is the leading cause of preventable trauma-related deaths, and histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following lethal hemorrhage. HDACI acetylate proteins, and acetylation regulates many cellular functions. Here we have investigated the effects of VPA treatment on extracellular signal-regulated kinase 1/2 (ERK) activation, as ERK is well known to modulate cell death, gene expression, and inflammation.


METHODS
Anesthetized Wistar-Kyoto rats were subjected to lethal (60%) blood loss, and then randomized (n = 5-6/group) to (1) VPA 300 mg/kg or (2) vehicle control. Survival was monitored for 24 h. A separate group of rats were subjected to sublethal (40%) hemorrhage and were treated with VPA or vehicle. Rats were sacrificed at 1, 4, and 20 h, and lung tissue was assessed for the degree of acetylation of histone 3, and activation (phosphorylation) of ERK. Sham animals served as normal controls.


RESULTS
Sixty percent hemorrhage resulted in severe shock. Only 17% of the vehicle-treated animals survived (most died within 1 h), whereas 80% of the VPA-treated animals survived (P < 0.05). Hemorrhage resulted in a significant increase in phosphorylated ERK (activated form) compared with sham at the 1 and 4 h time points, but not at the 20 h time point. VPA treatment significantly attenuated these changes, while increasing histone protein acetylation.


CONCLUSIONS
VPA treatment significantly improves survival following lethal hemorrhagic shock. Hemorrhage induces ERK activation, which is significantly attenuated by VPA treatment. This may represent one mechanism through which VPA promotes survival in otherwise lethal hemorrhagic shock.
Fukudome
Eugene Y
EY
Department of Surgery, Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
Kochanek
Ashley R
AR
Li
Yongqing
Y
Smith
Eleanor J
EJ
Liu
Baoling
B
Kheirbek
Tareq
T
Lu
Jennifer
J
Kim
Kyuseok
K
Hamwi
Kristopher
K
Velmahos
George C
GC
Alam
Hasan B
HB
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D051548:Histone Acetyltransferases; D048049:Extracellular Signal-Regulated MAP Kinases