TY - JOUR
T1 - Synergistic effects of hypertonic saline and valproic acid in a lethal rat two-hit model
AU - Liu, Zhengcai
AU - Li, Yongqing
AU - Liu, Baoling
AU - Deperalta, Danielle K.
AU - Zhao, Ting
AU - Chong, Wei
AU - Duan, Xiuzhen
AU - Zhou, Peter
AU - Velmahos, George C.
AU - Alam, Hasan B.
PY - 2013/4
Y1 - 2013/4
N2 - BACKGROUND: Hemorrhagic shock (HS) followed by an infection ("second hit") can lead to severe systemic inflammatory response and multiple-organ failure. Studies have shown that resuscitation with hypertonic saline (HTS) can blunt the inflammatory response. We demonstrated that large doses of valproic acid (VPA, 300 mg/kg), a histone deacetylase inhibitor, improves survival in a rodent two-hit model (HS followed by cecal ligation and puncture [CLP]). In the present study, we examined whether combination of HTS with VPA would allow us to achieve survival advantage at a lower dose of VPA (200 mg/kg). METHODS: Male Sprague-Dawley rats were subjected to HS (50% blood loss) and randomized into five groups (n = 7-8 per group) as follows: (1) isotonic sodium chloride solution (ISCS), (2) 7.5% saline, (3) VPA, (4) ISCS + VPA, and (5) HTS + VPA. After 24 hours, they underwent CLP, followed by the same doses of ISCS, HTS, and/or VPA and were monitored for 10 days. In a parallel experiment, blood, peritoneal irrigation fluid and lung homogenate were subjected to enzyme-linked immunosorbent assay 3 hours and 24 hours after CLP to measure myeloperoxidase activity and proinflammatory cytokines tumor necrosis factor α and interleukin 1β levels. Western blotting was performed to investigate the expression of pentraxin 3 protein in the lung homogenate at 24 hours after CLP. Hematoxylin and eosin staining of lungs at the 24 hours were performed to quantify the degree of acute lung injury. RESULTS: HTS + VPA treatment significantly improved survival (87.5%), compared with the other groups (14.3%; p < 0.05), while attenuating peritoneal myeloperoxidase levels and proinflammatory cytokine tumor necrosis factor α and interleukin 1β levels in the serum, peritoneal cavity, and lung. The degree of acute lung injury and expression of pentraxin 3 in the lung were significantly reduced in the HTS + VPA group. CONCLUSION: This is the first study to show that VPA and HTS can work synergistically to attenuate inflammation and improve survival in a lethal two-hit model.
AB - BACKGROUND: Hemorrhagic shock (HS) followed by an infection ("second hit") can lead to severe systemic inflammatory response and multiple-organ failure. Studies have shown that resuscitation with hypertonic saline (HTS) can blunt the inflammatory response. We demonstrated that large doses of valproic acid (VPA, 300 mg/kg), a histone deacetylase inhibitor, improves survival in a rodent two-hit model (HS followed by cecal ligation and puncture [CLP]). In the present study, we examined whether combination of HTS with VPA would allow us to achieve survival advantage at a lower dose of VPA (200 mg/kg). METHODS: Male Sprague-Dawley rats were subjected to HS (50% blood loss) and randomized into five groups (n = 7-8 per group) as follows: (1) isotonic sodium chloride solution (ISCS), (2) 7.5% saline, (3) VPA, (4) ISCS + VPA, and (5) HTS + VPA. After 24 hours, they underwent CLP, followed by the same doses of ISCS, HTS, and/or VPA and were monitored for 10 days. In a parallel experiment, blood, peritoneal irrigation fluid and lung homogenate were subjected to enzyme-linked immunosorbent assay 3 hours and 24 hours after CLP to measure myeloperoxidase activity and proinflammatory cytokines tumor necrosis factor α and interleukin 1β levels. Western blotting was performed to investigate the expression of pentraxin 3 protein in the lung homogenate at 24 hours after CLP. Hematoxylin and eosin staining of lungs at the 24 hours were performed to quantify the degree of acute lung injury. RESULTS: HTS + VPA treatment significantly improved survival (87.5%), compared with the other groups (14.3%; p < 0.05), while attenuating peritoneal myeloperoxidase levels and proinflammatory cytokine tumor necrosis factor α and interleukin 1β levels in the serum, peritoneal cavity, and lung. The degree of acute lung injury and expression of pentraxin 3 in the lung were significantly reduced in the HTS + VPA group. CONCLUSION: This is the first study to show that VPA and HTS can work synergistically to attenuate inflammation and improve survival in a lethal two-hit model.
KW - Hemorrhagic shock
KW - hypertonic saline
KW - rats
KW - sepsis
KW - valproic acid
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U2 - 10.1097/TA.0b013e31828583e3
DO - 10.1097/TA.0b013e31828583e3
M3 - Article
C2 - 23511136
AN - SCOPUS:84876197334
SN - 2163-0755
VL - 74
SP - 991
EP - 998
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 4
ER -