Synergistic effects of hypertonic saline and valproic acid in a lethal rat two-hit model

Abstract

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.

Polydatin: a new therapeutic agent against multiorgan dysfunction

“…Therefore, we hypothesize that PD could ameliorate multiple-organ dysfunction through multiple therapeutic targets. To confirm our hypothesis, we investigated the therapeutic effects and molecular mechanisms of PD in rats with MODS induced by a "two hit" model (combination of traumatic hemorrhagic shock and ligation and puncture of cecum [CLP]) [18].…”

“…The assayed variables included markers of the liver, kidney, heart, and lung function. Organ dysfunction was established on the basis of the standardized criteria proposed in 1995 by Marshall et al, and MODS was defined as dysfunction of two or more organs [18].…”

Distribution and differentiation of myeloid-derived suppressor cells after fluid resuscitation in mice with hemorrhagic shock

“…Studies based on different animal models suggest that HTS and HES could either directly or indirectly alter the expression of cytokines and activation of signaling pathways, including those above (Coimbra et al, 1996;Loomis et al, 2001;Ke et al, 2006;Wang et al, 2009;Chen et al, 2013;Esnault et al, 2013;Liu et al, 2013;Choi et al, 2014;Dong et al, 2014;Huang et al, 2014;Igarashi et al, 2014;Wright et al, 2014;Öztürk et al, 2015;Chang et al, 2016). Thus, the MDSC-related cytokines and signaling pathways in hemorrhagic shock resuscitation with different kinds of fluids need further research.…”

Hypertonic saline for treatment of shock: have we looked for everything?

“…The combination of hypertonic saline with valproic acid worked synergistically to attenuate inflammation and improve survival. In this report, by Liu et al, 42 no control standard of care treatment was used. In a hemorrhage + lipopolysaccharide model, Gao et al 59 report that hypertonic saline alone, and especially when combined with hydroxyethylstarch, reduces lung tissue damage and pulmonary edema.…”

“…I will restrict myself to discussing experiments in which a reasonable approximation to standard of care was used as a control, with two exceptions, both of which are included as Sepsis trials. 41,42 This discussion shall be divided into two sections, namely hemorrhage and sepsis trials.…”