SUBEROYLANILIDE HYDROXAMIC ACID ALLEVIATES ACUTE LUNG INJURY INDUCED BY SEVERE HEMORRHAGIC SHOCK AND RESUSCITATION IN RATS

Background: This study aimed to assess the severity of acute lung injury after mild or severe hemorrhagic shock and resuscitation, and to examine the therapeutic effects of suberoylanilide hydroxamic acid (SAHA) on lung injury. Methods: Mild and severe hemorrhagic shock were induced by total blood volume loss of 20% or 40%, respectively, which was maintained for 60 min. Then, resuscitation was performed by autologous blood and SAHA or a vehicle solution accordingly. Mean arterial pressure, heart rate, and arterial blood gas were measured during the experiment. Histological assays, wet/dry weight ratio, inflammatory cytokines, and the extent of histone acetylation were evaluated at 3 h post-resuscitation. Results: There were no significant differences of the most indicators measured between the mild hemorrhagic shock and Sham groups. Although in severe hemorrhagic shock group, mean arterial pressure was markedly reduced, lactic acid was significantly increased after hemorrhage. Moreover, the lung injury score was increased, the wet/dry weight ratio was elevated, inflammatory factor expression levels were upregulated, the expression of phosphorylated NF-kappa B/p65 was enhanced, and the extent of histone acetylation was decreased at 3 h post-resuscitation. Remarkably, adjuvant treatment with SAHA decreased the lactic acid, the pathological injury score, the wet/dry weight ratio, the content of inflammatory factor, as well as the level of activated NF-kappa B/p65, but promoted the expression of acetylated H4. Conclusions: Total blood volume loss of 40% results in acute lung injury, whereas loss of 20% does not. Treatment with SAHA alleviates lung injury induced by severe hemorrhagic shock and resuscitation and the underlying mechanism involves a reversal of decreased histone acetylation and inhibition of the NF-kappa B pathway.