Lung protection provided by suberoylanilide hydroxamic acid in a rat model of hemorrhagic shock after entering high altitude for the first time:comparison of resuscitation with different fluids

Abstract

Objective To compare the lung protection provided by suberoylanilide hydroxamic acid (SAHA) in a rat model of hemorrhagic shock after entering high altitude for the first time during resuscitation with different fluids. Methods Forty-eight male Wistar rats, aged 1.5-2.0 months, weighing 250-300 g, were transported from the breeding area at altitude 2 800 m to the experimental area at altitude 3 780 m. The rats were randomized into 4 groups (n=12 each) using a random number table: sham operation group (group Sham), hemorrhagic shock group (group HS), resuscitation with lactated Ringer′s solution combined with SAHA group (group LR+ SAHA), and resuscitation with hypertonic sodium chloride hydroxyethyl starch 40 solution (HSH40) combined with SAHA group (group HSH+ SAHA). Hemorrhagic shock was induced by removing 45%-55% of blood volume from the left femoral artery at a constant speed within 15 min until mean arterial pressure was reduced to 30-40 mmHg and maintained at this level for 90 min through blood-letting or reinfusion of the shed blood.In group Sham, only cannulation was performed, the rats received no blood-letting or resuscitation, blood samples were collected from the abdominal aorta at 3 h of observation, and then the rats were sacrificed.In group HS, hemorrhagic shock was induced, blood samples were collected from the abdominal aorta immediately after successful establishment of the model, and then the rats were sacrificed.In group LR+ SAHA, after successful establishment of the model, lactated Ringer′s solution (1.5 times the volume of blood loss) was infused over 20 min, and then SAHA 7.5 mg/kg (in 0.25 ml of normal saline) was infused over 5 min for resuscitation.In group HSH+ SAHA, after successful establishment of the model, HSH40 4 ml/kg was infused over 5 min, and then SAHA 7.5 mg/kg (in 0.25 ml of normal saline) was infused over 5 min for resuscitation.In LR+ SAHA and HSH+ SAHA groups, the animals were sacrificed after blood samples were collected from the abdominal aorta at 3 h after resuscitation.Blood samples from the abdominal aorta were obtained for blood gas analysis, the oxygenation index was calculated, and the occurrence of acute lung injury (oxygenation index ≤300 mmHg) was recorded.Lungs were removed for examination of the pathologic changes (with light microscope) and ultrastructure (with transmission electronic microscope) and for determination of wet to dry weight ratio (W/D ratio) and expression of claudin-3 and claudin-4 in lung tissues (by Western blot). The lung injury was scored. Results The incidence of acute lung injury was 70% in group HS, and no acute lung injury was found in Sham, LR+ SAHA and HSH+ SAHA groups.Compared with group Sham, the lung injury score and W/D ratio in lung tissues were significantly increased, and the expression of claudin-3 and claudin-4 in lung tissues was significantly down-regulated in HS, LR+ SAHA and HSH+ SAHA groups (P<0.05). Compared with group HS, the lung injury score and W/D ratio in lung tissues were significantly decreased, the expression of claudin-3 and claudin-4 in lung tissues was significantly up-regulated (P<0.05), and the pathologic changes were significantly attenuated in LR+ SAHA and HSH+ SAHA groups.Compared with group LR+ SAHA, the lung injury score and W/D ratio in lung tissues were significantly decreased, the expression of claudin-3 and claudin-4 in lung tissues was significantly up-regulated (P<0.05), and the pathologic changes were significantly attenuated in group HSH+ SAHA. Conclusion SAHA provides better lung protection when resuscitation is performed with HSH40 than with lactated Ringer′s solution in a rat model of hemorrhagic shock after entering high altitude for the first time. Key words: Hydroxamic acids; Sodium lactate; Saline solution, hypertonic; Hetastarch; Altitude; Shock, hemorrhagic; Respiratory distress syndrome, adult