| Background and ObjectiveMechanical ventilation is an essential means to maintain respiratory support for the ICU patients or the patients under general anesthesia. It can provide oxygen, while it's also a damage factor to induce or aggravate ventilator-induced lung injury(VILI). Many clinical and animal studies have shown that, even in previously healthy lungs, unreasonable mechanical ventilation can cause different degrees of lung injury.VILI is the result of various damage factors during mechanical ventilation, and the mechanism is not fully clarified. VILI includes mechanical injury and biotrauma. Biotrauma, a sort of acute inflammatory lung injury, is a hot spot at present. A variety of damage factors such as ischemia, hypoxia, oxidative stress and inflammation, etc, can result in acute lung injury. Presently, the role of apoptosis in the occurrence and development of lung injury is being focused gradually. In recent years, studies have showed that the activation of MAPK signal transduction pathway is one of the mechanisms of VILI. JNK signal transduction pathway, an important one in MAPKs' family, is considered as the inducer for apoptosis and inflammatory reaction. However, there are few researches about whether it is involved in the lung tissue apoptosis of VILI.Dexmedetomidine, a novel adrenal agonist of high ?2 selectivity, has the effect of sedation, analgesia, anti-sympathetic, inhibition of catecholamine release and slight respiratory inhibition. Dexmedetomidine can also protect the heart, brain and kidney organs and reduce inflammation in the lungs when VILI occurs. Besides, present studies confirm that dexmedetomidine has the effect of tissue damage and apoptosis resistance. However, whether dexmedetomidine is effective in the apoptosis resistance and how it works(such as the activation of related cell apoptosis signal transduction pathways) are not yet clear.This study is aimed to observe the effect of tissue damage resistance, apoptosis resistance and the activation of JNK signal transduction pathway of dexmedetomidine, and further disscuss the protective effect and the mechanism of lung protection of dexmedetomidine, when VILI occurs. Materials and Methods48 healthy male SD rats were randomly divided into 6 groups(n = 8): group C, group N, group H, group H + D1, group H + D2 and group H + D2 + Y. Group C kept spontaneous breathing. Group N was given standard ventilation(VT 8 ml/kg, RR 70 breaths/minute). Group H, group H + D1, group H + D2 and group H + D2 + Y were given the large tidal volume ventilation(VT 20 ml/kg, RR 50 breaths/minute). Group H + D1 and group H + D2 were respectively injected with 2.5 ?g/kg and 5.0 ?g/kg dexmedetomidine before the mechanical ventilation. Group H + D2 + Y was injected with 0.1 mg/kg yohimbine at 30 min before given the dexmedetomidine. Group C, group N and group H were injected with the same does of saline. After maintaining ventilation for 4 h, rats were sacrificed. The wet/dry weight ratio of the inferior lobe of right lung was measured. The middle lobe of right lung was processed for HE staining, immunohistochemistry and TUNEL. The protein of JNK and p-JNK of the superior lobe of right lung were measured by Western blot. Meanwhile, the level of the total protein in BALF was tested. Results 1. The wet/dry weight ratio change of lung tissueCompared with group C, the W/D ratio of group N had no statistically significant difference(P > 0.05), but the W/D ratio of group H increased obviously(P < 0.05). Compared with group H, the W/D ratio of group H + D1 had no statistically significant difference(P > 0.05), but it decreased significantly in group H + D2(P < 0.05). The W/D ratio of group H + D2 + Y raised when compared with group H + D2(P < 0.05). 2. The change of total protein content in BALFCompared with group C, the level of total protein content in BALF of group H raised(P < 0.05), while in group N, it had no statistically significant difference(P > 0.05). Compared with group H, the level of total protein content in BALF of group H + D2 decreased(P < 0.05), but it had no statistically significant difference in group H + D1(P > 0.05). The level of total protein content in BALF of group H + D2 + Y raised obviously when compared with group H + D2(P < 0.05). 3. The change of lung tissue pathologyThe lung tissue structure of rats in group C and group N were basicly normal. In group H, parts of alveolar cavities had more pink exudate, hemorrhage and inflammatory accumulation. The change of lung tissue pathology of rats in group H + D1 was similar to group H. Compared with group H, the change of lung tissue pathology of rats in group H + D2 relieved significantly. However, the change of lung tissue pathology of rats in group H + D2 + Y significantly aggravated when compared with group H + D2.4. The change of lung tissue apoptosis(TUNEL)The lung tissue of rats in group C had no apoptotic cells, and a small amount of apoptotic cells appeared in group N. But the number of positive cells of rats in group H increased significantly, and the similar situation occurred in group H + D1. Compared with group H, the number of positive cells of rats in group H + D2 decreased significantly. The number of positive cells in group H + D2 + Y increased significantly when compared with group H + D2. Furthermore, the positive cells were mainly pulmonary vascular endothelial cells, alveolar epithelial cells and small airway epithelial cells, and partly visible in inflammatory cells and stromal cells. The change of the lung tissue AI: the lung tissue AI of group H raised significantly when compared with group C and group N(P < 0.05). Compared with group H, the lung tissue AI of group H + D1 had no statistically significant difference(P > 0.05), but in group H + D2, it decreased significantly(P < 0.05). Moreover, in group H + D2 + Y, it raised significantly when compared with group H + D2(P < 0.05). 5. The expression and distribution of p-JNK protein in the lung tissue(immunohistochemistry)The lung tissue of rats in group C and group N had a small amount of positive cells. The number of positive cells increased significantly in group H, and the similar situation occurred in group H + D1. Compared with group H, the number of positive cells decreased significantly in group H + D2. And the number of positive cells increased significantly in group H + D2 + Y when compared with group H + D2. Furthermore, the positive cells were mainly pulmonary vascular endothelial cells, alveolar epithelial cells and bronchial epithelial cells, and partly visible in inflammatory cells and stromal cells. The expressive level of p-JNK protein in the lung tissue(a * b): compared with group C, the expressive level of p-JNK protein in the lung tissue of group N had no significant difference(P > 0.05), but in group H, it raised significantly(P < 0.05). Compared with group H, in group H + D1, the expressive level of p-JNK protein had no significant difference(P > 0.05), but in group H + D2, it decreased significantly(P < 0.05). The expressive level of p-JNK protein in group H + D2 + Y raised significantly when compared with group H + D2(P < 0.05). Thus it could be seen that the expression and distribution of p-JNK protein were in substantial agreement with the lung tissue apoptosis. 6. The expression of JNK and p-JNK protein in the lung tissue(Western blot)The expressive level of JNK protein in the lung tissue of each group had no significant difference(P > 0.05).Compared with group C, the expressive level of p-JNK protein in the lung tissue of group N had no significant difference(P > 0.05), but in group H, it raised significantly(P < 0.05). Compared with group H, the expressive level of p-JNK protein in group H + D1 had no significant difference(P > 0.05), while significant decrease occurred in group H + D2(P < 0.05). Meanwhile, the expressive level of p-JNK protein in group H + D2 + Y raised significantly when compared with group H + D2(P < 0.05). Conclusions1. The activation of JNK signal transduction pathway is involved in the lung tissue apoptosis of VILI;2. Dexmedetomidine can relieve VILI, and the mechanism may be related to interdicting JNK signal transduction pathway and reducing cell apoptosis simultaneously. |
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