Effect Of Dexmedetomidine On Intrapulmonary NF-κB Activity And Cytokines During Acute Lung Injury In Rats

Objective: To investigate the effect of dexmedetomidine on intrapulmonary NF-κB activity and cytokines during acute lung injury in rats. It’s aimed at providing one more potential option for clinical prevention and treatment of ALI. Methods: The activity of NF-κB in lung tissue, wet / dry weight ratio and the changes of cytokines of lung tissue were observed to evaluate protective effects of dexmedetomidine pretreatment with different doses and explore possible mechanisms in ALI rat model. Seventy-two health Sprague-Dawley rats, weighing 250~300g, were randomly divided into six groups(n=12) as control group(group C), ALI group(group A), PDTC group(group P), and groups D1、D2、D3(dexmedetomidine pretreatment with 3different doses). In group C, femoral artery and femoral vein were inserted and cannulated without bloodletting. In other groups, femoral artery and femoral vein were inserted and cannulated for bloodletting, MAP monitoring, infusion and drug administration. MAP was reduced to 35~45mmHg within 10 min by bloodletting, then maintained for 1h by balancing both bloodletting and transfusion. MAP was restored to normal by blood transfusion and normal saline equivalent to total volume of blood loss. Rats in Group D1 、 D2 and D3 were pretreated with respectively intravenous 0.5μg/kg、1.5μg/kg、4.5μg/kg of DEX at 30 min before bloodletting. Rats in Group P injected intraperitoneally with DEX 200μg/kg at 30 min before bloodletting. All rats were executed at 6 hour after procedure. The lung tissue was harvested for determinating the activity of NF-κB by immuno-histochemistry and W/D ratio. The bronchoalveolar lavage fluid(BALF) from remained lung was harvested for determinating content of IL-6、IL-10、TNF-α by enzyme-linked immunosorbent assay(ELISA). The pathological changes in lung tissue were checked by HE staining. Results:(1)Pathological changes: Observed under optical microscope, no any lesion was seen in group C. In group A, severe pulmonary interstitial edema, significant inflammatory cells infiltration, and a large number of red blood cells in the alveoli can be seen. Compared with group A, the changes of lung tissue described above were improved in group D1、D2 and D3. Moreover, the improved pathological changes were correlated with incremental dosages of DEX. Compared with group A, the lung injury induced by artificial hypotension or shock was remarkablely attenuated by specific NF-κB blocker PDTC in group P. The severity of lung injury did not differ between group P and group D3.(2)The activity of NF-κB in lung tissue: Few of NF-κB positive cells could be seen in group C. However,compared with group C a large amount of NF-κB positive cells were seen in group A(p<0.01). Compared with group A, the NF-κB positive cells were significantly decreased in group D2 and D3(p<0.01) except group D1, and the inhibited activity of NF-κB in lung tissue was correlated with incremental dosages of DEX. Compared with group D1,D2 and D3, the count of NF-κB positive cells in group P was decreased more significantly(p<0.01 OR p<0.05).(3)Content of cytokines in bronchoalveolar lavage fluid: Compared with group C, the IL-6、IL-10 and TNF-α in group A were significantly increased(p<0.01). Compared with group A, the IL-6、IL-10 and TNF-α in group D2 and D3 were significantly decreased(p<0.01)except group D1, and the production of cytokines in bronchoalveolar lavage fluid was also correlated with incremental dosages of DEX. More production of IL-6 、 IL-10 and TNF-α in group D1 was observed compared with group P(p<0.01). The production of IL-10 and TNF-α in group D2 increased significantly than that in group P(p<0.01).(4)The W/D ratio of lung tissue: Compared with group C, the W/D ratios of lung tissue in group A and group D1 were much higher(p<0.01). Compared with group A, the W/D ratios of lung tissue in group D2,group D3 and group P were significantly lower(p<0.01). Compared with group P, the W/D ratio of lung tissue was remarkablely higher in group D1(p<0.01). Conclusion:(1) Pretreatment with Dexmedetomidine can protect the lungs from injury induced by controlled shock during ALI in rat.(2)The potential mechanism of the protective effect of Dexmedetomidine may be related with inhibited activity of NF-κB and decreased production of cytokines during ALI in rat.