Protective Effects Of Dexmedetomidine Hydrochloride On Rat Model Of Ventilator-induced Lung Injury And Investigation Of Its Mechanism

Objective:To investigate the effect of dexmedetomidine hydrochloride on the inflammatoryresponse, pneumodynamics and ex-pulmonary organs function of the rat model ofventilator-induced lung injury(VILI) for the purpose of prevention of VILI.1. To elucidate the effect of dexmedetomidine hydrochloride on thephosphorylation of mitogen activated protein kinase (p38MAPK) and inflammatoryinjury of lung in a rat model of ventilator-induced lung injury (VILI).2. Aim of the present study was to elucidate the effect of dexmedetomidinehydrochloride on the lung injury and inflammatory reaction, as well as ex-pulmonaryorgans function of rats underwent high tidal volume mechanical ventilation.3. To investigate the mechanism of high tidal volume (TV) ventilation-inducedremote organs injury in isolated ventilated rat lungs perfused with salt solution andthe way to intervene it.Contents and methods:Part 1: Effects of dexmedetomidine hydrochloride on activation of p38mapk inventilator-induced lung injurySprague-Dawley rats were randomized to three groups(n=8): standard ventilation group(group C), high-tidal volume ventilation group(group H), and high-tidal volumeventilation plus propofol (group P). In the course of mechanical ventilation(MV), ratsof group P received intravenous pump of propofol, while rats of group C and Hreceived physiological saline only.All rats were sacrificed and the lung lavage liquid and lung tissue were collectedand stored. Lung wet and dry weight ratio(W/D) was calculated, lung pathologicchanges were observed under light microscope. Interleukin 1β(IL-1β), IL-6 andprotein content in bronchoalveolar lavage fluid(BALF)were determined. Theexpression of ERK and p-ERK were measured by Western Blot.Part 2: Protective Effects of Dexmedetomidine Hydrochloride on OrgansFunction of Rats Underwent High Tidal Volume Mechanical VentilationOther thirty six male Sprague-Dawley rats weighing 250 to 280g, 3~4 weeks, wererandomly allocated to three groups(n = 12 in each group): standard tidal volumeventilation group, high tidal volume ventilation group, and high tidal volumeventilation plus dexmedetomidine group. Which was noted as C group: tidal volume 8mL﹒kg-1, respiratory rate 90 breaths﹒min-1; V group: tidal volume 20 mL﹒kg-1,respiratory rate 50 breaths﹒ min-1; and D group: tidal volume 20 mL﹒ kg-1,respiratory rate 50 breaths﹒min-1 plus dexmedetomidine infusion with a dose of 0.5μg﹒kg-1﹒h-1.All rats of the three groups were ventilated for 4 hours with positive end expiratorypressure(PEEP) 0 cmH2O.At the end of the experiment, all rats were sacrificed and lung, heart, liver, andkidney tissue were collected and stored. Pulmonary pathological changes, circulatorycytokine level, ex-pulmonary organ wet to dry weight ratio, hepatic and renal function,and iNOS mRNA level of heart tissue were evaluated.Part 3: Lung-lung interaction in isolated perfused unilateral hyperventilated ratlungs and the protective effects of dexmedetomidine hydrochloride on itForty- eight male Sprague-Dawley rats weighing 250 to 280g, 3~4 weeks were used. Selective right lung (RL) hyperventilation (TV of 15 mL/kg with air containing5% CO2) in addition to left lung (LL) on 2.5 cm H2O continuous positive airwaypressure (CPAP) for 60 min.The animals was allocated to the following 5 groups: groups HNN and HNRunderwent hyperventilation with recirculation or nonrecirculation without the infusionof dexmedetomidine hydrochloride (Dex), groups HDN and HDR underwent hyperventilation with recirculation or nonrecirculation without the infusion of Dex, andgroup CNN served as the control group. Recirculation means the same perfusaterecirculates the system throughout the procedure.The TNF-αlevel and protein content of bronchoalveolar lavage fluid (BALF),cytokine level of perfusate, the he wet/dry ratio, MPO and COX-2 mRNAs oflung tissues were measured and compared between groups by Kruskal-Wallis test.ResultsResults:Part 1: Effects of dexmedetomidine hydrochloride on activation of p38mapk ina rat model of ventilator-induced lung injurySignificant pulmonary pathologic changes were not observed in group C, group Hand P showed significant lung injury, whereas group P had minor pathologic changesthan group H. Pulmonary W/D and p-ERK, BALF WBC count, protein content, IL-1βand IL-6 level of group H and P were significantly higher than those of group C,while these indices of group P were minor than that of group H.Part 2: Protective effects of dexmedetomidine hydrochloride on organs functionof rats underwent high tidal volume mechanical ventilationGroup H, as well as group D, showed significant lung pathological changes,elevated circulatory cytokine level, expulmonary organ wet to dry weight ratio,concentration of MDA and SOD, cardiac iNOS mRNA level, serum level ofglutamic-oxalacetic transaminase, glutamate pyruvate transaminase, blood ureanitrogen, creatinine, as well as serum level of TNF-α, IL-1β, IL-6, and IL-8, whencompared with those of group C. While the lung pathologic changes, circulatorycytokines levels and ex-pulmonary organ function indices were significantly lower in group D than in group H.Part 3: Lung-lung interaction in isolated perfused unilateral hyperventilatedrat lungs and the protective effects of dexmedetomidine hydrochloride on itRLs: increased wet/dry ratio, TNF-alpha level and protein content of BALF,cytokine level of perfusate, the he wet/dry ratio, MPO and COX-2 mRNAs oflung tissues was shown in the hyperventilated RLs with high TV ventilation comparedwith their corresponding CNN RLs. DEX prevented these injuries. Lung injury wasalso demonstrated in the recirculated LL compared with the nonrecirculated LL. DEXalso prevented these injuries.Conclusions:1. Dexmedetomidine hydrochloride attenuated VILI in rats, this effect may partlydue to blocking the activation of extracellular regulated protein and reducingpulmonary inflammation.2. Dexmedetomidine significantly attenuated high tidal volume ventilation inducedlung injury and circulatory cytokines levels, it also mitigate ex-pulmonary organdamage. These results showed protective effect of dexmedetomidine on pulmonaryand ex-pulmonary organ function of rats underwent high tidal volume mechanicalventilation.3. In our differential ventilation and perfusion model, cytokines was released fromthe selected right hyperventilated lungs with 0 PEEP, which resulted in lung edema inthe hyperventilated lung and injured the selected left CPAP lung via reperfusion.