Lung Protection Of Dexmedetomidine In Copd Rats With Mechanical Ventilation

Background and ObjectiveChronic obstructive pulmonary disease(COPD) is a kind of chronic respiratorydisease with limited airflow,and not fully reversible lung function.Early research hasshown that COPD mostly occurs with the harmful particles and toxious gasses.Which damage lungs tissues by inflammation,protease/anti-protease imbalancesand the stress imbalance of oxidation/antioxidant.Current research suggested that themain pathogenesis was inflammation, oxidative stress and protease/anti-proteaseimbalances,which led to inflammatory lesions in the lung parenchyma and airway.Oxidative stress (OS) refers to the reactive oxygen species (ROS) generatedwithin living cells beyond the scavenging capacity of antioxidants, leading to cellularoxidative/antioxidant imbalance stress, intracellular proteins, lipids and DNAdamage, such as loss of function of the structure.Mechanical ventilation is the necessary auxiliary ventilation measure of COPDpatients who are in acute aggravating period or general anesthesia, but it canaggravate lung injury in patients at the same time of ensuring the body oxygentransport. Recently, in a study of lung protective mechanical ventilation, strategyfocuses on different patterns, and the application of the drugs such ascorticosteroids as well.Its purpose is to reduce the damage to external stimuli,prevent the inflammatory reaction and the effects of oxidative stress. Dexmedetomidine is a new type of highly selective α2-adrenoceptoragonist,and has been widely used in the ICU and anesthesia. It has a sedative,analgesic, hypnotic, anti-sympathetic and inhibitory effects of release of plasmacatecholamine. In addition, in recent years, a number of studies have shown thatdexmedetomidine played an important role in protecting vital organs neuroprotection,cardioprotection, kidney protection, etc.Currently,the study of lung protection of dexmedetomidine is limited. In thisstudy,COPD rat model was established by intratracheal instillation oflipopolysaccharide along with passive inhalation of cigarette.Then the rats wereventilated with mechanical ventilation for two hours and intervention treatmentof different doses of dexmedetomidine.Disscuss the action and the mechanism of lungprotection.Materials and Methods48male adult Wistar rats with clean level, the average weight180±20g,purchased from experimental animal center of henan province,were randomlydivided into8groups:group D and D1were normal groups,group C,C1,C2and C3were COPD groups. Each group was provided mechanical ventilation for2hours in addition to group D and C. Tidal volume were set to8ml/kg.Group C2andC3were given a loading dose of dexmedetomidine1.0μg/kg/h and5.0μg/kg/h.GroupD1and C1were injected with the same amount of saline.COPD model wasestablished by intratracheal instillation of lipopolysaccharide twice and exposed tocigarette smoke every day.The lung tissue and blood gas were measured.The ratio ofwet weight and dry weight was assayed.The level of IL-1β，TNF-α，8-iso-PGF2αwere tested by ELISA.The lung tissue was dealed with HE staining to observe lungtissue changes.The protein and mRNAexpressionsof Nf2and HO-1in lung tissuewere measured by immunohistochemistry and reverse transcription polymerase chainreaction (RT-PCR). Statistical analysis:All results were statistically analysed by SPSS version17.0software.All valuesare expressed as mean±SD.Difference between two groups is analyzed by suingt-test.Analysis of variance (anova) was used to mean values for the differentgroups..Levels of significance test is α=0.05.Results:1. Lung tissue W/D changesCompared with group D, W/D level was significantly raised in group C (P＜0.05). It was higher in group D1than group D,but there was no significant difference(p＞0.05). The level was higher in Group C1than in group C2,group C2was higherthan group C3, but group C3was higher than group C (all P＜0.05).2. Changes of IL-1βand TNF-α in serumCompared with group D,serum IL-1β and TNF-α increased obviously in groupC (P＜0.05).Compared with group D, both expression quantity increased in groupD1,but there was no statistically significant difference (P＞0.05).The level of thetwo factors were higher in group C than in group D, group C1than in group C2,similarly group C2was higher than group C3, but group C3was higher than group C(all P＜0.05).3.8-iso-PGF2α changes in Lung tissueThe8-iso-PGF2α assay showed that the level was increased in group Dcompared to group D1(P＜0.05).Compared with group C,the8-iso-PGF2αquantity increased in group D,but there was no statistically significant difference (P＞0.05).The levels of the8-iso-PGF2a was higher in group C than in groupD,Group C1than in group C2,group C2was higher than group C3(all P＜0.05).4. Structural changes in the lung tissueThe results of HE staining showed that the rat lung tissue structure of group Dand group D1were basicly normal, texture clear, no bullae, but the rat lung tissue of group D1had a little inflammatory cell infiltration.The lung texture of group C,C1, C2and C3were disorder, there were clear lung bullaes, and had a large numberof inflammatory cells.5. The expression of Nrf2and HO-1mRNA in the Lung tissueThe mRNA expression of Nrf2and HO-1were strongly positive in COPD group(P＜0.05).Group C was higher than group D, group C2was higher than groupC1,group C3was higher than group C2(all P＜0.05).6. Nrf2and HO-1protein expression of lung tissueImmunohistochemistry result showed that: the protein expression of Nrf2andHO-1in group C was higher than group D (P <0.05).Group C was higher thangroup D, group C2was higher than group C1, group C3was higher than group C2(all P＜0.05).Conclusion:1. Mechanical ventilation has no effect on normal rat lung oxidative stress andinflammatory effect.However; it can aggravate COPD on rat lung by oxidative stressand inflammation, altimate it may exacerbate lung injury.2.During mechanical ventilation, rats with dexmedetomidine can relieve lunginjury of COPD.Continuous infusion of dexmedetomidine hydrochloride at5.0μg/kg/h has better lung protection of COPD rats than1.0μg/kg/h.