ABSTRACT
Objective To evaluate the role of PI3K∕Akt signaling pathway in dexmedetomidine-in-duced reduction of lung ischemia-reperfusion ( I∕R ) injury in rats undergoing cardiopulmonary bypass (CPB). Methods Twenty-four healthy adult male Sprague-Dawley rats, weighing 350-450 g, were di-vided into 3 groups (n＝8 each) using a random number table method: group I∕R, dexmedetomidine group ( group D) and dexmedetomidine plus wortmannin group (group D+W). Rats were anesthetized with pento-barbital sodium. Lung I∕R was induced by clamping the left hilum of lung for 60 min starting from 10 min of CPB, followed by 120-min reperfusion. Dexmedetomidine was injected via the tail vein in a dose of 3 μg∕kg at 10 min before clamping the left hilum of lung, followed by a continuous infusion of 1. 5 μg·kg-1·h-1 until the end of CPB in group D. Dexmedetomidine was injected via the tail vein in a dose of 3 μg∕kg at 10 min before clamping the left hilum of lung, followed by a continuous infusion of 1. 5 μg·kg-1·h-1until the end of CPB, and wortmannin was simultaneously injected via the tail vein in a dose of 15 μg∕kg, fol-lowed by a continuous infusion of 2. 0 μg·kg-1·min-1until the end of CPB in group D+W. Arterial blood samples were collected immediately before CPB ( T1), immediately after opening the left hilum of lung (T2) and at 1. 5 h after the end of CPB (T3), and oxygenation index (OI) and respiratory index (RI) were calculated. The rats were sacrificed at T3, and the left lung was removed for examination of the patho-logical changes which were scored and for determination of apoptosis rate ( by flow cytometry) and Akt, Bad, activated caspase-3, phosphorylated Akt ( p-Akt) and phosphorylated Bad ( p-Bad) in lung tissues ( by Western blot). Results Compared with the baseline at T1, OI was significantly decreased and RI was increased at T2and T3in the three groups (P＜0. 05). OI was significantly decreased and RI was increased at T3than at T2in the three groups ( P＜0. 05). Compared with group I∕R, OI was significantly increased and RI was decreased at T3, the pathological damage score and apoptosis rate were decreased, ratios of p-Akt∕Akt and p-Bad∕Bad were increased, and the expression of activated caspase-3 was down-regulated in group D, and OI was significantly decreased and RI was increased at T2in group D+W ( P＜0. 05). Com-pared with group D, OI was significantly decreased and RI was increased at T3, the pathological damage score and apoptosis rate were increased, ratios of p-Akt∕Akt and p-Bad∕Bad were decreased, and the ex-pression of activated caspase-3 was up-regulated in group D+W ( P＜0. 05). Conclusion Dexmedetomi-dine can reduce dexmedetomidine-induced reduction of lung I∕R injury through activating PI3K∕Akt signa-ling pathway and inhibiting cell apoptosis in rats undergoing CPB.
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Objective To evaluate the effects of pretreatment with exogenous insulin-like growth factor-1 (IGF-1) on lung injury in rats undergoing cardiopulmonary bypass (CPB).Methods Seventy-two SPF healthy male Sprague-Dawley rats,weighing 350-500 g,were divided into 4 groups (n =18 each) using a random number table:sham operation group (group S),CPB group,CPB plus left lung ischemia-reperfusion group (group LI) and IGF-1 group.The chest was only opened,and the rats underwent no CPB in group S.Only the CPB model was established in group CPB.The model of left lung ischemia-reperfusion injury was established based on the CPB model in group LI.The model of CPB and left lung ischemia-reperfusion injury was established,and IGF-1 30 μg/kg was intravenously injected at 10 min before clamping the hilum of lung and immediately after opening the hilum of lung in group IGF-1.Six rats were selected before operation (T1),10 min after opening the left hilum (T2) and at the end of operation (T3),and blood samples were collected from the femoral artery for blood gas analysis.The oxygenation index (OI) and respiratory index (RI) were calculated.Serum was obtained from blood,and the concentrations of interleukin-6 (IL-6),IL-1β and tumor necrosis factor-alpha (TNF-α) in serum were measured using enzyme-linked immunosorbent assay.The left upper lung tissues were removed for examination of the pathological changes which were scored with a light microscope.Results Compared with the baseline at T1,OI was significantly decreased,and RI,concentrations of IL-6,IL-1β and TNF-α in serum and pathological scores of lung tissues were increased at T3 in CPB,LI and IGF-1 groups (P＜0.05).Compared with group S,OI was significantly decreased,and RI,concentrations of IL-6,IL-1β and TNF-α in serum and pathological scores of lung tissues were increased at T3 in CPB,LI and IGF-1 groups (P＜0.05).Compared with group CPB,OI was significantly decreased,and RI,concentrations of IL-6,IL-1β and TNF-α in serum and pathological scores of lung tissues were increased at T3 in group LI (P＜0.05).Compared with group LI,OI was significantly increased,RI,concentrations of IL-6 and IL-1β in serum and pathological scores of lung tissues were decreased at T3,and the concentration of serum TNF-α was increased at T3 in group IGF-1 (P＜0.05).Conclusion IGF-1 pretreatment can reduce lung injury in rats undergoing CPB,and the mechanism is related to inhibiting inflammatory responses.
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Objective To investigate the effect of lung ischemic preconditioning (IP) on the expression of aquaporin-1 (AQP1) during lung ischemia-reperfusion (I/R) induced by cardiopulmonary bypass (CPB) in dogs.Methods Twelve adult mongrel dogs,weighing 15-20 kg,were randomly divided into 2 groups (n =6 each):lung I/R (group I/R) and ischemic preconditioning group (group IP).The left pulmonary artery was occluded at 10 min of off-pump CPB and mechanical ventilation was stopped in the left lung,60 min later occlusion was released,and mechanical ventilation was recovered to establish the model of left lung ischemia-reperfusion injury induced by CPB.In group IP,lung ischemic preconditioning was induced by 2 cycles of 5 min ischemia followed by 5 min reperfusion before occlusion of the left pulmonary artery.Before CPB (T1),immediately after occlusion of the left pulmonary artery (T2),at the end of CPB (T3),and at 2 h after the end of CPB (T4),pulmonary specimens were collected for determination of wet to dry lung weight ratio (W/D ratio) and expression of AQP1 and for examination of the pathological changes of lungs which were scored.Respiration index (RI),oxygenation index (OI),and alveolar-arterial oxygen tension difference (P(A-a)O2) were calculated at T1,T3 and T4,and the left pulmonary alveolar fluid clearance (AFC) was calculated at T4.Results Compared with group I/R,P(A-a) O2 and RI were significantly decreased,OI was increased,W/D ratio and pathological scores were decreased,the expression of AQP1 was up-regulated,and the AFC was increased at T3 and T4 in group IP.The pathological changes of the lung were significantly attenuated in group IP as compared with group I/R.Conclusion The mechanism by which lung ischemic preconditioning mitigates lung I/R injury induced by CPB is related to upregulation of the expression of AQP1 in dog lung tissues.
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Objective To evaluate the effects of modified ultrafiltration on the expression of aquaporin 1 (AQP1) in cardiopulmonary bypass (CPB)-induced lung injury in dogs.Methods Eighteen healthy adult dogs of either sex,weighing 15-20 kg,were randomly divided into 3 groups (n =6 each):control group (group C),group CPB and modified ultrafiltration group (group MUF).The dogs were anesthetized with intraperitoneal 2.5％pentobarbital 25 mg/kg.Thoracotomy was performed in all the three groups and in addition lung injury was produced by CPB in CPB and MUF groups.In group MUF,modified ultrafiltration was performed at 10-15 min after termination of CPB.Arterial blood samples were collected before mechanical ventilation (T1),at end of CPB (T2),and at 1 h after termination of CPB (T3) to calculate respiration index (RI) and oxygenation index (OI).The lungs were removed for microscopic examination of pathologic changes in lung tissues under light microscope and for detection of AQP1 mRNA expression by real-time PCR.Results RI and OI were significantly higher and AQP1 mRNA expression was lower at T2 and T3 than at T1 in CPB and MUF groups (P ＜ 0.05).Compared with group C,RI was significantly increased and AQP1 mRNA expression was down-regulated at T2,3 in CPB and MUF groups,and OI at T2.3 in CPB group and at T2 in MUF group was decreased (P ＜ 0.05).Compared with group CBP,RI was significantly decreased,OI was increased and AQP1 mRNA expression was up-regulated at T3 in group MUF (P ＜ 0.05).Conclusion Modified ultrafiltration can reduce CPB-induced lung injury in dogs and upregulation of AQP1 may be involved in the mechanism.
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Objective To evaluate the role of aquaporin 1(AQPI)expression in the cartiopulmonary bypass(CPB)-induced lung injury in dogs.Methods Twenty-four healthy dogs,weighing 15-20 kg,were randomly divided into 4 group(n =6 each):control group(group C),acetazolamide Ⅰ group(group A Ⅰ),acetazolamide Ⅱ group(group A Ⅱ),and acetazolarnide Ⅲ group(group AⅢ).Lung injury was produced by CPB.The traditional priming solution was infused in group C.Priming solutions containing acetaaolamide 20,40 and 60 mg/kgwere infused in groups A Ⅰ,A Ⅱ and A Ⅲ respectively.Blood samples were collected from the femoral artery before mechanical ventilation,at the end of CPB and at 1 h after end of CPB(T1-3)for arterial blood gas analysis.Respiration index(RI)and oxygenation index(OI)were calculated.The lung specimens were oblained for determination of AQPI mRNA and protein expression(by RT-PCR and Western blot)and for microscopic examination.The pathological changes of the lung were scored.Results Compared with group C,P(A-a)O2,RI and the pathological score were significantly increased at T2.3,OI was significantly decreased at T2.3,and AQP1 protein expression was down-regulated at T2.3 in groups A Ⅰ,A Ⅱ and AⅢ,and AQP1 mRNA expression was down-regulated at T2.3 in groups AⅡ and AⅢ(P＜0.05).Compared with group A Ⅰ,P(A-a)O2,RI and the pathological score were significantly increased at T2.3,OI was significantly decreased at T2.3,and AQP1 protein expression was down-regulated at T2.3 in groups A Ⅱ and AⅢ,and AQP1 mRNA expression was down-regulated at T2.3 ingroup A Ⅲ(P ＜ 0.05).Compared with group A Ⅱ,RI and the pathological score were significantly increased at T2.3,and AQP1 protein expression was down-regulated at T2.3 in group A Ⅲ(P ＜ 0.05).Conclutsion Down-regulation of AQPI expression is involved in the CPB-induced lung injury in dogs.