Characteristics, Mechanisms And Prevention Of Ischemia-Reperfusion-Induced Acute Lung Injury In Infants

Open-heart surgery is routinely performed to repair the congenital anatomical defects under total cardiopulmonary bypass(CPB).These procedures are inevitably associated with various periods of lung ischemia followed by reperfusion.Ischemia-reperfusion(IR)is well known to result in severe damage to lung,which is believed to cause a pulmonary dysfunction with morbidity of 15-30%in adult patients and over 60%in infant patients,especially in children with complicated CHD and pulmonary artery hypertension.IR induces a production of reactive oxygen species(ROS)in excess of the endogenous cellular capacity, referred to as the so-called oxidative stress which,together with other factors,e.g.inflammation,cause lung damage and cell death.It has been speculated that infants have a lower antioxidant capacity than adults, probably leading to a high susceptibility to the oxidative stress.Hydroxyl radical(HO^·)(ROS-HR)is one of the most reactive and harmful free radices and malondialdehyde(MDA)is a final product of lipid peroxidation.Free radical scavenger edaravone has been approved as only a new drug for treatment of stroke patients.Thus,we designed the two study to test our hypothesis that infant lung is more susceptible than adult lung to IR-induced injury and to examine whether pretreatment with edaravone could attenuate the IR-induced lung damage in infant rabbits.Partâ… Comparison between adult and infant lung injury in a rabbit ischemia-reperfusion modelObjectives:Ischemia-reperfusion may cause life-threatening lung damage to patients that undergo open-heart surgery to repair congenital anatomical defects of the heart under total cardiopulmonary bypass.The aim of the present study was to compare ischemia-reperfusion-induced lung damage between adult and infant rabbits and the potential mechanisms of the induced differences.Methods:Both infant(15-21 days old)and adult(5-6 months old)rabbits were subjected to either ischemia-reperfusion or sham operation. Ischemia-reperfusion was induced by clamping the right pulmonary hilum for 1 hour and then removal of the clamp for 4 hours under anesthesia.The lung tissue were sampled for histological examination by light and electron microcopies and for biological evaluation of mitochondrial alterations,including swelling rate,membrane potential difference and intramitochondrial Ca²⁺concentration.Production and expression of free radical species-hydroxyl radical(ROS-HR), malondialdehyde(MDA),superoxide dismutase(SOD),glutathione peroxidase(GSH-PX),myeloid differentiation factor-88(MyD-88),and nuclear factor-κB(NF-κB)in the lung tissue were also examined.In addition,circulating levels of interleukin-1βand tumor necrosis factor-αwere measured during the ischemia-reperfusion process.Results:In comparison to adult lungs,the infant lungs had more increased neutrophil infiltration,edema,swelled alveolar epithelial and endothelial cells,and severer mitochondrial impairment reflected by damage of the inner membrane as well as decrease in the membrane potential after ischemia-reperfusion.The lungs in infant animals subjected to sham operation displayed higher levels of intramitochondrial Ca²⁺,ROS-HR and MDA and lower levels of SOD and GSH-PX than those in adult controls.The lungs in infants with ischemia-reperfusion were found to further produce more ROS-HR,intramitochondrial Ca²⁺ and MDA,and less SOD and GSH-PX than the ischemia-reperfused adult lungs.Moreover,the circulating levels of interleukin-1βand tumor necrosis factor-αwere elevated during the period of ischemia-reperfusion, particularly in the infant animals,which appeared to be associated with the expression of MyD-88 and NF-κB in the lungs.Conclusion:Lung ischemia-reperfusion causes more severe lung damage in infants than in adults,probably due to combination of low antioxidant capacity and overproduction of ROS in infants. Partâ…¡Pretreatment with Edaravone reduces lung mitochondrial damage in an infant rabbit ischemia-reperfusion modelObjective:Free radical scavenger Edaravone has been approved as a new drug for treatment of stroke patients.The purpose of this study was to examine whether pretreatment with Edaravone could attenuate ischemia/reperfusion(IR)-induced lung damage in infant rabbits.Methods:New Zealand White rabbits at age from 15 to 21 days were subjected to sham operation,IR or Edaravone plus IR.IR was induced by clamping the right pulmonary hilum for 1h and then removal of the clamp for 4h.Edaravone(1 mg/kg,i.v.)was given 5 min before the clamping. Concentrations of reactive oxygen species-hydroxyl radical(ROS-HR) and malondialdehyde(MDA),as well as the activities of glutathione peroxidase(GSH-PX)and superoxide dismutase(SOD)in the lung tissue were measured.Mitochondrial membrane potential,swelling rate,and ultrastructure of the lung were analyzed,and histology of the lung was evaluated.And Temperature,hemodynamics,blood gases and neutrophil count were measured.Results:Edaravone pretreatment reduced markedly the production of ROS-HR and MDA and improved the activities of GSH-PX and SOD.It attenuated a decrease in mitochondrial membrane potential from 60%to 14%after IR.A near-maximal or maximal swelled mitochondria were observed in IR rabbits.Edaravone pretreatment increased the mitochondrial swelling rate and improved the mitochondrial and tissue damage evaluated by electron and light microscopies.As well as the great development of hemodynamics and blood gases in Edaravone pretreatment rabbits compared to IR rabbits.Conclusion:Edaravone pretreatment reduces the lung mitochondrial damage induced by IR in the infant rabbits.