| Cardiac surgeons with scientific competence combine clinical experience with scientific knowledge and intuition, translate scientific discoveries into practical applications in order to improve human health, referred as to“Translational Research of Cardiac Surgery”.Aortic stenosis is the most common cardiac valve disease, affecting about 3 percent of persons older than 65 years. Surgery with aortic valve replacement for severe symptomatic aortic stenosis is currently the only treatment option, resulting in a 5-year survival rate of 60-70%. Unfortunately, in patients with poor ventricular function, the mortality and long-term outcome is unsatisfied, and only a minority of these patients undergo surgery. Moreover, acute lung injury induced by ischemia-reperfusion during cardiopulmonary bypass exaggerates the operative risks of patients, especially of pediatric congenital cardiac surgery.The principal aim of this thesis is to better understand the molecular mechanisms by which aortic stenosis induces heart failing and by which ischemia-reperfusion induces acute lung injury. Furthermore, we explore possible pharmacological approaches to prevent the heart and lung damages, and to improve the postoperative recovery and decrease the mortality of patients, using animal models for Translational Research of Cardiac Surgery. Part I: Cardiac Hypertrophy and Cardioprotection in a Mouse Model of Aortic Stenosis.Objective: We hypothesize that pre-operative treatment with recombinant human form of erythropoietin will improve the aortic stenosis patients'condition, especially those with anemia and/or cardiac dysfunction, to be better suitable for aortic valve replacement. In the present study, we tested this hypothesis in mice with ligature-induced aortic stenosis (AS).Methods: Adult male mice were subjected to either AS or sham surgery. AS mice were treated with recombinant human erythropoietin or saline for 4 weeks. Cardiac function was evaluated by echocardiography. Hematocrit and levels of tumor necrosis factor-?and interleukin-10 in serum and hearts were measured. Myocyte hypertrophy, apoptosis and related intracellular signaling pathways were analyzed.Results: AS mice had cardiac hypertrophy, pulmonary congestion and left ventricular dysfunction. The levels of tumor necrosis factor-?in the serum and myocardium were elevated, while the levels of interleukin-10 were reduced in the myocardium but not in serum in AS mice. The rate of mytocyte apoptosis, level of cleaved caspase 3, activity of nuclear factor-?B and expression of p38-MAPK pathway were increased in aortic stenosis mice. Treatment of recombinant human erythropoietin increased hematocrit and did not prevent the development of cardiac hypertrophy. However, recombinant human erythropoietin reduced the apoptosis, prevented the increases in tumor necrosis factor-?, nuclear factor-?B activation and phosphorylation of p38, prevented the increases in lung weight, the reductions of LVEF and LVFS, and attenuated the increases in LVDd and LVDs.Conclusion: Exogenous recombinant human erythropoietin has cardioprotective effects in maladapive cardiac hypertrophy, probably by inhibiting nuclear factor-?B activation, phosphorylation of p38-MAPK pathway, and production of tumor necrosis factor-?, leading to a reduced apoptosis.Part II: Lung injury and lung protection in a rabbit model of ischemia-reperfusion.Objective: Ischemia-reperfusion (IR) causes lung damage to patients undergoing cardiac surgery with total cardiopulmonary bypass, especially to pediatric cardiac surgery. Free radical scavenger edaravone has been approved as a new drug for treatment of stroke patients. The aim of the present study was to compare IR induced lung damage between adults and infants, and to investigate whether pretreatment with edaravone could attenuate IR induced lung injury in infant rabbits.Methods: Both infant (15-21 days old) and adult (5-6 months old) rabbits were subjected to either IR or sham operation. Infant IR rabbits were treated with edaravone (1mg/kg, intravenous) or saline 5 minutes before ischemia. IR was induced by clamping the right pulmonary hilum for 1h and then removal of the clamp for 4h. The lung tissue samples were collected for histological examination by light and electron microcopies and for biological evaluation of mitochondrial alterations. Blood samples were taken for measurement of interleukin-1?and tumor necrosis factor-?.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 reduced swelling rate as well as membrane potential, intramitochondrial free Ca2+ difference after IR. The infant lungs produced higher levels of hydroxyl radical (ROS-HR) and malondialdehyde (MDA), and lower levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) than those in adults, especially after IR. The circulating levels of interleukin-1?and tumor necrosis factor-?were elevated during ischemia-reperfusion, particularly in the infants, which appeared to be associated with the expression of myeloid differentiation factor-88 and nuclear factor-?B in the lungs. Edaravone pretreatment reduced the productions of ROS-HR and MDA and increased the activities of GSH-PX and SOD. As results, the mitochondria and lung tissue damages were less, leading to an improved survival rate in IR rabbits pretreated with edaravone.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 reactive oxygen species in infants. Edaravone pretreatment reduces the IR-induced lung mitochondrial damage in infant rabbits. |
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