RESUMEN
In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used tert-butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used ex vivo and in vivo cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced in vivo with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.
Asunto(s)
Condrocitos , Peroxidación de Lípido , Mitocondrias , Oxidación-Reducción , Estrés Oxidativo , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cartílago Articular/metabolismo , Ratones , Células CultivadasRESUMEN
OBJECTIVE: To describe the sequence of hemodynamic changes associated with sudden circulatory deterioration compared with those of terminal patients to identify the earliest signs warning of shock and death. METHODS: This is a prospective observational study of 89 patients with thermodilution cardiac index and continuous noninvasive hemodynamic monitoring who had episodes of circulatory deterioration. These data were compared with the data of a second group of 24 patients in their terminal stage just before death. RESULTS: The earliest indications of impending collapse were decreased cardiac index, and tissue perfusion reflected by decreased transcutaneous O2 tension (PtcO2). This was followed by reduced blood pressure, tachycardia, reduced arterial hemoglobin saturation, and increased transcutaneous CO2 tension (PtcCO2). This pattern of changes was more pronounced in the nonsurvivors and was seen in exaggerated form in terminal patients. CONCLUSION: Sequential hemodynamic patterns revealed reduced blood flow and poor tissue perfusion as the earliest warning signs in both circulatory deterioration and death. These were followed by reduced mean arterial pressure, tachycardia, and low values of pulse oximetry. Adequate blood flow and even distribution of flow are needed for tissue perfusion.