The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.
Traumatic brain injury and ischemia can result in marked neuronal degeneration and residual impairment of cerebral function. However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) for acute intervention has been developed. The detailed pathophysiological cascade leading to -neurodegeneration in these conditions has not been elucidated, but cellular calcium overload and mitochondrial dysfunction have been implicated in a wide range of animal models involving degeneration of the CNS. In particular, activation of the calcium-induced mitochondrial permeability transition (mPT) is considered to be a major cause of cell death inferred by the broad and potent neuroprotective effects of -pharmacological inhibitors of mPT, especially modulators of cyclophilin activity and, more specifically, genetic inactivation of the mitochondrial cyclophilin, cyclophilin D. Reviewed are evidence and challenges that could bring on the dawning of mitochondrial medicine aimed at safeguarding energy supply following acute injury to the CNS.
The effects of high pressure mechanical pulmonary ventilation at a peak inspiratory pressure of 40 cmH(2)O were studied on the lungs of healthy newborn pigs (14-21 days after birth). Forty percent oxygen in nitrogen was used for ventilation to prevent oxygen intoxication. The control group (6 pigs) was ventilated for 48 hours at a peak inspiratory pressure less than 18 cmH(2)O and a PEEP of 3-5 cmH(2)O with a normal tidal volume, and a respiratory rate of 20 times/min. The control group showed few deleterious changes in the lungs for 48 hours. Eleven newborn pigs were ventilated at a peak inspiratory pressure of 40 cmH(2)O with a PEEP of 3-5 cmH(2)O and a respiratory rate of 20 times/min. To avoid respiratory alkalosis, a dead space was placed in the respiratory circuit, and normocarbia was maintained by adjusting dead space volume. In all cases in the latter group, severe pulmonary impairments, such as abnormal chest roentgenograms, hypoxemia, decreased total static lung compliance, high incidence of pneumothorax, congestive atelectasis, and increased lung weight were found within 48 hours of ventilation. When the pulmonary impairments became manifest, 6 of the 11 newborn pigs were switched to the conventional medical and ventilatory therapies for 3-6 days. However, all of them became ventilator dependent, and severe lung pathology was found at autopsy. These pulmonary insults by high pressure mechanical pulmonary ventilation could be occurring not infrequently in the respiratory management of patients with respiratory failure.
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