Reperfusion injuries

The lung may be susceptible to oxygen radical-mediated injury during ischaemia, as O2 tension will be high when ventilation is maintained and 

In female SPF Wistar rats, ultrastructural changes after temporary ischaemia were extraordinarily multiform (Amthor 1978). Type I pneumo-cytes showed vesiculation of the cytoplasm. From the second day on type II pneumocytes increased in number, but they contained only little osmiophilic material. 

Neutrophil apoptosis may be important in regulating the inflammatory process by controlling neutrophil numbers and thus activity. Exogenous inhaled nitric oxide is now a widely used therapy in patients with acute lung injury, and its effects on apoptosis may be important. In a model of nitric oxide-treated lung injury, Blaylock et al. (1998) incubated polymorphonuclear leucocytes isolated fi om venous blood for up to 16 h with and without 1.7 ng/ml lipopolysaccharide and the nitric oxide donor GEA-3162 or the peroxynitrite donor SIN-1. Apoptosis was attenuated when cells were exposed to lipopolysaccharide and both nitric oxide and peroxynitrite dose-dependently inhibited this suppression at all time points and was most apparent at 16 h (P = 0.004 and 0.001, respectively). 

In the lung, ischaemia-reperfusion does not necessarily imply hypoxia-reoxygenation, if ventilation is maintained during the period when blood flow is impaired. Pulmonary ischaemia-reperfusion injury is clinically manifest as pulmonary oedema 

In a canine model of left lung transplantation Gunther et al. (1997) analyzed the surfactant properties in fresh explants (control), explants kept ischaemic for 24 h (Euro-Collins/prostacyclin flush, 4 °C) and grafts and native lungs of recipients after 6 and 12 h of reperfiision under anaesthesia and 

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Superoxide dismutase has been approved by the FDA for preventing reperfusion injury or damage to donor organ tissue (178). This enzyme is prepared by recombinant DNA technology and marketed by Bristol-Myers and Pharmacia-Chiron. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

Wang W, Schulze CJ, Suarez-Pinzon WL et al (2002) Intracellular action of matrix metaUoproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106 1543-1549... 

Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke 2004 35 2659-2661. 

Tso and Lam suggested that astaxanthin could be useful for prevention and treatment of neuronal damage associated with age-related macular degeneration and may also be effective in treating ischemic reperfusion injury, Alzheimer s disease, Parkinson s disease, spinal cord injuries, and other types of central nervous system injuries. Astaxanthin was found to easily cross the blood-brain barrier and did not form crystals in the eye. 

Merry, P., Grootveld, M., Lunec, J. and Blake, D.R (1991). Oxidative damage to lipids within the inflamed human joint provides evidence of radical-mediated hypoxic-reperfusion injury. Am. J. Clin. Nutr. 53, 362S-369S. 

Turner, J.J.O., Rice-Evans, C., Davies, M.J. and Newman, E.S.R. (1990). Free radicals, myocytes and reperfusion injury. Biochem. Soc. Trans. 18, 1056-1059. 

Goldhaber, J.I., Ji, S., Lamp, S.T. and Weiss, J.N. (1989). Effects of exogenous free radicals on electromechanical function and metabolism in isolated rabbit and guinea pig ventricle. Implications for ischemia and reperfusion injury. J. Clin. Invest. 83, 1800-1809. 

Kim, M.-S. and Akera, T. (1987). O2 free radicals cause of ischemia-reperfusion injury to cardiac Na -K ATPase. Am. J. Physiol. 21, H252-H257. 

McCord, J.M. (1987). Oxygen-derived radicals a link between reperfusion injury and inflammation. Fed. Proc. 46, 2402-2406. 

Misra, H.P., Weglicki, W.B., Abdulla, R- and McCay, P.B. (1984). Identification of a carbon centered free radical during reperfusion injury in ischemic rat heart. Circulation II, 260 (abstract). 

Sakomoto, A., Ohnishi, S.T., Ohnishi, T. and Ogawa, R. (1991). Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain. Brain Res. 554, 186-192. 

Vasthare, U.S., Heinel, LA., Rosenwasser, R.H. and Tuma, R.F. (1990). Leukocyte involvement in cerebral ischemia and reperfusion injury. Surg. Neurol. 33, 261-265. 

The importance of iron in ischaemia-reperfusion injury through generation of ODFRs via the Haber-Weiss... 

Although these data provided indirect evidence of iron involvement in ischaemia-reperfusion injury in kidneys and the combined administration of DFX and indomethacin had proved beneficial in actual survival experiments (Gower etal., 1989a), we still felt fhistrated by our inability to generate more direct evidence. At that time, information was just emerging that a small pool of intracellular iron was available in catalytic form as chelates... 

Increased levels of cytosolic calcium could potentiate ischaemia-reperfusion injury in several ways. For example, conversion of xanthine dehydrogenase to xanthine oxidase may be catalysed by a calcium-dependent protease (McCord, 1985). However, because it has been so difficult to demonstrate the presence of xanthine... 

Koyama, L, Bulkley, G.B., Williams, G.H. and Im, H.J. (1985). The role of oxygen free radicals in mediating the reperfusion injury of cold-preserved ischaemic kidneys. Transplantation 40, 590-595. 

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