Hypoxic-Reperfusion Injury

The mechanism for the production of O2 in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the 

Deprived of their substrate in severe or prolonged hypoxia, some ATPase-driven systems, including ion pumps, may become impaired. Further, with the decrease in the availability of O2 as its terminal electron acceptor, the mitochondrial transport chain becomes increasingly unable to accept reducing equivalents from cellular metabolic processes. Hence the intracellular pH falls, subjecting the cell as a whole to a reductive stress and favouring those enzyme systems with acid pH optima. 

Reperfusion of the synovial membrane occurs when exercise is stopped and O2 is subsequently reintroduced to the tissue. O2 is a substrate required for xanthine oxidase activity and O2 is generated. Therefore, repeated cycles of rest-exercise-rest in the inflamed joint may provide a continuous flux of destructive ROM. 

Immunohistochemical studies carried out in our laboratories have demonstrated the presence of xanthine oxidase in synovial endothelial cells (Stevens etal., 1991). As expected, the activity of this enzyme per unit weight of tissue is generally higher in synovia taken from RA patients due to their increased vascularity (Allen et al., 1987). In addition, it has also been shown that rheumatoid synoviocytes contain increased levels of iron-saturated ferritin (Morris et d., 1986). Xanthine oxidase (but not dehydrogenase) is able to mobilize iron from ferritin, supplying the necessary transition metal catalyst for the Haber-Weiss reaction and promoting OH formation (Biemond eta/., 1986). 

Despite their short half-lives, it is possible to detect free radicals in biological tissues by the addition of nonradicals such as nitrones or nitroso compounds, which act as spin traps by forming relatively stable free radicals on reaction with the endogenous radical species. Utilizing the technique of electron spin resonance (e.s.r.) spectroscopy, we have demonstrated ROM generation by human rheumatoid synovium when subjected to cycles of hypoxia/normoxia in vitro. Using 3,5-dibromo-4-nitroso-benzenesulphonate (DBNBS) as a spin trap, a 

---

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. 

Hypoxic-reperfusion injury in the inflamed human joint. Lancet i, 289-293. 

Recently, we have provided evidence that hypoxic reperfusion injury occurs in the inflamed human joint [2,12,13]. Joint movement in patients with RA produces intra-articular pressures in excess of the synovial capillary perfusion pressure. This phenomenon does not occur in normal joints, where the pressure remains subatmospheric throughout a movement cycle. During exercise of the inflamed joint, the intra-articular pressure is transmitted directly to the synovial membrane vasculature, producing occlusion of the superficial synovial capillary bed and ischaemia. Reperfusion of the synovial membrane occurs when exercise is stopped. Recently, electron spin resonance spectroscopy with spin trapping was employed to demonstrate that synovial tissue from a patient with RA generated ROI following a transient hypoxic... 

Sawa, Y., Ichikawa, H., Kagisaki, K., Ohata, T., and Matsuda, H., Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium. J. Thorac. Cardiovasc. Surg. 116, 511-517 (1998). 

Gaseous nitric oxide is a short-lived molecule that has been used in the treatment of patients with primary pulmonary hypertension and is used in subgroups of severely ill and hypoxic children with persistent pulmonary hypertension of the newborn, in preterm infants of less than 34 weeks gestation, and in adults with acute lung injury and adult respiratory distress syndrome. There are some reports of its use for intestinal ischemia, reperfusion injury, thrombotic disorders, and sickle cell crises. 

Lemasters JJ, Nieminen AL,QianT,Trost LC, Flerman B.The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 1997 174 159-165. 

Kruidering M, Van de Water b, de Fleer E, Mulder GJ, Nagelkerke JF. Cisplatin-induced nephrotoxicity in porcine proximal tubular cells Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp 1997 280 638-649. Gunter T, Pfeiffer D. Mechanisms by which mitochondria transport calcium. Am J. Physiol 1990 258 C755-C786 (Abstract). LemastersJJ, Nieminen AE,QianT,Trost EC, Elerman B.The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem 1997 174 159-165. 

Recent researches have indicated that lipid peroxidation is involved in the pathogenesis of other human diseases such as hypoxic-ischemic reperfusion injury, cancers, Alzheimer s disease, rheumatoid arthritis, renal dysfunction, and diabetes mellitus. 

Heyman, S.N., Rosenberger, C., and Rosen, S. (2010) Experimental ischemia reperfusion biases and myths-the proximal vs. distal hypoxic tubular injury debate revisited. Kidney Int.. 77, 9-16. 

---