SELECTIVE ELEVATION OF GLUTATHIONE LEVELS IN TARGET TISSUES WITH L-2-OXOTHIAZOLIDINE-4-CARBOXYLATE (OTC) PROTECTS AGAINST HYPEROXIA-INDUCEDLUNG DAMAGE IN PROTEIN-ENERGY MALNOURISHED RATS - IMPLICATIONS FOR A NEW TREATMENT STRATEGY

It has become recognized that enhancing the antioxidant defense system during the early phase of rehabilitation is important to the survival of wasting protein-energy malnourished (PEM) patients. In this study, we compared the efficacy of dietary protein replenishment and supplem entation with L-2-oxothiazolidine-4-carboxylate (OTC, 3.5 mg/d), a cys teine precursor, to protect against hyperoxia-induced lung damage in P EM rats. The PEM rats were produced by feeding weanling rats a protein -deficient diet (0.5% protein) for 14 d. PEM rats were then divided in three dietary treatment groups, 0.5% protein (-Pr), 0.5% protein plus the OTC supplement (+OTC), or 15% protein (+Pr) during 4 d of either hyperoxia (85% O-2) Or air exposure. Increased lung-to-body weight rat ios, indicative of oxidative tissue damage, were observed following ex posure to hyperoxia in -Pr and +Pr rats, but not in +OTC rats, even th ough the OTC supplement and the 15% protein diet contained a comparabl e amount of cysteine. Tissue reduced glutathione (GSH) status, GSH-dep endent enzyme activity and antioxidant defense enzyme activities were monitored in the lung, liver and blood during 4 d of hyperoxia exposur e. OTC supplementation enhanced GSH levels significantly in the lung o f PEM rats, whereas protein repletion significantly elevated blood GSH concentrations. The protective effect of OTC was not a function of ch anges in activity of GSH-dependent enzymes or oxygen defense enzymes i n the lung. These results indicate that a short-term strategy that sel ectively elevates GSH levels in the lung is more effective than protei n repletion in protecting against hyperoxia-induced oxidative lung dam age in PEM rats.