N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reperfusion: a possible dual protective mechanism in a dose-response study.
BACKGROUND
Acute lung reperfusion injury (ALI) frequently follows an ischemic event in another organ, such as organ transplantation. We recently demonstrated that lung priming with N-acetyl-L-cysteine (NAC) prevented liver ischemia-reperfusion (IR)-induced ALI pending on reduced glutathione (GSH) amount of replenishment. We now assessed the therapeutic effect of NAC-in preventing ALI caused by liver IR-if administered to the lung during liver reperfusion.


METHODS
Rat isolated livers were stabilized (30 min) and then perfused with modified Krebs-Henseleit solution (control, n=20) or made globally ischemic (IR, n=20) for 2 hr. Rat lungs were isolated separately, ventilated, and stabilized (30 min) with Krebs plus 5% bovine albumin. Pairs of liver and lung were then reperfused together for 15 min, followed by only lung recirculation with the liver effluent for another 45 min. Three more controls (n=20 each) and three ischemic groups (n=20 each) included lungs which were treated with 100, 150 or 225 mg x kg(-1) NAC (0.5, 0.74, or 1.1 mmol, respectively) during the 15-min liver and lung reperfusion period.


RESULTS
Pulmonary artery and ventilatory pressures and vascular resistance increased by 60-80% of baseline, compliance decreased, and bronchoalveolar lavage volume and content were abnormally high in the IR-nontreated and the IR-100 lungs. Most parameters in IR-150 and IR-225 lungs remained almost similar to controls. Postinsult GSH content in IR-100, -150, and -225 lungs was at 20%, 110%, and 90% above the IR-nontreated lungs, respectively.


CONCLUSIONS
Lung treatment with NAC during its reperfusion with IR liver effluent prevented ALI. Lung GSH replenishment accounted for lung protection, but its content did not correlate directly with grade of protection; NAC itself seemingly afforded lung protection as well.
Weinbroum
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AA
Department of Anesthesiology, Tel Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel Aviv University, Israel. draviw@tasmc.health.gov.il
Rudick
V
V
Ben-Abraham
R
R
Karchevski
E
E
D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000201:enzymology; D008102:Liver Circulation; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D010477:Perfusion; D011652:Pulmonary Circulation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D012119:Respiration; D014969:Xanthine Oxidase / Q000378:metabolism
D016166:Free Radical Scavengers; D014969:Xanthine Oxidase; D005978:Glutathione; D000111:Acetylcysteine