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1 In the present study, the roles of nitric oxide (NO) and superoxide anions (O 2 7 ) in allergeninduced airway hyperreactivity (AHR) after the late asthmatic reaction (LAR) were investigated ex vivo, by examining the eects of the NO synthase inhibitor N o -nitro-L-arginine methyl ester (L-NAME) and superoxide dismutase (SOD) on the responsiveness to methacholine of isolated perfused guinea-pig treacheae from unchallenged (control) animals and from animals 24 h after ovalbumin challenge.2 At 24 h after allergen challenge, the animals developed AHR in vivo, as indicated by a mean 2.63+0.54 fold (P50.05) increase in sensitivity to histamine inhalation. 3 Compared to unchallenged controls, tracheal preparations from the ovalbumin-challenged guinea-pigs displayed a signi®cant 1.8 fold (P50.01) increase in the maximal response (E max ) to methacholine, both after intraluminal (IL) and extraluminal (EL) administration of the agonist. No changes were observed in the sensitivity (pEC 50 ) to the agonist. Consequently, the DpEC 50 (EL-IL), as a measure of epithelial integrity, was unchanged. 4 In the presence of L-NAME (100 mM, IL), tracheae from control guinea-pigs showed a 1.6 fold (P50.05) increase in the E max of IL methacholine. By contrast, the E max of IL methacholine was signi®cantly decreased in the presence of 100 u ml 71 EL SOD (54% of control, P50.01). 5 Remarkably, the increased responsiveness to IL methacholine at 24 h after allergen challenge was reversed by L-NAME to control (P50.01), and a similar eect was observed with SOD (P50.01). 6 The results indicate that both NO and O 2 7 are involved in the tracheal hyperreactivity to methacholine after the LAR, possibly by promoting airway smooth muscle contraction through the formation of peroxynitrite.

Aim of the study was to evaluate treatment efficacy and safety of a scaled-up version of our porcine hepatocytes based BAL system in pigs with complete liver ischemia (LIS). Thirty-one pigs underwent total devascularization of the liver (LIS) by termino-lateral porta-caval shunts and sutures around the bile duct, the common hepatic and gastroduodenal arteries and their accessory branches. The hepato-duodenal ligament was completely transected. Four experimental groups were studied: the first control group (LIS Control, n = 10) received glucose infusion only, the second control group (LIS Plasmapheresis, n = 8) was connected to a centrifugal plasma-separator with a bottle representing the bioreactor volume, the third control group (LIS Empty-BAL, n = 5) received BAL treatment without cells, and the treated group (LIS Cell-BAL, n = 8) was connected for a maximum period of 24 hours to our scaled-up BAL seeded with around 14 billion viable primary porcine hepatocytes. BAL treatment significantly prolonged life in large animals (approximately 35 kg) with complete LIS (Controls, mean +/- SEM: 33.1 +/- 3 h, Cell-BAL: 51.1 +/- 3.4 h; p = 0.001; longest survivor 63 h). In addition, blood ammonia and total bilirubin levels decreased significantly, indicating metabolic activity of porcine hepatocytes in the bioreactor. No significant differences were noticed among the three control groups, indicating that there was no device effect and that the plasmapheresis procedure was well tolerated. No important adverse effects were observed.