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Background. We have recently reported that perioperative low-dose carbon monoxide (CO) inhalation decreases lung ischemia-reperfusion injury in miniature swine. The aims of this study were to establish a large animal model of pulmonary allograft rejection using polymerase chain reaction-typed major histocompatibility complex (MHC)-inbred CLAWN miniature swine and to examine the effects of CO on allograft survival. Methods. Eleven CLAWN miniature swines received fully MHC-mismatched lungs followed by 12 days of tacrolimus (days 0-11; blood level 35-45 ng/mL). Six recipients received tacrolimus alone (control group). Five recipients were additionally treated with inhaled CO (180 min for donors until graft harvest; 390 min for recipients until 2 hr after reperfusion). Results. All recipients treated with tacrolimus alone uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. CO treatment was effective in prolonging allograft survival from a mean of 47±7 to 82± 13 days (P=0.017), with one CO-treated animal maintaining function until postoperative day 120. Development of antidonor antibodies and donor-specific responsiveness by cell-mediated lympholysis and mixed lymphocyte reaction assays was delayed in animals that received CO therapy. Furthermore, serum concentrations of proinflammatory cytokines (interleukin-1β and -6) 1 day after transplant were significantly decreased in the CO-treated group. Conclusions. Fully MHC-mismatched lungs in CLAWN miniature swine were consistently rejected within 63 days, suggesting that this is a robust large animal model ideal for investigating mechanisms and treatment of lung rejection. Perioperative low-dose CO inhalation prolonged graft survival and inhibited antidonor antibody production and was associated with decreased proinflammatory mediators in this model.

Mechanical unloading (MU) of a failing heart using a left ventricular assist device (LVAD) can lead to "bridge to recovery" in some patients. However, it is still unknown how to determine when to withdraw assistance. We sought to determine the optimal duration of MU by investigating its short- and long-term effects using a rat model of heterotopic heart transplantation.Heart failure (HF) was induced in Lewis rats by ligating the left anterior descending artery. In the MU-HF groups, failing hearts were harvested and heterotopically transplanted. In the non-unloaded HF groups and the control group, hearts were not transplanted. After 2, 4 and 8 weeks, we evaluated papillary muscle function, histologic change and cardiac gene expression. Normal hearts served as the control group.In the MU-HF groups, papillary muscle function improved significantly in the early period of unloading. It peaked and normalized at 4 weeks of unloading, but decreased to 50% the level of a normal heart at 8 weeks. In parallel with papillary muscle function, expression of brain natriuretic peptide (BNP) mRNA and SERCA2a mRNA normalized at 2 and 4 weeks of unloading, respectively, but deteriorated after 4 weeks. Cardiomyocyte hypertrophy was normalized at 2 weeks of unloading, but extended unloading induced cardiac atrophy. Myocardial fibrosis increased after unloading.Mechanical unloading of the failing heart can help normalize cardiac function, cardiomyocyte hypertrophy and cardiac gene expression for an optimal duration (4 weeks), but this normalization deteriorates with prolonged support.