Ischemia-reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120 min of warm left lung ischemia, rats received approximately 15 x 10(6) vIL-10-engineered MSCs (MSC-vIL-10), empty vector-engineered MSCs (MSC-vec), or saline intravenously. Mean blood oxygenation (PaO(2)/FiO(2) ratio, mmHg) was measured at 4 hr, 24 hr, 72 hr, and 7 days. As early as 4 hr post-IR injury with MSC-vIL-10 treatment, blood oxygenation was significantly (p < 0.05) improved (319 +/- 94; n = 7) compared with untreated (saline) controls (63 +/- 19; n = 6). At 24 hr post-IR injury, in the MSC-vIL-10-treated group there was a further increase in blood oxygenation (353 +/- 105; n = 10) compared with the MSC-vec group (138 +/- 86; n = 9) and saline group (87 +/- 39; n = 10). By 72 hr, oxygenation reached normal (475 +/- 55; n = 9) in the MSC-vIL-10-treated group but not in the saline-treated and MSC-vec-treated groups. At 4 hr after IR injury, lungs with MSC-vIL10 treatment had a lower (p < 0.05) injury score (0.9 +/- 0.4) compared with lungs of the untreated (saline) group (2.5 +/- 1.4) or MSC-vec-treated group (2 +/- 0.4). Lung microvascular permeability and wet-to-dry weight ratios were markedly lower in the MSC-vIL10 group compared with untreated (saline) controls. ISOL (in situ oligonucleotide ligation for DNA fragmentation detection) and caspase-3 staining demonstrated significantly (p < 0.05) fewer apoptotic cells in MSC-vIL10-treated lungs. Animals that received MSC-vIL10 therapy had fewer (p < 0.05) CD4(+) and CD8(+) T cells in bronchoalveolar lavage fluid compared with untreated control animals. A therapeutic strategy using vIL-10-engineered MSCs to prevent IR injury in lung transplantation seems promising.

Ubiquitin treatment enhances the Th2 cytokine response in postischemic lungs during reperfusion, reduces lung edema formation, and improves pulmonary function during lung ischemia-reperfusion injury. This study further defines ubiquitin's anti-inflammatory properties, and suggests that it could be used therapeutically to improve function of postischemic lungs.