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.