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1 Department of Pediatrics, Division of Pulmonary and Critical Care, University of Minnesota, Minneapolis, MN, USA
2 Department of Pediatrics, Division of Pulmonary and Critical Care, University of Minnesota, Minneapolis, MN, USA; Division of Bone Marrow Transplantation and Cancer Center, University of Minnesota, Minneapolis, MN, USA
3 Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA
4 Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
5 Division of Bone Marrow Transplantation and Cancer Center, University of Minnesota, Minneapolis, MN, USA
* To whom correspondence should be addressed. E-mail: hadda003{at}umn.edu.
Myeloperoxidase (MPO)-derived oxidants participate in the respiratory antimicrobial defense system, but are also implicated in oxidant-mediated acute lung injury. We hypothesized that MPO contributes to lung injury commonly observed after bone marrow transplantation (BMT). MPO sufficient (MPO+/+) and deficient (MPO-/-) mice were given cyclophosphamide and lethally irradiated followed by infusion of inflammation-inducing donor spleen T cells at
time of BMT. Despite suppressed generation of nitrative stress, MPO-/- recipient mice unexpectedly exhibited accelerated weight loss and increased markers of lung dysfunction compared to MPO+/+ mice. The increased lung injury during MPO deficiency was a result of donor T cell-dependent inflammatory responses because bronchoalveolar fluids (BALF) from MPO-/- mice contained increased number of inflammatory cells and higher levels of the
proinflammatory cytokine, TNF-
, and the chemoattractant, MCP-1, compared to wild type mice. Enhanced inflammation in MPO-/- mice was associated with suppressed apoptosis of BALF inflammatory cells. The inflammatory process in MPO-/- recipients was also associated with enhanced necrosis of freshly isolated alveolar type (ATII) cells, critical for preventing
capillary leak. We conclude that suppressed MPO-derived oxidative/nitrative stress is associated with enhanced lung inflammation and persistent alveolar epithelial injury.
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