Myeloperoxidase deficiency enhances inflammation after allogeneic marrow transplantation.
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 with MPO+/+ mice. The increased lung injury during MPO deficiency was a result of donor T cell-dependent inflammatory responses because bronchoalveolar lavage fluids (BALF) from MPO-/- mice contained increased numbers of inflammatory cells and higher levels of the proinflammatory cytokine TNF-alpha and the monocyte chemoattractant protein-1 compared with 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 II 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.
Milla
Carlos
C
Division of Pulmonary and Critical Care, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Yang
Shuxia
S
Cornfield
David N
DN
Brennan
Marie-Luise
ML
Hazen
Stanley L
SL
Panoskaltsis-Mortari
Angela
A
Blazar
Bruce R
BR
Haddad
Imad Y
IY
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid; D007249:Inflammation / Q000453:epidemiology* / Q000235:genetics; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018384:Oxidative Stress; D009195:Peroxidase / Q000172:deficiency*; D011650:Pulmonary Alveoli / Q000293:injuries*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000009:adverse effects*
D009195:Peroxidase