Tumor necrosis factor-α neutralization reduces lung injury after experimental allogeneic bone marrow transplantation

Background, Idiopathic pneumonia syndrome (IPS) is a frequent and potentially fatal complication of bone marrow transplantation (BR;TT), We have previously shown that experimental TPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-alpha (TNF alpha) in the bronchoalveolar lavage (BAL) fluid, and that administration of LPS to animals with extensive graft versus host exacerbated underlying lung injury (Blood 1996; 88: 3230). Methods. Lethally irradiated CBA mice received BMT from allogeneic (BIO,ER) or syngeneic (CBA) donors. The role of TNF alpha in the exacerbation of pulmonary toxicity caused by LPS injection and in the evolution of TPS after allogeneic BMT was examined by neutralizing TNFa after BMT using a soluble binding protein (rhTNFR:Fc). Results. Five weeks after BR IT, administration of rhTNFR:Fc dramatically reduced mortality and prevented the exacerbation of lung injury caused by LPS administration, This protective effect was associated with preservation of pulmonary function and with marked reductions of cells, neutrophils, and EPS in the BAL fluid of treated animals. TNF alpha neutralization from week 4 to 6 after allogeneic BMT effectively halted the progression of systemic GVHD and significantly reduced, but did not prevent lung injury that developed during the treatment period. Conclusions. We conclude that TNF alpha is central to early LPS induced toxicity in this model and is a significant, but not the exclusive contributor to the development of IFS after allogeneic BMT.