Tumor necrosis factor-alpha 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 (BMT). We have previously shown that experimental IPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-alpha (TNFalpha) 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 (B10.BR) or syngeneic (CBA) donors. The role of TNFalpha in the exacerbation of pulmonary toxicity caused by LPS injection and in the evolution of IPS after allogeneic BMT was examined by neutralizing TNFalpha after BMT using a soluble binding protein (rhTNFR:Fc).


RESULTS
Five weeks after BMT, 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 LPS in the BAL fluid of treated animals. TNFalpha 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 TNFalpha is central to early LPS induced toxicity in this model and is a significant, but not the exclusive contributor to the development of IPS after allogeneic BMT.
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
K R
KR
Cooke
G R
GR
Hill
A
A
Gerbitz
L
L
Kobzik
T R
TR
Martin
J M
JM
Crawford
J P
JP
Brewer
J L
JL
Ferrara
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D005260:Female; D006084:Graft Rejection; D006086:Graft vs Host Disease / Q000517:prevention & control; D008070:Lipopolysaccharides; D008171:Lung Diseases / Q000139:chemically induced / Q000209:etiology; D051379:Mice; D008808:Mice, Inbred CBA; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000517:prevention & control*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha