Absence of host tumor necrosis factor receptor 1 attenuates manifestations of idiopathic pneumonia syndrome.
The interaction of TNF-alpha with TNF receptor 1 (TNFR1) activates several signal transduction pathways that lead to apoptosis or NF-kappa B-dependent inflammation and immunity. We hypothesized that host TNFR1 expression contributes to noninfectious lung injury and inflammation commonly observed after bone marrow transplantation (BMT), termed idiopathic pneumonia syndrome (IPS). C57BL/6 TNFR1-sufficient (TNFR1(+/+)) and -deficient (TNFR1(-/-)) mice were total body irradiated with or without cyclophosphamide conditioning and were given bone marrow plus IPS-inducing donor spleen T cells from B10.BR wild-type mice. TNFR1(-/-) recipient mice exhibited improved early post-BMT survival associated with decreased permeability edema. In addition, the low lung compliance measured in anesthetized, ventilated TNFR1(+/+) mice on day 7 after BMT was restored to baseline during TNFR1 deficiency. Importantly, bronchoalveolar lavage fluid (BALF) inflammatory cells from TNFR1(-/-) vs. TNFR1(+/+) mice generated less nitric oxide (.NO) and nitrating species and exhibited suppressed programmed cell death as assessed using flow cytometry. However, cellular infiltration and levels of proinflammatory cytokines and chemokines were generally higher in BALF collected on day 7 after BMT from TNFR1(-/-) compared with TNFR1(+/+) recipient mice. Our results support a major role of host TNFR1 in regulation of .NO production and lung dysfunction after allogeneic BMT.
Shukla
Mayank
M
Dept. of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Yang
Shuxia
S
Milla
Carlos
C
Panoskaltsis-Mortari
Angela
A
Blazar
Bruce R
BR
Haddad
Imad Y
IY
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000401:mortality; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D017563:Lung Diseases, Interstitial / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000276:immunology*; D015996:Survival Rate; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine