PMID- 9843922
OWN - NLM
STAT- MEDLINE
DCOM- 19990119
LR  - 20081121
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 19
IP  - 6
DP  - 1998 Dec
TI  - The locus of tumor necrosis factor-alpha action in lung inflammation.
PG  - 881-91
AB  - The pulmonary host response to infection and inflammation appears, at least in 
      part, to be compartmentalized from the systemic host response. Tumor necrosis 
      factor-alpha (TNF-alpha) has been implicated in lung inflammation and injury, but 
      its site(s) of action has not been clearly defined. To investigate this, 
      transgenic mice (surfactant apoprotein C promotor/soluble TNF receptor type II-Fc 
      fusion protein ([SPCTNFRIIFc] mice) were generated in which TNF-alpha was 
      selectively antagonized in the distal lung through tissue-specific expression of 
      sTNFRIIFc, a soluble TNF inhibitor. The lung inflammatory response in these mice 
      to pulmonary challenge with Micropolyspora faeni antigen or lipopolysaccharide 
      (LPS) was compared with the response of wild-type mice, wild-type mice treated 
      with recombinant sTNFRIIFc intravenously, and type I TNF-receptor knockout mice. 
      Recruitment of polymorphonuclear leukocytes (PMN) to the lung after challenge 
      with M. faeni antigen was essentially abolished in the TNFRI knockout mice and 
      markedly reduced in the SPCTNFRIIFc mice. Wild-type mice given sTNFRIIFc 
      intravenously in amounts resulting in lung concentrations similar to those in 
      SPCTNFRIIFc mice also showed significantly reduced lung PMN recruitment, whereas 
      those given doses that achieved such concentrations in the blood but low levels 
      in the lung did not. In contrast, PMN recruitment to the lung following aerosol 
      challenge with LPS was reduced significantly in the TNFRI knockout mice and in 
      mice given high-dose sTNFRIIFc intravenously, but was not reduced significantly 
      in SPCTNFRIIFc mice. Thus, inhibition of PMN recruitment in response to M. faeni 
      antigen correlated largely with the extent of intrapulmonary inhibition of 
      TNF-alpha, whereas the response to LPS correlated best with the extent of 
      extrapulmonary inhibition of TNF-alpha. These studies indicate that TNF-alpha may 
      act at different loci to mediate lung inflammation, with the site of action 
      depending in part on the nature of the inflammatory stimulus, and that 
      SPCTNFRIIFc mice provide a tool by which the locus of TNF action can be 
      addressed.
FAU - Smith, S
AU  - Smith S
AD  - Departments of Pediatrics and Immunology, Medicine, and Pathology, University of 
      Washington School of Medicine and Children's Hospital Medical Center, Seattle, WA 
      98195, USA.
FAU - Skerrett, S J
AU  - Skerrett SJ
FAU - Chi, E Y
AU  - Chi EY
FAU - Jonas, M
AU  - Jonas M
FAU - Mohler, K
AU  - Mohler K
FAU - Wilson, C B
AU  - Wilson CB
LA  - eng
GR  - DK51807/DK/NIDDK NIH HHS/United States
GR  - HD 18184/HD/NICHD NIH HHS/United States
GR  - HL 30543/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Apolipoproteins C)
RN  - 0 (Immunoglobulin Fc Fragments)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Administration, Intranasal
MH  - Animals
MH  - Antigens, Bacterial/administration & dosage/immunology
MH  - Apolipoproteins C/genetics
MH  - Immunoglobulin Fc Fragments/genetics
MH  - Lipopolysaccharides/administration & dosage
MH  - Lung/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Micromonosporaceae/immunology
MH  - Neutrophils/pathology
MH  - Pneumonia/*immunology/pathology
MH  - Promoter Regions, Genetic
MH  - Receptors, Tumor Necrosis Factor/genetics
MH  - Recombinant Fusion Proteins/pharmacology
MH  - Tumor Necrosis Factor-alpha/*physiology
EDAT- 1998/12/09 00:00
MHDA- 1998/12/09 00:01
CRDT- 1998/12/09 00:00
PHST- 1998/12/09 00:00 [pubmed]
PHST- 1998/12/09 00:01 [medline]
PHST- 1998/12/09 00:00 [entrez]
AID - 10.1165/ajrcmb.19.6.3146 [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 1998 Dec;19(6):881-91. doi: 10.1165/ajrcmb.19.6.3146.