The Locus of Tumor Necrosis Factor- α Action in Lung Inflammation
| Autor: | Sherilyn Smith, Mechthild Jonas, Kendall Mohler, Shawn J. Skerrett, Christopher B. Wilson, Emil Y. Chi |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Lipopolysaccharides
Pulmonary and Respiratory Medicine Genetically modified mouse Lipopolysaccharide Neutrophils Recombinant Fusion Proteins medicine.medical_treatment Clinical Biochemistry Mice Transgenic Inflammation Biology Receptors Tumor Necrosis Factor Mice chemistry.chemical_compound Antigen medicine Animals Apolipoproteins C Promoter Regions Genetic Lung Molecular Biology Administration Intranasal Mice Knockout Antigens Bacterial Tumor Necrosis Factor-alpha Micromonosporaceae Pneumonia Cell Biology Immunoglobulin Fc Fragments TNF inhibitor Mice Inbred C57BL medicine.anatomical_structure chemistry Immunology Knockout mouse Tumor necrosis factor alpha medicine.symptom |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 19:881-891 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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