Overexpression of tumor necrosis factor-α in the lungs alters immune response, matrix remodeling, and repair and maintenance pathways.
Increased production of tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) is a feature of inflammatory lung diseases, including emphysema and fibrosis, but the divergent pathological characteristics that result indicate involvement of other processes in disease pathogenesis. Transgenic mice overexpressing TNF-α in type II alveolar epithelial cells under the control of the surfactant protein (SP)-C promoter develop pulmonary inflammation and emphysema but are resistant to induction of fibrosis by administration of bleomycin or transforming growth factor-β. To study the molecular mechanisms underlying the development of this phenotype, we used a microarray approach to characterize the pulmonary transcriptome of SP-C/TNF-α mice and wild-type littermates. Four-month-old SP-C/TNF-α mice displayed pronounced pulmonary inflammation, airspace enlargement, increased MMP-2 and MMP-9 levels, and altered expression of 2332 probes. The functional assessment of genes with increased expression revealed enrichment of inflammatory/immune responses and proteases, whereas genes involved in protease inhibition, angiogenesis, cross-linking of basement membrane proteins, and myofibroblast differentiation were predominantly decreased. Comparison with multiple lung disease models identified a set of genes unique to the SP-C/TNF-α model and revealed that lack of extracellular matrix production distinguished SP-C/TNF-α mice from fibrosis models. Activation of inflammatory and proteolytic pathways and disruption of maintenance and repair processes are central features of emphysema in this TNF-overexpression model. Impairment of myofibroblast differentiation and extracellular matrix production may underlie resistance to induction of fibrosis.
Hazard Identification Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada. errol.thomson@hc-sc.gc.ca
Errol M
EM
Thomson
Andrew
A
Williams
Carole L
CL
Yauk
Renaud
R
Vincent
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000502:physiology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D037721:Pulmonary Surfactant-Associated Protein C; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010447:Peptide Hydrolases