Overexpression of tumor necrosis factor-α in the lungs alters immune response, matrix remodeling, and repair and maintenance pathways

Am J Pathol. 2012 Apr;180(4):1413-30. doi: 10.1016/j.ajpath.2011.12.020. Epub 2012 Feb 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Disease Models, Animal
  • Extracellular Matrix / physiology
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / physiology
  • Inflammation Mediators / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Lung / immunology*
  • Lung / metabolism
  • Lung / pathology
  • Lung / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Myofibroblasts / pathology
  • Neovascularization, Physiologic / genetics
  • Oligonucleotide Array Sequence Analysis / methods
  • Peptide Hydrolases / metabolism
  • Peptides / genetics
  • Peptides / physiology
  • Pneumonia / genetics
  • Pneumonia / immunology*
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / immunology*
  • Pulmonary Emphysema / metabolism
  • Pulmonary Emphysema / pathology
  • Pulmonary Surfactant-Associated Protein C
  • Real-Time Polymerase Chain Reaction / methods
  • Regeneration / genetics
  • Regeneration / physiology
  • Signal Transduction / genetics
  • Transcriptome
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics


  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Pulmonary Surfactant-Associated Protein C
  • Sftpc protein, mouse
  • Tumor Necrosis Factor-alpha
  • Peptide Hydrolases