title: Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.
abstract: BACKGROUND
  Tumor necrosis factor alpha (TNF-alpha) has been implicated as a key cytokine in many inflammatory lung diseases. These effects are currently unclear, because a transgenic mouse overexpressing TNF-alpha in the lung has been shown in separate studies to produce elements of both emphysema and pulmonary fibrosis.
  
  
  OBJECTIVE
  We sought to elucidate the phenotypic effects of TNF-alpha overexpression in a mouse model.
  
  
  METHODS
  We established the phenotype by measuring lung impedance and thoracic gas volume, and using micro-computed tomography and histology.
  
  
  RESULTS
  We found that airways resistance in this mouse was not different to control mice, but that lung tissue dampening, elastance, and hysteresivity were significantly elevated. Major heterogeneous abnormalities of the parenchyma were also apparent in histologic sections and in micro-computed tomography images of the lung. These changes included airspace enlargement, loss of small airspaces, increased collagen, and thickened pleural septa. We also found significant increases in lung and chest cavity volumes in the TNF-alpha-overexpressing mice.
  
  
  CONCLUSIONS
  We conclude that TNF-alpha overexpression causes pathologic changes consistent with both emphysema and pulmonary fibrosis combined with a general lung inflammation, and consequently does not model any single human disease. Our study thus confirms the pleiotropic effects of TNF-alpha, which has been implicated in multiple inflammatory disorders, and underscores the necessity of using a wide range of investigative techniques to link gene expression and phenotype in animal models of disease.
authors.affiliation: Vermont Lung Center, University of Vermont College of Medicine, HSRF 230, 149 Beaumont Avenue, Burlington, VT 05405-0075, USA. lennart.lundblad@uvm.edu
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.forename: John
authors.initials: J
authors.lastname: Thompson-Figueroa
authors.forename: Timothy
authors.initials: T
authors.lastname: Leclair
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sullivan
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011656:Pulmonary Emphysema / Q000235:genetics / Q000473:pathology*; D011663:Pulmonary Surfactants / Q000032:analysis; D012016:Reference Values; D012129:Respiratory Function Tests; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed; D014109:Total Lung Capacity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha