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Published ahead of print on April 1, 2005, doi:10.1164/rccm.200410-1349OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 1363-1370, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200410-1349OC

Original Article

Tumor Necrosis Factor–{alpha} Overexpression in Lung Disease

A Single Cause behind a Complex Phenotype

Lennart K. A. Lundblad, John Thompson-Figueroa, Timothy Leclair, Michael J. Sullivan, Matthew E. Poynter, Charles G. Irvin and Jason H. T. Bates

Vermont Lung Center, University of Vermont, Burlington, Vermont; and Department of Clinical Physiology, Malmö University Hospital, Lund University, Malmö, Sweden

Correspondence and requests for reprints should be addressed to Lennart K.A. Lundblad, B.Sc., University of Vermont College of Medicine, HSRF 230, 149 Beaumont Avenue, Burlington, VT 05405-0075. E-mail: lennart.lundblad{at}uvm.edu

Rationale: 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. Objectives: We sought to elucidate the phenotypic effects of TNF-{alpha} overexpression in a mouse model. Measurements: We established the phenotype by measuring lung impedance and thoracic gas volume, and using micro–computed tomography and histology. Main 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.

Key Words: emphysema • micro–computed tomography • plethysmography • pulmonary fibrosis




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