Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse

Am J Respir Crit Care Med. 2004 Sep 1;170(5):492-8. doi: 10.1164/rccm.200404-511OC. Epub 2004 Jun 7.


Mice lacking tumor necrosis factor-alpha (TNF-alpha) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-alpha in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non-neutrophil-mediated matrix breakdown. We conclude that TNF-alpha-mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-alpha causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-alpha-independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Desmosine / metabolism
  • Hydroxyproline / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Emphysema / etiology*
  • Pulmonary Emphysema / metabolism
  • Receptors, Tumor Necrosis Factor / physiology*
  • Smoking / adverse effects*
  • Tumor Necrosis Factor-alpha / physiology


  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Desmosine
  • Matrix Metalloproteinases
  • Hydroxyproline