Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse.
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.
Churg
Andrew
A
Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. achurg@interchange.ubc.ca
Wang
Rong D
RD
Tai
Hsin
H
Wang
Xiaoshan
X
Xie
Changshi
C
Wright
Joanne L
JL
D000818:Animals; D003895:Desmosine / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003895:Desmosine; D020782:Matrix Metalloproteinases; D006909:Hydroxyproline