Tumor Necrosis Factor-α Drives 70% of Cigarette Smoke–induced Emphysema in the Mouse

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Abstract
Mice lacking tumor necrosis factor-α (TNF-α) 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-α 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-α–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-α causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-α–independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

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