The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema

Jeffrey J. Atkinson, Barbara A. Lutey, Yoko Suzuki, Holly M. Toennies, Diane G. Kelley, Dale K. Kobayashi, Whitney G. Ijem, Gaetan Deslee, Carla H. Moore, M. Eileen Jacobs, Susan H. Conradi, David S. Gierada, Richard A. Pierce, Tomoko Betsuyaku, Robert M. Senior

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Abstract

Rationale: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages thatmaybe involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. Objectives: To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. Methods: Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. Measurements and Main Results: Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. Conclusions: These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

Original languageEnglish
Pages (from-to)876-884
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number7
DOIs
Publication statusPublished - 2011 Apr 1
Externally publishedYes

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Keywords

  • Laser capture microdissection
  • Mice, knockout
  • Pulmonary disease, chronic obstructive

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Atkinson, J. J., Lutey, B. A., Suzuki, Y., Toennies, H. M., Kelley, D. G., Kobayashi, D. K., Ijem, W. G., Deslee, G., Moore, C. H., Jacobs, M. E., Conradi, S. H., Gierada, D. S., Pierce, R. A., Betsuyaku, T., & Senior, R. M. (2011). The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema. American Journal of Respiratory and Critical Care Medicine, 183(7), 876-884. https://doi.org/10.1164/rccm.201005-0718OC