| The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema. | |
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MedLine Citation:
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PMID: 21057003 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be 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). |
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Authors:
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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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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-05 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 183 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-07 Completed Date: 2011-06-17 Revised Date: 2012-04-02 |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 876-84 Citation Subset: AIM; IM |
Affiliation:
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Washington University School of Medicine, St. Louis, MO 63110, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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ClinicalTrials.gov/NCT00757120 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aged Analysis of Variance Animals Biopsy, Needle Bronchoalveolar Lavage Fluid / cytology Disease Models, Animal Enzyme-Linked Immunosorbent Assay Humans Immunohistochemistry Male Matrix Metalloproteinase 9 / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Monocytes / metabolism Pulmonary Emphysema / chemically induced, enzymology*, pathology* Pulmonary Surfactant-Associated Protein D / metabolism* RNA, Messenger / analysis Reference Values Reverse Transcriptase Polymerase Chain Reaction Smoke Smoking Tissue Culture Techniques |
| Grant Support | |
ID/Acronym/Agency:
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K08 HL081270/HL/NHLBI NIH HHS; P01 HL29594/HL/NHLBI NIH HHS; P50 HL084922/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Pulmonary Surfactant-Associated Protein D; 0/RNA, Messenger; 0/Smoke; EC 3.4.24.35/Matrix Metalloproteinase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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