The Role of Matrix Metalloproteinase-9 in Cigarette Smoke-induced Emphysema

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 al...

Full description

Saved in:

Bibliographic Details
Published in:	American journal of respiratory and critical care medicine Vol. 183; no. 7; pp. 876 - 884
Main Authors:	ATKINSON, Jeffrey J, LUTEY, Barbara A, CONRADI, Susan H, GIERADA, David S, PIERCE, Richard A, BETSUYAKU, Tomoko, SENIOR, Robert M, SUZUKI, Yoko, TOENNIES, Holly M, KELLEY, Diane G, KOBAYASHI, Dale K, IJEM, Whitney G, DESLEE, Gaetan, MOORE, Carla H, EILEEN JACOBS, M
Format:	Journal Article
Language:	English
Published:	New York, NY American Thoracic Society 01-04-2011
Subjects:	Aged Analysis of Variance Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Automation B. Chronic Obstructive Pulmonary Disease Biological and medical sciences Biopsy, Needle Bronchoalveolar Lavage Fluid - cytology Chronic obstructive pulmonary disease Cigarettes Disease Models, Animal Drug toxicity and drugs side effects treatment Emphysema Enzyme-Linked Immunosorbent Assay Humans Immunohistochemistry Inflammation Intensive care medicine Lasers Lung diseases Lung transplants Male Matrix Metalloproteinase 9 - metabolism Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Monocytes - metabolism Pathogenesis Pharmacology. Drug treatments Proteins Pulmonary Emphysema - chemically induced Pulmonary Emphysema - enzymology Pulmonary Emphysema - pathology Pulmonary Surfactant-Associated Protein D - metabolism Reference Values Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - analysis Smoke Smoking Surfactants Tissue Culture Techniques Tomography Toxicity: blood Variance analysis knockout Lung disease Intensive care Respiratory disease pulmonary disease Rodentia laser capture microdissection mice Vertebrata Chronic Mammalia Mouse Animal Bronchus disease chronic obstructive Obstructive pulmonary disease Emphysema Resuscitation
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. 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. 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. 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).
Bibliography:	This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Author Disclosure: J.J.A. received grant support from the NIH (more than $100,001) and the Alpha-one Foundation ($50,001–$100,000). B.A.L. has received salary from an NIH grant (less than $50,000/yr). Y.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.G.K. received grant support from the NIH (more than $100,001). D.K.K. received grant support from the NBHL ($50,001–$100,000) and the NIH (more than $100,001). W.G.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.H.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.E.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.H.C. received grant support from the NIH ($10,001–$50,000). D.S.G. received grant support from Pfizer, the NIH (more than $100,001), and the Barnes-Jewish Hospital Foundation ($50,001–$100,000). R.A.P. received grant support from the NIH (more than $100,001). T.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M.S. received grant support from the NIH (more than $100,001) and from the Barnes-Jewish Hospital Foundation ($50,000–$100,000). Originally Published in Press as DOI: 10.1164/rccm.201005-0718OC on November 5, 2010 Supported by NIH grants P50 HL084922, K08 HL081270, and PO1 HL29594, and the Alan and Edith Wolff Charitable Trust/Barnes-Jewish Hospital Foundation.
ISSN:	1073-449X 1535-4970
DOI:	10.1164/rccm.201005-0718oc