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


OBJECTIVE
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.


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).
Washington University School of Medicine, St. Louis, MO 63110, USA.
Jeffrey J
JJ
Atkinson
Barbara A
BA
Lutey
Yoko
Y
Suzuki
Holly M
HM
Toennies
Diane G
DG
Kelley
Dale K
DK
Kobayashi
Whitney G
WG
Ijem
Gaetan
G
Deslee
Carla H
CH
Moore
M Eileen
ME
Jacobs
Susan H
SH
Conradi
David S
DS
Gierada
Richard A
RA
Pierce
Tomoko
T
Betsuyaku
Robert M
RM
Senior
D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke; D012907:Smoking; D046509:Tissue Culture Techniques
D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D012906:Smoke; D020780:Matrix Metalloproteinase 9