Cigarette smoke condensate induces MMP-12 gene expression in airway-like epithelia.
Cigarette smoke (CS)-induced emphysema is attributable to matrix metalloproteinase-12 (MMP-12) in mice, however, a relationship between CS and MMP-12 is absent in human emphysema. Here, we show that cigarette smoke condensate (CSC) induces MMP-12 gene expression in airway-like epithelia through a hydrogen peroxide (H(2)O(2))-dependent pathway involving NADPH oxidase, AP-1, and TNF-alpha. Cigarette smoke condensate-induced H(2)O(2) production and MMP-12 gene expression were inhibited by apocynin, a specific inhibitor of NADPH oxidases, while 3-aminobenzamide, an inhibitor of AP-1, attenuated CSC-induced MMP-12 gene expression. Messenger RNAs encoding phagocytic NADPH oxidase components and a homologue of p67phox, p51 (NOXA1), were detected, while mRNA of dual oxidase (Duox)1 was unchanged by CSC. Enbrel, an inhibitor of TNF-alpha function, reduced CSC-induced H(2)O(2) production and MMP-12 expression. These findings provide novel evidence of a direct relationship between CS exposure and MMP-12 in human airway epithelia and suggest several targets for modulation of this potentially pathogenic pathway.
Lavigne
Mark C
MC
Wyeth Research, Cardiovascular and Metabolic Diseases, Cambridge, MA 02140, USA.
Eppihimer
Michael J
MJ
D001483:Base Sequence; D001980:Bronchi / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D017931:DNA Primers; D004789:Enzyme Activation; D004848:Epithelium / Q000201:enzymology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics*; D019255:NADPH Oxidases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012906:Smoke; D014026:Nicotiana; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D017931:DNA Primers; D012333:RNA, Messenger; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12