Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-alpha signaling.
Cigarette smoke exposure causes vascular remodeling and pulmonary hypertension by poorly understood mechanisms. To ascertain whether cigarette smoke exposure affects production of matrix metalloproteinases (MMPs) in the pulmonary vessels, we exposed C57Bl/6 (C57) mice or mice lacking TNF-alpha receptors (TNFRKO) to smoke daily for 2 wk or 6 mo. Using laser capture microdissection and RT-PCR analysis, we examined gene expression of MMP-2, MMP-9, MMP-12, MMP-13, and tissue inhibitor of metalloproteinase (TIMP-1) and examined protein production by immunohistochemistry for MMP-2, MMP-9, and MMP-12 in small intrapulmonary arteries. At 2 wk, mRNA levels of TIMP-1 and all MMPs were increased in the C57, but not TNFRKO, mice, and immunoreactive protein for MMP-2, MMP-9, and MMP-12 was also increased in the C57 mice. Increased gelatinase activity was identified by in situ and bulk tissue zymography. At 6 mo, only MMP-12 mRNA levels remained increased in the C57 mice, but at a much lower level; however, MMP-2 mRNA levels increased in the TNFRKO mice. We conclude that smoke exposure increases MMP production in the small intrapulmonary arteries but that, with the exception of MMP-12, increased MMP production is transient. MMPs probably play a role in smoke-induced vascular remodeling, as they do in other forms of pulmonary hypertension, implying that MMP inhibitors might be beneficial. MMP production is largely TNF-alpha dependent, further supporting the importance of TNF-alpha in the pathogenesis of cigarette smoke-induced lung disease.
Wright
J L
JL
Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5, USA. jlwright@interchange.ubc.ca
Tai
H
H
Wang
R
R
Wang
X
X
Churg
A
A
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D017931:DNA Primers; D018124:Receptors, Tumor Necrosis Factor; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12