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Signaling
1 Pathology, University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed. E-mail: jwright{at}providencehealth.bc.ca.
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 mice or mice lacking TNF
receptors (TNFRKO) to daily smoke for two weeks or six months. Using laser capture microdissection and RT-PCR analysis we examined gene expression of MMP-2, -9, -12, and -13, and TIMP-1, and examined protein production by immunohistochemistry for MMP-2,-9 and -12 in small intrapulmonary arteries. At two weeks, mRNA levels were increased for TIMP-1 and all MMPs in the C57, but not the TNFRKO mice, and there was also increased immunoreactive protein for MMP-2, 9, and -12 in the C57 mice. Increased gelatinase activity was identified by in-situ and bulk tissue zymography. At six months, only MMP-12 mRNA levels remained increased in the C57 mice, but at a much lower level; however, there was increased MMP-2 in the TNFRKO mice. We conclude that smoke exposure causes increased 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 dependent, further supporting the importance of TNF in the pathogenesis of cigarette smoke induced lung disease.
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