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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 504-511, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0124OC

Tissue Inhibitor of Metalloproteinase-3 Downregulation in Lymphangioleiomyomatosis

Potential Consequence of Abnormal Serum Response Factor Expression

Xiaoning Zhe, Yan Yang, Sandhya Jakkaraju and Lucia Schuger

Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan

Address correspondence to: Lucia Schuger, M.D., Department of Pathology, Wayne State University, 540 E. Canfield St., Rm. 9248, Detroit, MI 48201. E-mail: lschuger{at}med.wayne.edu

Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle–like cell proliferation leading to tissue destruction and cyst formation. We demonstrate that serum response factor (SRF), a critical smooth muscle transcription factor, is overexpressed in LAM cells. To determine whether abnormal SRF levels might have a pathogenic role in LAM, we transfected SRF into mouse lung fibroblasts and performed a cDNA array analysis. High SRF level upregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-14, two MMPs previously shown to be increased in LAM. In addition, SRF down-regulated tissue inhibitor of metalloproteinase (TIMP)-3, one of their inhibitors. TIMP-3 inhibition was further confirmed by reverse transcriptase/polymerase chain reaction, immunoblotting, and immunostaining of human lung fibroblasts transfected with SRF fused to DsRed2 (a red variant of green fluorescent protein). To determine the in vivo significance of our findings, we immunostained 12 LAM cases for TIMP-3. In eight of them, TIMP-3 was ubiquitously present in normal lung parenchyma, but it was absent in LAM lesions. In the remaining cases, including two out of five normal control lungs, the antibody immunoreacted exclusively with elastin, probably due to suboptimal tissue processing. Because timp-3–null mice develop spontaneous emphysema, our findings suggest that SRF-mediated TIMP-3 inhibition might contribute to the tissue damage seen in LAM.

Abbreviations: extracellular matrix, ECM • lymphangioleiomyomatosis, LAM • matrix metalloproteinases, MMPs • reverse transcriptase/polymerase chain reaction, RT-PCR • serum response factor, SRF • smooth muscle, SM • tissue inhibitor of metalloproteinases, TIMPs • tuberous sclerosis complex, TSC




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