Tuesday, June 19, 2007 - 10:20 AM
Douglas Firs (Boise Centre on the Grove)

Active Remodeling in Lymphangioleiomyomatosis as Revealed by Serial Analysis of Gene Expression (SAGE)

Tiffany J. Whitney1, Maureen Brandon1, and Blanca Camoretti-Mercado2. (1) Idaho State University, Pocatello, ID, (2) University of Chicago Medical School, Chicago, IL

LAM patients exhibit symptoms and histological characteristics similar to other pulmonary diseases. Smooth muscle (SM) cells from the lung can produce and secrete extracellular matrix (ECM) modulators, including cytokines and transforming growth factor (TGF) beta. It was recently reported that LAM lesions expressed abundant TGF beta.

We constructed a SAGE library of primary LAM-derived cultured cells. We sequenced 17,904 cDNA tags that represent 2,111 genes with at least two copies. We identified nearly all 2,111 genes, and compared their expression levels to a normal lung SAGE library (GSM762). We were unable to detect the presence of TSC2 transcripts, the tumor suppressor frequently found mutated in LAM. Interestingly, TSC1 was expressed at lower levels (60%) than in normal lung. While the expression of many genes including caveolin, TGF alpha, and several ribosomal proteins were equivalent in both libraries, we observed at least a two-fold increase in expression of many genes involved in TGF beta signaling, including connective tissue growth factor, TGF beta receptor type I, and Smad3. Moreover, upregulation and / or induction of TGF-beta responsive genes like thrombospondin-1 and -4, and of the ECM protein-encoding genes collagen type I, III, IV, VI, laminin, and fibronectin 1 was evident. Matrix metalloproteinases (MMP) 1, 2, 3, 14, and 19 were also more abundant in LAM-derived cells. However, TIMP1, TIMP2 and TIMP3 transcripts showed augmented abundance. Our data suggest the presence of active remodeling in LAM relative to normal lung, which we speculate is likely driven by activation of TGF beta signaling.