P-111: Changes in the Expression of TGF-β variants in Tissues and Cells Exposed to Mustard Gas (Pages: 89-90)

Mirzaei B *, Valizadeh M , Mohammadian A , Banaei M , Tavalaee M , Noorani MR , Mowla SJ ,


Objective: Sulfur mustard (SM) is a chemical warfare agent with cytotoxic, mutagenic, and vesicatingproperties. It effectuates cutaneous blisters, respiratory tract damage, eye lesions and bone marrow depression. Biological actions of SM occur through -at first hand- alkylation of cellular targets (DNA, RNA, protein, lipid and small electrophilic molecules such as glutathione). Cells exposed to SM confront problems in DNA replication, transcription and translation, which are manifested as necrosis/apoptosis, or alteration in several pathways including cell cycle control, cell adhesion, morphogenesis, repair, and inflammatory response. Transforming growth factor-b family (TGF-β) are multipotent cytokines modulating cell growth, proliferation, differentiation, recognition, apoptosis, inflammation, cellular homeostasis and angiogenesis. Altered expression of TGF-β and/or mutation in its signaling pathway has been linked to numerous diseased states, including cancer, inflammation and fibrosis. As these conditions are seen in Iranian veterans, we hypothesized that TGF-β signaling might play a pivotal role in SM-induced pathogenesis. Materials and Methods: Normal human fibroblasts were maintained in RPMI medium (37°C, 5% CO2). Near-confluent cultures were used for SM exposure. 50, 150, and 300 micromoles of SM, in fresh medium without serum, were added to cell cultures for different times (30, 60, 960 minutes). After RNA extraction and cDNA synthesis, expression of TGF-β variants was assayed using real time PCR. Expression of TGF-β variants was also evaluated in skin biopsies from Iranian veterans. Results: TGFβ1 and TGFβ2 were both over-expressed in skin biopsies. In exposed fibroblasts, TGF-β1 was initially (t = 30 minutes) down-regulated in a dose-dependent manner, but was over expressed at 16 hours post exposure. TGF-β2 was down-regulated at both time points, and TGFβ-3 was upregulated at 60 minutes post-exposure. Conclusion: Battlefield exposure to sulfur mustard results in early and late effects, especially on skin and lungs. As signaling pathways like IL6-8, VEGF, EGFR, TNF-α, and TGF-β have been indicated in skin and lung complications, determining the changes in the expression of TGF-β could have potential benefits in treatment of SM-exposed patients.