Background Epidermal growth factor (EGF) acts prominent roles on the proliferation and differentiation of cells. In vitro EGF applications are reported to induce the expression of TGF-b receptor type II (TGFbRII) by human dermal fibroblasts. Increased expression of EGF by scleroderma dermal fibroblasts has also shown. Lapatinib is an orally administered small-molecule tyrosine kinase inhibitor targeting EGF receptors (EGFR) and Her2/Neu, and it is widely used in the treatment of breast cancer.
Objectives The aim of the present study was to research potential prophylactic and therapeutic effects of lapatinib on the bleomycin (BLM)-induced experimental scleroderma model.
Methods 60 Balb/c female mice were included in the study. They were divided 6 groups as prophylactic-early (group I [control I], group II [sham I] and group III [lapatinib I]) and therapeutic-late (group IV [control II], group V [sham II] and group VI [lapatinib II]) groups. Phosphate buffered saline (PBS) was injected subcutaneously and daily to shaved upper back skin in the control groups (groups I and IV). Daily subcutaneous BLM (100 mg BLM dissolved in 100 ml PBS for each mouse) was injected to shaved upper back skin for three weeks in the groups II and III, and for 6 weeks in the groups V and VI. The groups II and V were placebo (sham) groups. In addition to BLM, lapatinib (30 mg/kg two times in a day) was applied orally, for first three weeks in the group III (prophylactic lapatinib), and second three weeks in the group VI (therapeutic lapatinib)
Mice in the groups I, II and III (prophylactic application groups) were sacrificed at the end of third week, while groups IV, V and VI (therapeutic application groups) mice were sacrificed at the end of 6th week. Skin tissue samples were harvested for histological and real-time PCR (RT-PCR) analysis. Tissue mRNA expressions of TGF-β1 and fibronectin-1 were evaluated by RT-PCR.
Results Repeated BLM applications increased dermal inflammatory cell counts (Figure 1A), dermal thickness (Figure 1B) and led to dermal fibrosis at both third and 6th weeks. Moreover, mRNA expressions of TGF-β1 and fibronectin-1 were higher in the BLM-injected sham groups compared to their controls (p<0.05 for all). TGF-β1 and fibronectin-1 mRNA expressions were increased 40 and 6 –folds, respectively in the sham I group (in which BLM applied three weeks), while their expressions were increased 690 and 280 –folds, respectively in the sham II group (in which BLM applied 6 weeks). On the other hand, TGF-β1 and fibronectin-1 mRNA expressions were significantly decreased in both prophylactic and therapeutic lapatinib groups compared to the own sham groups (p<0.05 for all). Similarly, in both prophylactic and therapeutic applications of lapatinib decreased dermal inflammatory infiltrations and dermal thickness (Figure 1).
Conclusions The present study documents that lapatinib has anti-fibrotic actions on experimentally induced dermal fibrosis. It can be suggested that EGFR and lapatinib are candidate to research in the pathogenesis and treatment of scleroderma, respectively.
Disclosure of Interest None declared
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