Abstract
BackgroundSystemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGFβ activation is implicated in the pathogenesis of SSc. Aberrant TGFβ/Smad signaling can be controlled by stabilization of microtubules with paclitaxel.Methods and FindingsSSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGFβ signaling, fibrosis, and neovessel formation were evaluated by quantitative RT-PCR and immunohistochemical staining. Paclitaxel markedly suppressed Smad2 and Smad3 phosphorylation and collagen deposition in SSc grafts. As a result, the autonomous maintenance/reconstitution of the SSc phenotype was prevented. Remarkably, SSc grafts showed a 2-fold increase in neovessel formation relative to normal grafts, regardless of paclitaxel treatment. Angiogenesis in SSc grafts was associated with a substantial increase in mouse PECAM-1 expression, indicating the mouse origin of the neovascular cells.ConclusionLow-dose paclitaxel can significantly suppress TGFβ/Smad activity and lessen fibrosis in SCID mice. Transplantation of SSc skin into SCID mice elicits a strong angiogenesis—an effect not affected by paclitaxel. Although prolonged chemotherapy with paclitaxel at higher doses is associated with pro-fibrotic and anti-angiogenic changes, the findings described here indicate that low-dose paclitaxel may have therapeutic benefits for SSc via modulating TGFβ signaling.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive deposition of extracellular matrix (ECM) proteins and obliterative vascular lesions in the skin and internal organs [1]
Transplantation of SSc skin into severe combined immunodeficient (SCID) mice elicits a strong angiogenesis—an effect not affected by paclitaxel
Prolonged chemotherapy with paclitaxel at higher doses is associated with pro-fibrotic and anti-angiogenic changes, the findings described here indicate that low-dose paclitaxel may have therapeutic benefits for SSc via modulating TGFb signaling
Summary
Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive deposition of extracellular matrix (ECM) proteins and obliterative vascular lesions in the skin and internal organs [1]. Several of these antifibrotic agents have been tested in clinical trials [4] These include D-penicillamine, colchicine, interferon gamma, and relaxin. Systemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Systemic sclerosis or scleroderma (SSc) is the name for a group of progressive diseases, all of which involve the abnormal growth of connective tissue. SSc is triggered when the body’s immune system turns against the body, causing abnormal production of collagen that can be limited to the skin or extend to the blood vessels and internal organs. Previous work has shown that microtubules can be affected by drugs, such as the one in this study, paclitaxel, which stabilizes the microtubules
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