Last updated on January 2014

A proposal to search for evidence of active platelet-derived TGF-ß1 and its impact on leukocytes in Systemic Sclerosis

Brief description of study

A proposal to search for evidence of active platelet-derived TGF-ß1 and its impact on leukocytes in Systemic Sclerosis

Detailed Study Description

Systemic Sclerosis (SSc) is a devastating and often life threatening illness predominantly affecting women characterized by autoimmunity, widespread microvascular disease, and fibrosis, especially of the skin, gastrointestinal tract, and lung. Multiple studies have shown evidence of platelet activation in SSc. Chronic intermittent vasospasm in the microvasculature combined with platelet aggregation and activation may foster an environment in which TGF-ß1 is released and activated. Our laboratory has shown that latent TGF-ß1, a complex composed of mature TGF- ß1 dimer noncovalently attached to latency associated peptide (LAP) dimer, which in turn is disulfide-bonded to latent TGF-ß1 binding protein-1 (LTBP-1), is activated in vitro by shear by a mechanism that includes thiol-disulfide exchange. Latent TGF-ß1 is released from most cells and tissues as large latent complexes (LLCs) comprised of LTBP-1, LAP, and TGF-ß1. Platelets are the largest source of TGF-ß1 in normal blood. Since high shear can both induce platelet activation, with release of granule contents, and activate TGF-ß1 in vitro, we hypothesize that high shear in the stenotic and compromised microvasculature of SSc patients results in platelet release of latent TGF-ß1 as well as other profibrotic, vasoconstrictive, and proinflammatory mediators. The released latent TGF-ß1 may then undergo activation, at least in part, by intravascular shear force. In addition, the other released platelet mediators may abet the vascular leak seen in SSc and allow extravasation of leukocytes and egress of both active and latent TGF-ß1 into the skin and other affected tissues, where the latter can be stored and/or activated in the extracellular matrix. TGF-ß1 signaling is known to induce other cells to produce TGF-ß1 in a feed-forward manner.

We hypothesize that if targeted early, anti-platelet agents may help diminish inflammation and forestall the pro-fibrotic program in SSc that leads to end-stage organ damage.

Clinical Study Identifier: TX137544

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Recruitment Status: Open

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