Markers of Inflammation and Fibrosis in the Orbital Fat/Connective Tissue of Patients with Graves’ Orbitopathy: Clinical Implications

Abstract

Purpose. To assess FGF-β, TGF-β, and COX2 expression and immunocompetent cells in the orbital tissue of patients with severe and mild Graves' orbitopathy. Patients and Methods. Orbital tissue was taken from 27 patients with GO: (1) severe GO (n = 18), the mean clinical activity score (CAS) being 8.5 (SD 2.5); and (2) mild GO (n = 9), the mean CAS being 2.2 (SD 0.8), and from 10 individuals undergoing blepharoplasty. The expression of CD4+, CD8+, CD20+, and CD68 and FGF-β, TGF-β, and COX2 in the orbital tissue was evaluated by immunohistochemical methods. Results. We demonstrated predominant CD4+ T cells in severe GO. CD68 expression was observed in the fibrous connective area of mild GO and was robust in severe GO, while the prominent TGF-β expression was seen in all GO. Increased FGF-β expression was observed in the fibroblasts and adipocytes of severe GO. No expression of COX2 was found in patients with GO. Conclusions. Macrophages and CD4 T lymphocytes are both engaged in the active/severe and long stage of inflammation in the orbital tissue. FGF-β and TGF-β expression may contribute to tissue remodeling, fibrosis, and perpetuation of inflammation in the orbital tissue of GO especially in severe GO.

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

“…TGF-β is known to transcriptionally regulate cell growth, motility, matrix remodeling, and pericellular proteolytic activity (Samarakoon et al 2013); TGF-β is also known to stimulate PAI-1 transcription and to up-regulate the expressions of certain genes that encode elements of the ECM, such as fibronectin, collagen I, and proteoglycans in non-orbital tissues (Matrisian & Hogan 1990, Wight & Potter-Perigo 2011. Furthermore, TGF-β has been shown to be present in the orbits of GO patients (Pawlowski et al 2014). Indeed, we found that TGF-β was a potent stimulator of PAI-1 synthesis at all densities in OFs, resulting in up to a fivefold PAI-1 increase above baseline at high cell densities (Fig.…”

“…The expression of PAI-1 is regulated by various cytokines and growth factors including transforming growth factor β (TGF-β) (Ghosh & Vaughan 2012). Strong TGF-β expression has been found in the orbital tissue of patients with mild and severe GO, which correlated positively with the clinical activity score (CAS) (Pawlowski et al 2014). It has been demonstrated that OFs synthesize PAI-1, and that PAI-1 expression is up-regulated by TGF-β, interferon-γ (IFN-γ), and leukoregulin (Smith et al 1992, Cao et al 1995; however, the role of PAI-1 in the pathogenesis of GO is still unclear.…”

Morphofunctional characteristics and immunological regulation of the orbital fibroblasts function in endocrine ophthalmopathy

“…Значительное повышение уровня IL-17 приводит к развитию фиброза мягких ретробульбарных тканей у пациентов с ЭОП, ввиду того, что данный цитокин напрямую усиливает экспрессию αгладкомышечного актина (α-SMA) и продукцию компонентов межклеточного матрикса [52]. Также IL-17 через усиление продукции ТGF-β, индуцируется фиброгенез мягких ретробульбарных тканей вследствие стимулирования дифференцировки орбитальных фибробластов CD90+ в миофибробласты и избыточной секреции компонентов межклеточного матрикса [50,54]. Более того, IL-17 усиливает восприимчивость CD90+ к действию ТGF-β [55].…”

Favorable Effect of Bromocriptine and Pentoxifylline in Mild Graves Disease Orbitopathy: A Randomized, Open, Clinical Trial

“…Copyright: © 2016 Houldsworth, et al 31]. In addition, angiogenesis could also play a role in the pathogenesis of GO [32,33].…”