Background/Purpose:

Systemic Sclerosis (SSc) is characterized by severe fibroproliferative vasculopathy, exaggerated deposition of extracellular matrix molecules (ECM) in skin and multiple internal organs, and alterations of humoral, cellular and innate immunity. Vascular changes are responsible for the earliest SSc clinical manifestations; however the mechanisms responsible have not been elucidated.

The goal of this study was to analyze the gene expression differences between normal and SSc lung microvascular endothelial cells (EC) to improve the understanding of SSc vasculopathy pathophysiology.

Methods:

Pulmonary microvascular EC were isolated employing immunomagnetic procedures from lungs from patients with SSc undergoing lung transplantation. Control EC were isolated from autopsies of individuals who died from non-related pulmonary causes. Following isolation, microarrays were performed in EC from each group. Expression of genes with the highest differential expression was validated with RT-PCR, Western blots and confocal laser microscopy.

Results:

Interferon-stimulated genes (ISGs) including IFI44L, IFI44, IFI6, IFIH1, IFIT1, displayed the highest differential expression; being overexpressed in EC obtained from SSc donors. Others genes such as those encoding ECM production related proteins, genes associated with post-translational methylation and genes for numerous chemokines were also differentially overexpressed in SSc EC. Increased gene expression and increased protein levels of selected ISGs were confirmed by Western blots and confocal laser microscopy.

Conclusion:

Numerous ISGs are differentially overexpressed in SSc pulmonary microvascular EC in comparison with normal control EC. These results suggest that events leading to an interferon response in these cells may play a role in the pathogenesis of SSc lung vasculopathy.

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