Session Type: Abstract Submissions (ACR)
Background/Purpose: Pulmonary arterial hypertension (PAH) and pulmonary fibrosis (PF) are the two major lung complications associated with the autoimmune disease systemic sclerosis (SSc), and constitute the leading causes of mortality and morbidity in patients with SSc. Endothelial dysfunction and inflammation have both been described in these two diseases. We hypothesize that disturbed transcriptional control of endothelial cell function can induce inflammation in the lung, which in turn drives the initiation and progression of PAH and PF in SSc. Deficiency of the ETS family transcription factor FLI1 has been implicated in scleroderma vasculopathy, while its closest homolog, ERG, has been demonstrated to suppress inflammatory gene expression in endothelial cells. The purpose of this study is to determine whether ERG and FLI1 deficiency plays a pathogenic role in SSc-associated lung manifestations.
Methods: Paraffin sections of lung samples from patients with SSc were subjected to immunohistochemical staining for ERG and FLI1. ERG and FLI1 were inhibited in human pulmonary arterial endothelial cells (HPAEC) with siRNA, and gene expression changes were analyzed by microarray and then validated with quantitative RT-PCR. Erg and Fli1 double heterozygote mice were generated and lung samples from these mice were analyzed.
Results: ERG protein level was significantly reduced in the endothelium of lung samples from patients with SSc, while FLI1 was similarly reduced but to a lesser extent, suggesting that the loss of ERG and FLI1 is associated with the vascular changes occurring in the lung of patients with SSc. In HPAECs treated with ERG and FLI1 siRNA, a number of inflammatory genes, including CXCL10, IL8, IRF1, GBP1, IFIT2, VCAM1, were upregulated, whereas genes regulating endothelial homeostasis and cell-cell adhesion, such as APLN, FABP4, PECAM1 and VECADHERIN, were downregulated. Simultaneous knockdown of both ERG and FLI1 had a synergistic effect on the expression of these genes, suggesting that ERG and FLI1 co-regulate at least a subset of their target genes. Consistent with the upregulation of inflammatory genes seen in vitro with ERG and FLI1 knockdown, Erg and Fli1 double heterozygote mice show increased lymphocyte infiltration in the lung.
Conclusion: Loss of ERG and FLI1 might contribute to the pathogenesis of SSc-associated lung complications through the induction of inflammation in the tissue.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/erg-and-fli1-in-systemic-sclerosis-associated-pulmonary-complications/