Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension

Abstract

Objective. Pulmonary complications, including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality in patients with systemic sclerosis (SSc). The aim of this study was to compare the molecular fingerprint of lung tissue and matching primary fibroblasts from patients with SSc with that of lung tissue and fibroblasts from normal donors, patients with idiopathic pulmonary fibrosis (IPF), and patients with idiopathic pulmonary arterial hypertension (IPAH).Methods. Lung tissue samples were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, and patients with IPAH. Microarray data were analyzed using efficiency analysis for determination of the optimal data-processing methods. Real-time polymerase chain reaction and immunohistochemistry were used to confirm differential levels of messenger RNA and protein, respectively.Results. Consensus efficiency analysis identified 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. SSc-PF and IPF lungs shared enriched functional groups in genes implicated in fibrosis, insulin-like growth factor signaling, and caveolin-mediated endocytosis. Gene functional groups shared by SSc-PAH and IPAH lungs included those involved in antigen presentation, chemokine activity, and interleukin-17 signaling.Conclusion. Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts from patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease specific (SSc) and phenotype specific (PF versus PAH). These signatures provide new insights into the pathogenesis and potential therapeutic targets of SScrelated lung disease.

A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis

“…Recent genomic studies using surgical biopsies from patients with IPF support these findings, and have, in addition, demonstrated pathological gene expression changes in processes such as coagulation, angiogenesis, inflammation, apoptosis, and regeneration (11)(12)(13)(14)(15). These studies revealed a number of possible pathological pathways, and helped to identify candidate biomarkers that could be used for early diagnosis, prognosis, and disease progression monitoring (16)(17)(18)(19)(20).…”

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…Such unbiased approaches to gene expression analysis in PAH have been performed on peripheral blood mononuclear cells (12), whole lung tissue (13), and microdissected vessels (14). A recent study investigated proteomic changes in blood outgrowth ECs from four control subjects and four heritable patients with PAH (15) and another compared metabolomic and transcriptomic changes in PAECs engineered with a BMPR2 mutation (16), but no studies to date have specifically addressed changes in gene expression and the functional significance of those features in PAECs derived from patients with IPAH versus those from control lungs.…”

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

“…Additionally, we and others have identified gene expression patterns that distinguish IPF from hypersensitivity pneumonitis, variants of disease that characterize distinct patterns of progression and characterize patients with pulmonary hypertension (9,(13)(14)(15)(16). A common limitation to all of these studies was the starting material used for analysis, since the IPF lung is known for its variable involvement and temporal heterogeneity (1).…”