Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases

Abstract

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Pulmonary hypertension in the setting of interstitial lung disease: Approach to management and treatment. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension

“…There is a rationale for the use of these agents over and above their role as vasodilators. Specifically, preclinical information indicated that endothelin‐1 (ET‐1) is both profibrotic and a mitogen 85 . ERAs were an obvious choice as treatments of PH‐ILD, to tackle both components 86 .…”

“…Specifically, preclinical information indicated that endothelin‐1 (ET‐1) is both profibrotic and a mitogen. 85 ERAs were an obvious choice as treatments of PH‐ILD, to tackle both components. 86 In the BUILD‐1 study of IPF, bosentan did not significantly improve 6MWD over placebo.…”

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

“… 186–188 Endothelin-1 stimulates fibroblasts to convert to activated myofibroblasts with increased ECM secretion, intimal hyperplasia, luminal narrowing, reduced capillary blood flow vessel obliteration, and ischemia. 189 Local secretion of von Willebrand factor causes platelet aggregation, hypercoagulability, and fibrin deposition leading to terminal vascular damage. 186–188 Myofibroblasts are also created by the endothelial-to-mesenchymal transition.…”

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers

“…Markers of pulmonary vasculopathy, such as vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), and asymmetric dimethylarginine (ADMA), have been reported as useful biomarkers of ILD in RA patients and can help in the differential diagnosis of RA-ILD from IPF [ 108 ]. Other reported biomarkers include endothelin-1 [ 109 ], interleukin 13, 18 [ 107 ], 36a and 36γ [ 110 ], and HE4 [ 111 ]. It appears that patients with RA-ILD have short telomeres compared to other CTD-ILDs, and they have worse outcomes in terms of survival and lung function than the other CTD-ILDs, suggesting that telomere length plays an important prognostic role in this disease [ 112 ].…”