Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis. Although the median survival is 3 years, the clinical course varies to a large extent among IPF patients. To date, there has been no definitive prognostic marker. Extracellular vesicles (EVs) are known to hold nucleic acid, including microRNAs, and to regulate gene expression in the recipient cells. Moreover, EVs have been shown to express distinct surface proteins or enveloped microRNAs depending on the parent cell or pathological condition. We aimed to identify serum EV microRNAs that would be prognostic for IPF.MethodsTo determine target microRNAs in IPF, we measured serum EV microRNA expression profiles using microRNA PCR arrays in a bleomycin mouse model and validated the microRNAs in additional mice using RT-PCR. Secondly, we enrolled 41 IPF patients and conducted a 30-month prospective cohort study. Expression of serum EV miR-21-5p was normalized by dividing by the EV amount. The relative amount of EVs was measured using the ExoScreen method. We calculated the correlations between baseline serum EV miR-21-5p expression and other clinical variables. Furthermore, we determined if serum EV miR-21-5p can predict mortality during 30 months using the Cox hazard model. According to the median level, we divided the IPF patients into two groups. Then we compared the survival rate during 30 months between the two groups using the Kaplan-Meier method.ResultsSerum EV miR-21-5p was elevated in both the acute inflammatory phase (day 7) and the chronic fibrotic phase (day 28) in the mouse model. In the clinical setting, serum EV miR-21-5p was significantly higher in IPF patients than in healthy control subjects. The baseline serum EV miR-21-5p was correlated with the rate of decline in vital capacity over 6 months. Furthermore, serum EV miR-21-5p was independently associated with mortality during the following 30 months, even after adjustment for other variables. In the survival analysis, IPF patients whose baseline serum EV miR-21-5p was high had a significantly poorer prognosis over 30 months.ConclusionsOur results suggest that serum EV miR-21-5p has potential as a prognostic biomarker for IPF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0427-3) contains supplementary material, which is available to authorized users.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis
We examined the levels of serum Extracellular vesicle (EV) microRNAs in a mouse model of lung fibrosis via quantitative PCR array, which revealed that miR-21-5p was significantly increased in serum EVs of the mouse model
MicroRNA expression profiling revealed an increase in certain microRNAs, including miR-21-5p, in the serum EVs during experimental lung fibrosis in mice To identify the serum EV microRNAs that could serve as biomarkers for fibrotic lung diseases, we first utilized a mouse bleomycin-induced lung fibrosis model to investigate the differences in the expression of serum EV microRNAs compared to controls
Summary
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis. We aimed to identify serum EV microRNAs that would be prognostic for IPF. Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease for which no treatment is capable of providing a complete cure [1,2,3]. The median survival for IPF patients from the time of diagnosis is approximately 3 years [3]. New therapeutic targets for IPF have been identified, and some of the proposed therapies are expected to slow its progression [2]. IPF patients differ in terms of the disease progression rate and prognosis, complicating the prediction of survival. MicroRNAs have been shown to affect physiological and pathological conditions, including lung disease [5]. MicroRNAs have received considerable attention as potential therapeutic targets in IPF, as well
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