Reviews and prospectives of signaling pathway analysis in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing disease with disappointing survival rate, and uneffective therapeutic progress has been made in the last few years, forcing the urgent need to improve research to this disease. The commonly accepted pathogenic hypothesis of IPF is the trigger from continuous alveolar epithelium microinjuries and in the following series events, many signaling pathways were reported to lead to abnormal tissue repair and lung structure derangement in IPF, such as TGF-β, wnt, VEGF and PI3K–Akt signaling pathways. Traditional research of IPF related signaling pathway always focus on the independent function of pathway and disease signals, but the crosstalks and interactions among them were rarely valued. In this review, we summarize the signaling pathways which were reported to play important roles in the pathologic changes of IPF and the synergistic effect among those pathways. Next we discuss the application of genomics research and bioinformatics tools on IPF related pathway analysis, and give a systems biology perspective by integrating multi-level disease related data. The novel prospective of pathway analysis could tease out the complex pathway interaction profiles of IPF, and is powerful to detect IPF related biomarkers for early diagnose and potential therapeutic targets.

Introduction

IPF is one of the most pernicious and enigmatic form of lung fibrogenesis, the average survival time is about two to three years after diagnosis in affected patients [1]. Although some autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis), genetic variants (e.g. MUC5B, VEGFA and TGF-b) and environment factors (e.g. viral infection, aging) have been reported to be risk factors of IPF, but the pathogenesis of this disorder is not fully understood [2].

Previous studies reported that IPF was characterized by continuous alveolar epithelium microinjuries and hyperplasia [3]. Injured epithelium could release growth factors, cytokines and matrix metalloproteinase, which caused the activation/proliferation of mesenchymal cell, deposition of extracellular matrix and the accumulation of fibroblasts. Next it may lead to basal membrane disruption, fibrin formation, abnormal wound repair and angiogenesis [4].

During those processes, several signaling pathways were activated to transmit important regulation signals to cell apoptosis, survival, migration or communication (see Table 1), such as transforming growth factor-beta (TGF-β) [5], wnt [6], vascular endothelial growth factor (VEGF) [7] and phosphoinositide 3-kinase (PI3K–Akt) [8], [9]. Therefore, many attentions had focused on the functions of disease related signaling pathways in IPF pathological research [9], [10]. Here, we summarized the signaling pathways which were reported to be key players in the pathogenesis of fibrosis, including the activation, hyperplasia and accumulation of myofibroblasts, and discussed the potential utility of signal molecules as future treatment targets in IPF.

However, along with the development of experiment technology and especially the implementation of many whole genome sequencing project, the number of disease related genomic data is rapidly increasing [11], [12], [13]. From the aspect of pathway research, the number of disease related signals is generating and the function of disease related signaling pathways is being comprehensive [14]. Whereas traditional pathway analysis has worked on the independent pathogenetic principles of signaling pathway and the independent function of related signal molecules, the crosstalk and interaction between pathways were rarely analyzed [15]. In this review, we discuss the novel integrative analysis prospective from systematic biological approach. In order to better clarify the associations between different signal molecules, and to comprehensively tease out the functional pathway profiles involved in the development and progression of IPF, the integrative analysis of genomic data is powerful and imperative. In the mean time, the comprehensive mapping of the signaling pathways in IPF would be powerful to detect novel early diagnosis marker and therapeutic targets, and give new research perspective on IPF research.