Comprehensive gene expression profiling identifies distinct and overlapping transcriptional profiles in non-specific interstitial pneumonia and idiopathic pulmonary fibrosis

Matthew J Cecchini,Christopher J Howlett,Marco Mura,Karishma Hosein,Mariamma Joseph

doi:10.1186/s12931-018-0857-1

Abstract

BackgroundThe clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging. We sought to investigate the gene expression profiles of IPF and NSIP vs. normal controls.MethodsGene expression from explanted lungs of patients with IPF (n = 22), NSIP (n = 10) and from normal controls (n = 11) was assessed. Microarray analysis included Significance Analysis of Microarray (SAM), Ingenuity Pathway, Gene-Set Enrichment and unsupervised hierarchical clustering analyses. Immunohistochemistry and serology of proteins of interest were conducted.ResultsNSIP cases were significantly enriched for genes related to mechanisms of immune reaction, such as T-cell response and recruitment of leukocytes into the lung compartment. In IPF, in contrast, these involved senescence, epithelial-to-mesenchymal transition, myofibroblast differentiation and collagen deposition. Unlike the IPF group, NSIP cases exhibited a strikingly homogenous gene signature. Clustering analysis identified a subgroup of IPF patients with intermediate and ambiguous expression of SAM-selected genes, with the interesting upregulation of both NSIP-specific and senescence-related genes. Immunohistochemistry for p16, a senescence marker, on fibroblasts differentiated most IPF cases from NSIP. Serial serum levels of periostin, a senescence effector, predicted clinical progression in a cohort of patients with IPF.ConclusionsComprehensive gene expression profiling in explanted lungs identifies distinct transcriptional profiles and differentially expressed genes in IPF and NSIP, supporting the notion of NSIP as a standalone condition. Potential gene and protein markers to discriminate IPF from NSIP were identified, with a prominent role of senescence in IPF. The finding of a subgroup of IPF patients with transcriptional features of both NSIP and senescence raises the hypothesis that “senescent” NSIP may represent a risk factor to develop superimposed IPF.

Highlights

The clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging
Better prognosis and response to therapy are reported for NSIP compared to IPF, which is defined by a histologic pattern of usual interstitial pneumonia (UIP) [2]
We examined the expression of disease-specific genes in the intermediate group, and found that Insulin growth factor binding protein-5 (IGFBP-5) level was similar to that of the “pure” IPF cluster, while in contrast, the expression of Mucin-5B was reduced to the same level observed in NSIP cases

Summary

Introduction

The clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging. Better prognosis and response to therapy are reported for NSIP compared to IPF, which is defined by a histologic pattern of usual interstitial pneumonia (UIP) [2]. Both conditions represent a common indication for lung transplantation (LTx) [3]. Patients with NSIP will often have a good response to corticosteroids, while IPF can worsen on prednisone [6], and is currently treated with anti-fibrotic agents [7, 8] This differential response to treatment further highlights the dissimilarities in the molecular basis that defines IPF and NSIP. The frequent finding of mixed UIP-NSIP patterns on lung biopsies [9] supported the hypothesis that NSIP may represent an early form of IPF [10]

Methods

Results

Discussion

Conclusion