The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis

doi:10.1016/j.cellsig.2019.109482

Cellular Signalling

Volume 66, February 2020, 109482

https://doi.org/10.1016/j.cellsig.2019.109482 Get rights and content

Highlights

•
Idiopathic pulmonary fibrosis is a progressive and devastating epithelial-driven disease of unknow etiology.
•
Common and rare variants affecting lung epithelium integrity and regeneration underlie initiation and progression of IPF.
•
Exaggerated hallmarks of aging, contribute to the aberrant behavior of lung epithelial cells.
•
Abnormally re-programmed epithelial cells induce the activation of fibroblasts, and the chaotic production of ECM.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and devastating interstitial lung disease of unknown etiology, where the normal lung architecture is lost and replaced by fibrotic tissue leading to an irreversible and progressive respiratory insufficiency. Historically, IPF was considered a chronic inflammatory disorder, which gradually progressed to established fibrosis. However, strong clinical and experimental evidence indicates that the disease represents an epithelial-driven disorder which results from a complex interplay of genetic and environmental risk factors, aging-associated processes and a profibrotic epigenetic reprogramming. The convergence of these factors results in the aberrant activation of epithelial cells that initiate the development of the disease, producing virtually all the mediators that participate in the migration, proliferation and activation of fibroblasts, their differentiation to myofibroblasts and the excessive and chaotic secretion of extracellular matrix proteins. Although progress has been made in understanding the causes and consequences of this abnormal behavior of distal airways and alveolar epithelium, the mechanisms that initiate and perpetuate the vicious circle of multidirectional abnormal communications between the epithelium and fibroblasts and other resident cells have not been elucidated. In this review, we discuss the role of epithelial cells and the mechanisms underlying the fibrotic response in IPF, and highlight some promising therapeutic targets for these cells.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually irreversible and lethal interstitial lung disease of unknown etiology. The disease has substantial impact on survival and IPF progression is associated with an estimated median survival time of 2–5 years following diagnosis [1].

IPF occurs worldwide although its prevalence and incidence remain unclear and with a large variability across studies. In general, the incidence fluctuates among 3 to 9 cases per 100,000 person-years and the prevalence between 20 and 40 cases per 100,000 person-years. Both, incidence and prevalence seem to be increasing, although it is unclear whether it represents a real increase or is the result of a growing clinical awareness for IPF [2].

IPF is more common in males than females and occur in older adults that usually have a median age of 60 years at the time of diagnosis. Actually, incidence and prevalence of IPF increases dramatically with age, and in patients >65 years, the estimated prevalence may be as high as 400 cases per 100,000 persons [3].

In this context, aging is considered a driven force for the development of IPF, and most of the cellular and molecular alterations described in aging cells are occurring, prematurely or exaggeratedly, in epithelial and mesenchymal lung cells from these patients [4].

The treatment of IPF is challenging, and numerous drugs have been studied in multiple clinical trials without success. Currently only two drugs, nintedanib and pirfenidone are accepted but they only reduce the rate of lung function decline, and new therapeutic options are needed [4]. Other interstitial lung diseases (inflammatory disorders in nature) may also have a progressive fibrosing phenotype, and share some pathogenic mechanisms with IPF including fibroblast activation and excessive ECM accumulation. These disorders are usually treated with anti-inflammatory and immunosuppressive drugs, and more recently the putative antifibrotic drugs indicated for IPF are also being explored [5]. In general, pharmacological approaches to IPF (and now to other progressive fibrotic lung disorders) have been focused on altered pathways of fibroblasts. However, IPF, by far the most aggressive fibrotic lung disorder, differs from the others by the leading pathogenic role of the lung epithelium.

Although IPF was originally thought to be an inflammation-driven disease, strong clinical and experimental evidence indicate that the disease represents an epithelial-driven disorder which results from a complex interplay of genetic and environmental risk factors, aging-associated processes and a profibrotic, partially stochastic, epigenetic reprogramming [1,[6], [7], [8]]. (Fig. 1).

Section snippets

Genetic architecture affecting epithelial function result in lung fibrosis

Genetic studies provided some of the most convincing evidences that alterations of the lung epithelium underlie disease initiation and progression in both sporadic and familial IPF. For example, the variant rs35705950 of the promoter of the gene encoding mucin 5B (MUC5B) is strongly associated with the risk to develop sporadic and familial IPF [9]. Epithelial cells expressing MUC5B are the dominant mucin-expressing cell type in microscopic honeycomb cysts indicating that in addition to the

Environmental factors, epigenetic and epithelial reprogramming

Environmental exposures, primarily from cigarette smoke, and others such as inhalation of wood and metal dusts, as well as microaspiration of gastroesophageal reflux have been identified as risk factors for IPF and may contribute to recurrent injury to the “genetically predisposed” lung epithelium [[27], [28], [29]]. Among others, these exposures may provoke epigenomic modifications, leading to altered regulation of key genes that may contribute to the phenotypic changes observed in the IPF

The hallmarks of aging and the aberrant behavior of lung epithelial cells

Few years ago, nine candidate cellular and molecular hallmarks were proposed as critical contributors to the aging process [36]. Several of them have been described as occurring prematurely or exaggeratedly in epithelial cells from IPF lungs.

Genomic instability

Cells are exposed to numerous DNA lesions per day, most of them efficiently repaired. However, the ability to preserve genetic stability usually declines with age leading to gradual accumulation of damaged DNA. If repair does not occur properly, genomic instability may have catastrophic consequences for age-related diseases.

Several studies have reported genomic instability in epithelial cells of IPF in the form of an increased incidence of microsatellite instability (MSI) and loss of

Telomere attrition

Telomeres shorten physiologically with age, but abnormally short telomeres recapitulate several premature aging phenotypes and are linked to disease susceptibility [40]. Telomere dysfunction is the result of shortening of telomeric DNA repeats which trigger a DNA damage response that induce either cellular senescence or apoptosis. In IPF, this abnormal process affects predominantly the alveolar epithelial cells and associates with fibrotic lesions in IPF lungs, likely limiting the regenerative

Cellular senescence

Cell senescence is a cell fate that involves essentially irreversible replicative arrest, apoptosis resistance, and the acquisition of a senescence-associated secretory phenotype (SASP), characterized by the release of a variety of inflammatory, growth-regulating and tissue-remodeling factors [43].

Growing body of evidence have demonstrated epithelial cell senescence in IPF lungs, and single-cell RNA sequencing of epithelial cells have revealed strong upregulation of p16 and p21, as well some

Mitochondrial dysfunction

Mitochondria play multiple important roles in cellular physiology including the production of ATP via oxidative phosphorylation and modulation of several signaling pathways through the release of ROS and calcium. As a consequence of its critical role, mitochondrial dysfunction is linked to aging deterioration and aging-associated diseases [55].

In this context, there is evidence that alveolar epithelial cells of IPF lungs exhibit an age-related mitochondrial dysfunction with altered structure

The protagonist role of epithelial cells in the pathogenesis of IPF

In IPF, lung epithelial cells undergo strong phenotypic and functional changes and this “reprogramming” shift their normal reparative response to injury, and constitutes the initial and crucial event of a progressive and multistep process that involves fibroblast activation, extracellular matrix remodeling and culminates in the end-stage fibrosis.

The source of these “aberrantly reprogrammed” epithelial cells, that finally result in abnormal re-epithelization and remodeling is uncertain, but can

IPF epithelial cells in the era of single-cell RNAseq

Single-cell RNA sequencing (scRNA-seq) has been recently used to capture and sequence the RNA contents of a single cell allowing a description of transcriptional heterogeneity in cell populations in the normal lung and associated biopathological processes involved in the pathogenesis of IPF.

This technological progress accompanying with computational methodologies has made more evident the complexity and diversity of the lung cellular populations in IPF, and specifically of epithelial cells [46,

Treatment of IPF focused on epithelial cells

Up to date, pharmacological approach to IPF has focused on fibroblasts but no attempt exists to stimulate or facilitate a correct re-epithelialization.

Stem/progenitor epithelial cells

Normally, in the face of damage, lung-resident stem cells are activated and subsequently proliferate and differentiate into different lineages to efficiently regenerate the injured lung [95]. Several subsets of lung epithelial cells located in distinct niches show self-renewal and differentiation capacity contributing to regeneration. These stem/progenitor epithelial cells include among others, basal cells, secretory or club cells, variant club cells, submucosal gland duct cells, AEC2s, and

Fibroblast growth factor (FGF) 10 and hepatocyte growth factor (HGF)

Fgf10 and its tyrosine kinase receptor Fgfr2b (fibroblast growth factor receptor 2b), are essential for distal lung development during branching morphogenesis and it has been shown that attenuates lung injury promoting lung epithelial regeneration after different injuries [102,103]. Thus, for example, loss of Fgf10-Fgfr2b signaling in bronchial epithelial cells impairs the generation of neobasal cells and alveolar epithelial cells, both type 1 and type 2, after bleomycin injury. By contrast,

Summary

Epithelial cells are critical components in the initiation and progression of IPF, leading to permanent scarring and organ malfunction and ultimately to premature death. The mechanisms affecting the lung epithelium are not yet entirely understood but are likely multifactorial. Thus, at least three factors should converge to change the epithelial behavior: 1) To be born with a set of common gene variants or a rare variant that affect epithelial cell integrity and regeneration capacity; 2) To

Author contributions

MS and AP conceived the idea, reviewed the literature, discuss the relevant aspects and wrote the manuscript.

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The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis

Highlights

Abstract

Introduction

Section snippets

Genetic architecture affecting epithelial function result in lung fibrosis

Environmental factors, epigenetic and epithelial reprogramming

The hallmarks of aging and the aberrant behavior of lung epithelial cells

Genomic instability

Telomere attrition

Cellular senescence

Mitochondrial dysfunction

The protagonist role of epithelial cells in the pathogenesis of IPF

IPF epithelial cells in the era of single-cell RNAseq

Treatment of IPF focused on epithelial cells

Stem/progenitor epithelial cells

Fibroblast growth factor (FGF) 10 and hepatocyte growth factor (HGF)

Summary

Author contributions

Lancet.

Lancet Respir. Med.

Lancet Respir. Med.

Lancet Respir. Med.

Lancet Respir. Med.

Chest

Chest

Lancet

Cell.

EBioMedicine.

J. Biol. Chem.

Int. J. Biochem. Cell Biol.

Am. J. Pathol.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

Am. J. Pathol.

J. Thromb. Haemost.

Cell.

Cell

Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline

Am. J. Respir. Crit. Care Med.

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Nat. Rev. Drug Discov.

Antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis

Eur. Respir. Rev.

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann. Intern. Med.

Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers

Proc. Am. Thorac. Soc.

Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. an integral model

Am. J. Respir. Crit. Care Med.

A common MUC5B promoter polymorphism and pulmonary fibrosis

N. Engl. J. Med.

Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice

Nat. Commun.

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Nat. Genet.

Resequencing study confirms that host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis

Am. J. Respir. Crit. Care Med.

Telomerase mutations in families with idiopathic pulmonary fibrosis

N. Engl. J. Med.

Adult-onset pulmonary fibrosis caused by mutations in telomerase

Proc. Natl. Acad. Sci. U. S. A.

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening

Nat. Genet.

Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema

Sci. Transl. Med.

Short telomeres are a risk factor for idiopathic pulmonary fibrosis

Proc. Natl. Acad. Sci. U. S. A.

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease

Am. J. Respir. Crit. Care Med.

Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred

Am. J. Respir. Crit. Care Med.

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

JCI Insight.

Expression of mutant Sftpc in murine alveolar epithelial drives spontaneous lung fibrosis

J. Clin. Invest.

Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis

Am. J. Respir. Crit. Care Med.

Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis

Am. J. Respir. Crit. Care Med.