Elsevier

The Lancet

Volume 380, Issue 9842, 18–24 August 2012, Pages 680-688
The Lancet

Series
New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis

https://doi.org/10.1016/S0140-6736(12)61144-1Get rights and content

Summary

Idiopathic pulmonary fibrosis is a serious and progressive chronic lung disease that is characterised by altered cellular composition and homoeostasis in the peripheral lung, leading to excessive accumulation of extracellular matrix and, ultimately, loss of lung function. It is the interstitial pneumonia with the worst prognosis—mortality 3–5 years after diagnosis is 50%. During the past decade, researchers have described several novel cellular and molecular mechanisms and signalling pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis, resulting in the identification of new therapeutic targets. These advances will hopefully result in increased survival rates and improved quality of life for patients with this disorder in future.

Introduction

Idiopathic pulmonary fibrosis is the interstitial pneumonia with the worst prognosis1—mortality 3–5 years after diagnosis is 50%.2 Although genetic determinants, environmental exposures, and common insults, such as smoking,3 pollutants, gastro-oesophageal reflux,4, 5 occupational exposures,6 viral infections,7 and ageing8 have been identified as risk factors for this disorder, its origin and onset are not fully understood. Onset is thought to involve perpetuated microinjuries to the alveolar epithelium, leading to dysregulation of cellular homoeostasis in the alveolar epithelial–mesenchymal unit, reactivation of developmental signalling pathways (eg, TGFβ [transforming growth factor β],9 Wnt,10 SHH [sonic hedgehog],11 Notch12), induction of cell dysfunction and death, formation of scar tissue, and, consequently, distortion of lung homoeostasis and lung structures.

Whereas much attention has focused on the general pathogenetic principles in idiopathic pulmonary fibrosis,13, 14, 15 we discuss novel concepts of distorted cellular homoeostasis and plasticity. We focus on newly described signalling pathways that are related to initiation, mediation, or perpetuation of lung fibrosis, drawing attention to those developments with potential to translate into clinical settings.

Section snippets

Pathognomonic hallmarks

Diagnostic criteria for idiopathic pulmonary fibrosis have changed several times during the past decade, and the definition of this disorder has been refined.2, 16 Although an open lung biopsy sample with a usual interstitial pneumonia pattern is the most convincing evidence of the altered structures in idiopathic pulmonary fibrosis, for many patients diagnosis of this disorder can nowadays be accurately made by clinicians and radiologists during multidisciplinary discussions. These newly

Cellular plasticity in pathogenesis

The lung contains more than 40 different cell types, yet most of the increased extracellular matrix that is deposited in idiopathic pulmonary fibrosis is ascribed to activated myofibroblasts in fibroblast foci. These lesions do not arise in healthy lungs, yet are frequently identified in idiopathic pulmonary fibrosis biopsy samples and their number correlates with survival.22, 23 Potential sources for activated myofibroblasts include alveolar epithelial cells or mesothelial cells (via

Reactivation of developmental programmes

Whereas some of the recently discovered pathways act in a very cell-specific fashion, others exert pleiotropic effects on several cell types during the pathogenesis of idiopathic pulmonary fibrosis. In this context, aberrant reactivation of developmental signalling pathways has been identified as a key mechanism. These pathways include, among others, Wnt, SHH, Notch, and BMP (bone morphogenic protein) signalling, and they determine cell-cell communication, survival, and stem-cell

Soluble mediators of fibrotic injury

Serotonin transporters have been identified as a novel signalling pathway that controls fibroblast activation. Increased expression of HTR1A, HTR1B, HTR2A, and HTR2B was detected in patients with idiopathic pulmonary fibrosis or non-specific interstitial pneumonia, with HTR2A expression being specific for idiopathic pulmonary fibrosis. Lung fibroblasts abundantly express HTR2A, whereas epithelial cells largely express HTR2B. Treatment with HTR2A and HTR2B inhibitors in bleomycin-injured mice

microRNAs

Although several genetic, epigenetic, and proteomic studies have been done so far, studies investigating micro RNA (miRNA) regulatory networks in idiopathic pulmonary fibrosis have only recently gained much attention. miRNAs are small non-coding RNAs that specifically repress or induce the expression of a set of related target genes. Emerging evidence shows that miRNAs are fibrotic modulators in several organs, including the lung.80, 81, 82 Rather than working via one pathway, miRNA networks

Autophagy

Autophagy is a newly recognised regulatory mechanism of cellular homoeostasis and survival in lung diseases.85 It is a highly conserved catalytic pathway controlling protein and organelle transport and degradation via lysosomes in health and disease.86 Noxious environmental stimuli, such as pathogens, cigarette smoke, allergens, reactive oxygen species, or hyperoxia activate autophagic processes as an initial defence mechanism and in homoeostatic regulation of the lung microenvironment.

Future perspectives

The past two decades have seen an unprecedented expansion of our understanding of the cellular origins of activated myofibroblasts, soluble mediators of lung injury, and novel regulatory mechanisms of idiopathic pulmonary fibrosis. Currently, interest in the research community is focused on endogeneous and exogeneous repair mechanisms of distorted lung architecture and novel approaches for lung regeneration. The studies we have discussed, and stem-cell approaches that have not been included in

Search strategy and selection criteria

We searched PubMed and ClinicalTrials.gov with the terms “idiopathic pulmonary fibrosis”, “lung fibrosis”, “epithelial injury fibrosis”, “fibroblast fibrosis”, “pericytes fibrosis”, and “mesothelium fibrosis”. We mainly selected work published after January, 2007, although older articles that we deemed very relevant to this topic were included. The search was restricted to reports published in English and the last search was done in June, 2012.

References (96)

  • BD Humphreys et al.

    Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis

    Am J Pathol

    (2010)
  • SL Fabian et al.

    Hedgehog-Gli pathway activation during kidney fibrosis

    Am J Pathol

    (2012)
  • P Patel et al.

    Platelet derived growth factor B and epithelial mesenchymal transition of peritoneal mesothelial cells

    Matrix Biol

    (2010)
  • T Liu et al.

    FIZZ1 stimulation of myofibroblast differentiation

    Am J Pathol

    (2004)
  • T Liu et al.

    Notch1 signaling in FIZZ1 induction of myofibroblast differentiation

    Am J Pathol

    (2009)
  • KR Levental et al.

    Matrix crosslinking forces tumor progression by enhancing integrin signaling

    Cell

    (2009)
  • HM Rodriguez et al.

    Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor

    J Biol Chem

    (2010)
  • S Yang et al.

    Participation of miR-200 in pulmonary fibrosis

    Am J Pathol

    (2012)
  • HZ Yang et al.

    TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury

    Am J Pathol

    (2012)
  • JR Rock et al.

    Notch-dependent differentiation of adult airway basal stem cells

    Cell Stem Cell

    (2011)
  • O Eickelberg et al.

    Update in diffuse parenchymal lung disease 2009

    Am J Respir Crit Care Med

    (2010)
  • G Raghu et al.

    An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management

    Am J Respir Crit Care Med

    (2011)
  • CK Oh et al.

    Smoking and idiopathic pulmonary fibrosis

    Pulm Med

    (2012)
  • G Raghu et al.

    High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis

    Eur Respir J

    (2006)
  • JS Lee et al.

    Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2011)
  • VS Taskar et al.

    Is idiopathic pulmonary fibrosis an environmental disease?

    Proc Am Thorac Soc

    (2006)
  • I Lasithiotaki et al.

    Detection of herpes simplex virus type-1 in patients with fibrotic lung diseases

    PLoS One

    (2011)
  • R Faner et al.

    Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2012)
  • TA Wynn

    Integrating mechanisms of pulmonary fibrosis

    J Exp Med

    (2011)
  • M Konigshoff et al.

    WNT signaling in lung disease: a failure or a regeneration signal?

    Am J Respir Cell Mol Biol

    (2010)
  • LM Crosby et al.

    Epithelial repair mechanisms in the lung

    Am J Physiol Lung Cell Mol Physiol

    (2010)
  • K Aoyagi-Ikeda et al.

    Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-β-Smad3 pathway

    Am J Respir Cell Mol Biol

    (2011)
  • WR Coward et al.

    The pathogenesis of idiopathic pulmonary fibrosis

    Ther Adv Respir Dis

    (2010)
  • American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001

    Am J Respir Crit Care Med

    (2002)
  • DW Visscher et al.

    Histologic spectrum of idiopathic interstitial pneumonias

    Proc Am Thorac Soc

    (2006)
  • S Misumi et al.

    Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression

    Proc Am Thorac Soc

    (2006)
  • BB Moore et al.

    Murine models of pulmonary fibrosis

    Am J Physiol Lung Cell Mol Physiol

    (2008)
  • CD Cool et al.

    Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum

    Am J Respir Crit Care Med

    (2006)
  • KR Flaherty et al.

    Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease

    Am J Respir Crit Care Med

    (2003)
  • TR Martin et al.

    Apoptosis and epithelial injury in the lungs

    Proc Am Thorac Soc

    (2005)
  • KK Kim et al.

    Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix

    Proc Natl Acad Sci USA

    (2006)
  • A Jayachandran et al.

    SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis

    Thorax

    (2009)
  • V Pozharskaya et al.

    Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis

    PLoS One

    (2009)
  • H Tanjore et al.

    Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis

    Am J Respir Crit Care Med

    (2009)
  • HA Chapman et al.

    Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice

    J Clin Invest

    (2011)
  • JR Rock et al.

    Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition

    Proc Natl Acad Sci USA

    (2011)
  • M Konigshoff et al.

    WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

    J Clin Invest

    (2009)
  • J Milara et al.

    Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition

    Thorax

    (2012)
  • Cited by (356)

    View all citing articles on Scopus
    View full text