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.
SeriesNew cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis
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
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