Mechanistic links between aging and lung fibrosis

Our understanding of the biology of aging has advanced significantly in recent years. This has resulted in the recent formulation of the “hallmarks of aging” that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that results from the accumulation of scar tissue in the lungs of affected individuals. IPF is a disease of aging that most commonly affects human subjects older than 60 years of age. While progress has been made in elucidating key pathological processes in IPF, the relationship of these processes to those that occur during aging are not well defined. In this review, we explore existing and emerging paradigms in the pathogenesis of IPF in light of the recently defined hallmarks of aging.     

Commonalities between the pro-fibrotic mechanisms in COPD and IPF

COPD and IPF are two chronic lung diseases which are characterized by a decline in lung function, resulting in significant morbidity and mortality. Both of these diseases are more commonly associated with an aging population and the duration for which the disease has been underlying is often unknown. Significant matrix deposition occurs, resulting in either non-reversible airways obstruction in the case of COPD and impaired gas exchange and parenchymal consolidation in IPF. There are no approved therapies that have been demonstrated to target these underlying fibrotic changes in the lung. This may in part be due to the challenges of quantitating lung fibrosis in a temporal manner in specific regions of the lung. However, this may also be due to our understanding of aberrant and pathogenic collagen deposition being somewhat limited. The core processes associated with lung fibrosis are often observed in normal wound healing. Moreover, in the extreme fibrotic setting of IPF, the remodelling is sometimes associated with uncontrolled wound healing responses. As wound healing is a critical aspect to maintaining tissue function and homeostasis, targeting this process directly may result in safety concerns. This review therefore describes some of the recent advances in ascertaining pathways promoting lung fibrosis that may be amenable to therapeutic intervention in both COPD and IPF.     

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

Aging is a natural process characterized by progressive functional impairment and reduced capacity to respond appropriately to environmental stimuli and injury. The incidence of two common chronic respiratory diseases (chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF]) increases with advanced age. It is plausible, therefore, that abnormal regulation of the mechanisms of normal aging may contribute to the pathobiology of both COPD and IPF. This review discusses the available evidence supporting a number of aging mechanisms, including oxidative stress, telomere length regulation, cellular and immunosenescence, as well as changes in a number of antiaging molecules and the extracellular matrix, which are abnormal in COPD and/or IPF. A better understanding of these abnormalities may help in the design of novel and better therapeutic interventions for these patients.     

Pathognomonic remodeling of blood and lymphatic capillaries in idiopathic pulmonary fibrosis

Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients. Notably, we consistently found that the fibrotic lesions in IPF lungs, which are composed mainly of dense collagen with myofibroblasts, featured a reduction in capillaries. This finding provides a plausible explanation for the intractability of IPF, as this reduced vascularization would result in poor delivery of anti-fibrotic agents to these lesions. We also reported the disappearance of subpleural and interlobular lymphatics in IPF lungs, which likely results in poor alveolar clearance in the diseased lungs. Finally, we assessed the autopsied lungs of patients with IPF who died because of acute exacerbation and observed increased and dilated alveolar capillaries. These capillaries are likely to be “leaky” owing to exposure to VEGF produced by regenerated alveolar type II epithelial cells. Furthermore, poor alveolar clearance may prolong the high mobility group box 1 (HMGB1)-induced lung injury in acute exacerbation of IPF. Our data obtained from the assessment of blood and lymphatic capillary alterations in IPF provide novel pathogenetic insights and may provide the basis for new therapeutic strategies targeting IPF.     

Angiogenesis in pulmonary fibrosis: too much or not enough?

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension. In order to understand the process of vascular integrity and repair, it is necessary to identify the factors associated with angiogenesis in IPF. A delicate balance of angiogenic and angiostatic factors regulates vessel homeostasis in normal physiologic conditions in the lungs. Although earlier studies have proposed that IPF is associated with an increase of angiogenesis, there is some more recent evidence that angiogenesis in fibrotic lungs may actually be decreased, causing some controversy in the literature in this area. This review, therefore, discusses the concept of angiogenesis in pulmonary fibrosis and speculates on how the spatial and temporal heterogeneity of IPF might explain the controversial findings about vessel density in fibrotic lungs.     

Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients

Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach.     

The impact of smoking on mechanical properties of the lungs in idiopathic pulmonary fibrosis and sarcoidosis

Interstitial lung disease is characterized by interstitial inflammatory cell infiltration and fibrosis, a reduction in lung volumes, an increase in lung elastic recoil, and rapid shallow respirations. However, the alterations in lung volumes and elastic recoil as well as in breathing pattern are extremely variable, and the values are normal in a number of patients. In order to determine whether the effects of smoking could account for the variability in lung volumes and breathing pattern, we evaluated the elastic properties of the lung and the respiratory frequency at rest and during exercise in smokers and in nonsmokers with idiopathic pulmonary fibrosis (IPF) or with sarcoidosis. The volume-pressure curve in patients with IPF who smoked was positioned upwards and to the left when compared with that in nonsmokers. Conversely, the volume-pressure curve in patients with sarcoidosis who smoked was shifted downwards and to the right. In both conditions the respiratory rate while at rest and during exercise was greater in the group of patients who demonstrated the lower positioning of volume-pressure curves of the lungs (i.e., nonsmokers with IPF and smokers with sarcoidosis). We conclude that the impact of smoking may account, at least in part, for the variability in lung volume and volume-pressure characteristics of the lungs as well as the variability in respiratory rates in patients with interstitial lung disease.     

What parameters can be used to identify early idiopathic pulmonary fibrosis?

Elucidating the disease process of early idiopathic pulmonary fibrosis (IPF) will help clinicians in addressing the contentious issues of when and in which patients, therapeutic intervention should be initiated. Here, we discuss several possible parameters for diagnosing early IPF and their clinical impacts. Physiologically, early IPF can be considered as IPF with normal or mild impairment in pulmonary function. Radiologically, early IPF can be considered as IPF with a small extent and/or early features of fibrosis. Symptomatically, early IPF can be considered as asymptomatic or less symptomatic IPF. IPF at Gender-Age-Physiology index stage I can be considered early IPF. Interstitial lung abnormalities are defined as parenchymal abnormalities in more than 5% of the lung in patients with no prior history of interstitial lung disease, and in some cases, this seems to be equivalent to early IPF. Previous clinical trials showed the effect of antifibrotic therapies in early IPF, but the effects of therapy are uncertain in early IPF outside of clinical trials, such as in cases of IPF with normal pulmonary function, IPF without honeycombing or traction bronchiectasis, and asymptomatic IPF. Moreover, little has been reported on disease progression in such conditions. Because the conceptual framework of early IPF may vary depending on its definition, not only is a diagnosis of early IPF important but prediction of disease progression is also crucial. Further investigations are needed to identify biomarkers that can detect patients who may experience greater degrees of disease progression and require treatment even with those forms of early IPF.     

Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.     

Glucose Transporter-1 Distribution in Fibrotic Lung Disease: Association With [18F]-2-Fluoro-2-Deoxyglucose-PET Scan Uptake,Inflammation, and Neovascularization

Background[¹⁸F]-2-fluoro-2-deoxyglucose (FDG)-PET scan uptake is increased in areas of fibrosis and honeycombing in patients with idiopathic pulmonary fibrosis (IPF). Glucose transporter-1 (Glut-1) is known to be the main transporter for FDG. There is a paucity of data regarding the distribution of Glut-1 and the cells responsible for FDG binding in fibrotic lung diseases.MethodsWe applied immunofluorescence to localize Glut-1 in normal, IPF, and Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis lung tissue specimens as well as an array of 19 different lung neoplasms. In addition, we investigated Glut-1 expression in inflammatory cells from BAL fluid (BALF) from healthy volunteers, subjects with IPF, and subjects with HPS pulmonary fibrosis.ResultsIn normal lung tissue, Glut-1 immunoreactivity was seen on the surface of erythrocytes. In tissue sections from fibrotic lung diseases (IPF and HPS pulmonary fibrosis), Glut-1 immunoreactivity was present on the surface of erythrocytes and inflammatory cells. BALF inflammatory cells from healthy control subjects showed no immunoreactivity; BALF cells from subjects with IPF and HPS pulmonary fibrosis showed Glut-1 immunoreactivity associated with neutrophils and alveolar macrophages.ConclusionsGlut-1 transporter expression in normal lung is limited to erythrocytes. In fibrotic lung, erythrocytes and inflammatory cells express Glut-1. Together, these data suggest that FDG-PET scan uptake in IPF could be explained by enhanced inflammatory and erythrocytes uptake due to neovascularization seen in IPF and not an upregulation of metabolic rate in pneumocytes. Thus, FDG-PET scan may detect inflammation and neovascularization in lung fibrosis.     

Elevation of Anti-cytokeratin 19 Antibody in Sera of the Patients With Idiopathic Pulmonary Fibrosis and Pulmonary Fibrosis Associated With Collagen Vascular Disorders

It has been suggested that cytokeratin 19 is expressed in regenerated bronchoepithelial cells in patients with pulmonary fibrosis, and serum cytokeratin 19 fragment is elevated in patients with pulmonary fibrosis. We hypothesized that serum antibodies to cytokeratin 19 may be formed in patients with pulmonary fibrosis. To prove the existence of anti-cytokeratin 19 antibodies in patients' sera, human recombinant cytokeratin 19 was stained with patients' sera by a Western immunoblot. Then, we tried to establish an enzyme-linked immunosorbent assay to quantitate anti-cytokeratin 19 antibody in the sera of patients with idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD). We demonstrated the anti-cytokeratin 19 antibody in patient' sera by a Western immunoblot. In patients with IPF and PF-CVD, significantly high anti-cytokeratin 19 antibody was demonstrated compared with normal volunteers, patients with chronic bronchitis, and patients with pneumonia. These results suggest that anti-cytokeratin 19 antibody may have played a role in the process of lung injury in pulmonary fibrosis. Accepted for publication: 27 May 1999     

Host-environment interactions in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the pulmonary parenchyma, leading to respiratory failure and death. Several epidemiological and theoretical observations link the pathogenesis of this disease to environmental injury to the lungs. We discuss the theoretical framework of this hypothesis and we present data in support of the concept that genetic and nongenetic host susceptibility may interact with repetitive environmental injury to lead to IPF.     

Lack of evidence for a role of Epstein-Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is known as an independent risk factor for lung cancer. Because Epstein-Barr virus (EBV) may be involved in the genesis of IPF as well as certain malignancies, we investigated whether EBV contributes to the increased incidence of lung cancer in IPF The formalin-fixed and paraffin-embedded lung sections were prepared from 22 lung cancer patients with IPF and 22 lung cancer patients without IPF All ofthe IPF patients pathologically showed usual interstitial pneumonia. In situ hybridization for EBV-encoded small non-polyadenylated RNAs failed to show positive signals in the cancer tissues of either IPF or non-IPF patients. This study did not provide evidence for an etiologic role of EBV in the development of lung cancer in IPF.     

Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) has a high mortality rate, and current therapies are only marginally effective. A serum biomarker that predicts clinical outcome would be useful to stage disease, indicate prognosis and the need for aggressive therapy, and help stratify patients for clinical trials. The goals of this study were to determine whether serum levels of surfactant protein-A (SP-A) or surfactant protein-D (SP-D) would distinguish between IPF and other types of interstitial lung disease and whether serum SP-A or SP-D levels predict outcome in patients with IPF. The authors found that serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and that SP-D correlated with radiographic abnormalities in patients with IPF. In addition, the authors found that both serum SP-A and SP-D levels were highly predictive of survival in patients with IPF. This is the largest North American data set of surfactant protein measurements in idiopathic pulmonary fibrosis and the first report using multivariate analysis comparing serum surfactant proteins-A and -D to other commonly measured predictors of survival in idiopathic pulmonary fibrosis. Based on these results, the authors propose that serum surfactant proteins may prove to be useful biomarkers in patients with idiopathic pulmonary fibrosis.     

Altered DNA methylation profile in idiopathic pulmonary fibrosis

Rationale: DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF). Objectives: To determine the DNA methylation changes in IPF and their effects on gene expression. Methods: Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels. Measurements and Main Results: DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression. Conclusions: Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.     

Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease. Current therapeutic approaches target at apoptosis, epithelial replacement, fibroblasts/myofibroblasts, procoagulant activity, growth factors production, angiogenesis, Th1 and Th2 cytokines and oxidative stress. Increased epithelial cells apoptosis can contribute to fibrosis, while on the other hand, decreased fibroblast or myofibroblast apoptosis promotes fibrosis. Recent findings support the notion that therapy directed at either inhibition of angiogenic or augmentation of angiostatic CXC chemokines may be a novel approach in the treatment of IPF. Additionally, there is little doubt that the development of novel therapeutic strategies for pulmonary fibrosis should target some profibrotic growth factors and key type II cytokines, such as inteleukin-13. Importantly, persistent activation of intra-alveolar procoagulant activity and subsequent abnormal fibrin turnover enhances a fibrotic response. Furthermore, increased procoagulant activity may interfere with fibrin accumulation and lack of activation of some matrix metalloproteinases responsible for an imbalance in matrix turnover. Finally, oxidative stress with increased production of oxidants in IPF is an additional mechanism proposed to explain epithelial cell apoptosis in this disease. The challenge of future targets for therapeutic intervention is to reconcile different pathogenetic pathways, and we strongly suspect that no single approach will be sufficient for a lethal disease with few therapeutic options.     

胃食管反流与特发性肺纤维化之间相关性探讨

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是一种不断进展的间质性肺疾病.很多实验室证据提示胃酸与肺纤维化有关,进一步的临床观察也发现IPF患者有着高得惊人的食管异常酸反流,且很多人没有胃食管反流的典型症状,这意味着胃食管反流病可能是一个常常被人们忽视的IPF潜在的病理性作用因子.     

Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of IPF. The development of effective IPF clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of IPF. Advances in understanding of the pathogenetic processes involved in the development of pulmonary fibrosis have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.     

Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms?

Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.