Systems medicine advances in interstitial lung disease

Fibrotic lung diseases involve subject–environment interactions, together with dysregulated homeostatic processes, impaired DNA repair and distorted immune functions. Systems medicine-based approaches are used to analyse diseases in a holistic manner, by integrating systems biology platforms along with clinical parameters, for the purpose of understanding disease origin, progression, exacerbation and remission.Interstitial lung diseases (ILDs) refer to a heterogeneous group of complex fibrotic diseases. The increase of systems medicine-based approaches in the understanding of ILDs provides exceptional advantages by improving diagnostics, unravelling phenotypical differences, and stratifying patient populations by predictable outcomes and personalised treatments. This review discusses the state-of-the-art contributions of systems medicine-based approaches in ILDs over the past 5 years.

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Antifibrotic Therapies and Progressive Fibrosing Interstitial Lung Disease (PF-ILD): Building on INBUILD

Journal of Clinical Medicine ◽

10.3390/jcm10112285 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2285

Author(s):

John N. Shumar ◽

Abhimanyu Chandel ◽

Christopher S. King

Keyword(s):

Interstitial Lung Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Lung Diseases ◽

Interstitial Lung Diseases ◽

Treatment Pathway ◽

Antifibrotic Therapy ◽

New Treatment ◽

Fibrotic Lung Diseases

Progressive fibrosing interstitial lung disease (PF-ILD) describes a phenotypic subset of interstitial lung diseases characterized by progressive, intractable lung fibrosis. PF-ILD is separate from, but has radiographic, histopathologic, and clinical similarities to idiopathic pulmonary fibrosis. Two antifibrotic medications, nintedanib and pirfenidone, have been approved for use in patients with idiopathic pulmonary fibrosis. Recently completed randomized controlled trials have demonstrated the clinical efficacy of antifibrotic therapy in patients with PF-ILD. The validation of efficacy of antifibrotic therapy in PF-ILD has changed the treatment landscape for all of the fibrotic lung diseases, providing a new treatment pathway and opening the door for combined antifibrotic and immunosuppressant drug therapy to address both the fibrotic and inflammatory components of ILD characterized by mixed pathophysiologic pathways.

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When things go wrong: Exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases

European Respiratory Journal ◽

10.1183/13993003.04507-2020 ◽

2021 ◽

pp. 2004507

Author(s):

Moisés Selman ◽

Annie Pardo

Keyword(s):

Pulmonary Fibrosis ◽

Lung Diseases ◽

Molecular Mechanisms ◽

Lung Parenchyma ◽

Interstitial Lung Diseases ◽

Unknown Etiology ◽

Clinical Behavior ◽

The Past ◽

Appropriate Treatment ◽

Different Types

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

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Idiopatic pulmonary fibrosis: A new paradigm

Terapevticheskii arkhiv ◽

10.17116/terarkh2017891112-122 ◽

2017 ◽

Vol 89 (1) ◽

pp. 112-122 ◽

Cited By ~ 5

Author(s):

S N Avdeev

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Elderly People ◽

Lung Diseases ◽

Interstitial Lung Diseases ◽

Common Disease ◽

Middle Aged ◽

New Paradigm ◽

The Past ◽

New Evidence

Idiopathic pulmonary fibrosis ((IPF) is the most common disease from a group of interstitial lung diseases, which occurs mainly in middle-aged and elderly people. Over the past decade, there have been considerable changes in approaches to diagnosing and treating IPF. The paper presents an update on the epidemiology of IPF, the results of new studies of its pathogenesis, and main approaches to diagnosing the disease. In addition, there is new evidence on therapy for IPF.

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The burden of Progressive Fibrotic Interstitial lung disease across the UK

10.1101/2020.11.16.20229591 ◽

2020 ◽

Author(s):

Thomas Simpson ◽

Shaney L Barratt ◽

Paul Beirne ◽

Nazia Chaudhuri ◽

Anjali Crawshaw ◽

...

Keyword(s):

Lung Disease ◽

Lung Diseases ◽

Progressive Disease ◽

Workforce Planning ◽

Interstitial Lung Diseases ◽

Specialist Centre ◽

Patients At Risk ◽

Fibrotic Lung Diseases ◽

Fibrotic Lung Disease ◽

The Uk

AbstractWhile Idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therap. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as Progressive Fibrotic Interstitial Lung diseases (PF-ILD). Previous estimates suggest that between 18 to 40% of all fILD will develop progressive disease, however, the exact burden remains unknown. This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD across England.All new referrals seen across nine UK centres for their first outpatient clinic appointment between 1st August 2017 and 31st January 2018 were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial. A total of 1749 patients with fILD were assessed. In this cohort of patients at risk of developing PF-ILD the INBUILD criteria were met in 14.5% (253/1749) of all new non-IPF fILD referrals. The average time from referral to specialist centre to diagnosis of progressive phenotype was 311 days. Of the progression events the majority were driven by a measured drop in FVC, with more than half of patients experiencing a drop of 10%. Almost one quarter of patients (24.1%) were diagnosed with progressive disease on the basis of radiological and symptomatic progression alone without a spirometric deterioration.This study represents a fair and balanced approach to assessing the incidence of objectively measurable and treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than that reported in previous studies however our methodology is likely to give a more accurate result than estimates based on extrapolation from general disease statistics, from physician-reported estimates prone to significant biases, or insurance claim processes also substantially prone to bias. This information has implication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond.

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The past, present, and future of humidifier disinfectant-associated interstitial lung diseases in children

Clinical and Experimental Pediatrics ◽

10.3345/cep.2019.01326 ◽

2020 ◽

Vol 63 (7) ◽

pp. 251-258 ◽

Cited By ~ 1

Author(s):

Eun Lee ◽

So-Yeon Lee ◽

Soo-Jong Hong

Keyword(s):

Health Effects ◽

Lung Diseases ◽

Therapeutic Strategies ◽

Interstitial Lung Diseases ◽

Toxic Chemicals ◽

The Past ◽

Radiologic Findings ◽

Pathologic Findings

Exposure to environmental factors can cause interstitial lung diseases (ILDs); however, such types of ILDs are rare. From 2007 to 2011, an ILD epidemic occurred in South Korea owing to inhalational exposure to toxic chemicals in humidifier disinfectants (HDs). HD-associated ILDs (HD-ILDs) are characterized by rapidly progressing respiratory failure with pulmonary fibrosis and a high mortality rate of 43.8%−58.0%. Although 18.1%−31.1% of the general population used HDs, only a small proportion of HD users were diagnosed with HD-ILDs. This finding suggests that investigation of the pathophysiologies underlying HD-ILDs is needed in addition to the identification of susceptibility to HD-ILDs. Further, there have been several concerns regarding the diverse health effects of exposure to toxic chemicals in HDs, including those that have not been identified, and long-term prognoses in terms of pulmonary function and residual pulmonary lesions observed on follow-up chest images. In this review, we summarize the clinical features, pathologic findings, and changes in radiologic findings over time in patients with HD-ILDs and the results of previous experimental research on the mechanisms underlying the effects of toxic chemicals in HDs. Studies are currently underway to identify the pathophysiologies of HD-ILDs and possible health effects of exposure to HDs along with the development of targeted therapeutic strategies. The experience of identification of HD-ILDs has encouraged stricter control of safe chemicals in everyday life.

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Environmental hazards and demographic and clinical data of childhood interstitial lung diseases in a tertiary institute in Egypt

Egyptian Journal of Bronchology ◽

10.1186/s43168-020-00048-5 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Sally Raafat Ishak ◽

Azza Mohammed Hassan ◽

Terez Boshra Kamel

Keyword(s):

Environmental Factors ◽

Cigarette Smoke ◽

Lung Diseases ◽

Environmental Hazards ◽

Interstitial Lung Diseases ◽

Climatic Conditions ◽

Industrial Wastes ◽

Contributing Factors ◽

The Past ◽

Financial Issues

Abstract Background There incidence of childhood interstitial lung diseases increased in the last years in Egypt. Changes in environmental and climatic conditions may be contributing factors. Also, raising birds at home increased in the past years due to financial issues. Other environmental factors include increased industries, traffic, and pollution. Our study aimed to assess the environmental hazards and the severity of childhood interstitial lung diseases. Results Sixty-five percent of patients with childhood interstitial lung diseases (chILD) were exposed to cigarette smoke; 45% were exposed to birds, 30% to industrial wastes, 20% to grass and pesticides, and 10% to animals. Conclusions Exposure to cigarette smoke and birds increases the risk of development of chILD.

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The pronounced high expression of discoidin domain receptor 2 in human interstitial lung diseases

ERJ Open Research ◽

10.1183/23120541.00138-2016 ◽

2018 ◽

Vol 4 (1) ◽

pp. 00138-2016 ◽

Cited By ~ 4

Author(s):

Huan Bian ◽

Xiaowei Nie ◽

Xin Bu ◽

Feng Tian ◽

Libo Yao ◽

...

Keyword(s):

Lung Diseases ◽

Surface Protein ◽

Interstitial Lung Diseases ◽

Membrane Receptors ◽

Discoidin Domain Receptor ◽

Cellular Effects ◽

Tissue Sections ◽

Collagen Receptors ◽

Discoidin Domain Receptor 2 ◽

Fibrotic Lung Diseases

The most typical structural feature of human interstitial lung diseases (ILDs) is the accumulation of vast amounts of collagens within the lung interstitium. The membrane receptors that are responsible for recognising collagens and then transducing signals into the cells include four members of the integrin family (α1β1, α2β1, α10β1 and α11β1) and two members of the discoidin domain receptor family (DDR1 and DDR2). However, it remains unknown whether these six collagen receptors similarly contribute to the pathogenesis of fibrotic lung diseases.Quantitative real-time PCR (qPCR) was utilised to assess the mRNA expression of the genes studied. Immunoblot experiments were performed to analyse the protein abundance and kinase activity of the gene products. The tissue location was determined by immunohistochemical staining.qPCR data showed that DDR2 mRNA displays the most dramatic difference between idiopathic pulmonary fibrosis (IPF) patients and healthy groups. The outstanding increases in DDR2 proteins were also observed in some other types of ILD besides IPF. DDR2-expressing cells in ILD tissue sections were found to exhibit spindle or fibroblastic shapes.Our investigation suggests that DDR2 might represent a major cell surface protein that mediates collagen-induced cellular effects in human ILD and, hence, is suitable for their diagnosis and therapy.

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Interstitial Lung Diseases: a State of the Art Series

Histopathology ◽

10.1111/j.1365-2559.2006.02308.x ◽

2006 ◽

Vol 48 (6) ◽

pp. 763-763

Author(s):

S Stewart

Keyword(s):

Lung Diseases ◽

State Of The Art ◽

Interstitial Lung Diseases

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miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20100035 ◽

2010 ◽

Vol 207 (8) ◽

pp. 1589-1597 ◽

Cited By ~ 609

Author(s):

Gang Liu ◽

Arnaud Friggeri ◽

Yanping Yang ◽

Jadranka Milosevic ◽

Qiang Ding ◽

...

Keyword(s):

Lung Fibrosis ◽

Lung Diseases ◽

Tissue Injury ◽

Pulmonary Fibroblasts ◽

Novel Approach ◽

Fibrotic Diseases ◽

Fibrotic Lung Diseases ◽

Mirna Therapeutics ◽

Tgf Β1

Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5–7 d after initiation of pulmonary injury. TGF-β1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-β1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.

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