Aging and Interstitial Lung Diseases: Unraveling an Old Forgotten Player in the Pathogenesis of Lung Fibrosis

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

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Progressive Fibrosing Interstitial Lung Diseases: A Current Perspective

Biomedicines ◽

10.3390/biomedicines9091237 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1237

Author(s):

Carlo Albera ◽

Giulia Verri ◽

Federico Sciarrone ◽

Elena Sitia ◽

Mauro Mangiapia ◽

...

Keyword(s):

Lung Fibrosis ◽

Lung Diseases ◽

Current Knowledge ◽

Relevant Literature ◽

Interstitial Lung Diseases ◽

Current Perspective ◽

Similar Disease ◽

Diagnostic Approaches ◽

Disease Behavior ◽

A Current

Interstitial lung diseases (ILDs) are a large and diverse group of rare and chronic respiratory disorders, with idiopathic pulmonary fibrosis (IPF) being the most common and best-studied member. Increasing interest in fibrosis as a therapeutic target and the appreciation that fibrotic mechanisms may be a treatable target of IPF prompted the development and subsequent approval of the antifibrotics, pirfenidone and nintedanib. The management of ILDs has changed considerably following an understanding that IPF and some ILDs share similar disease behavior of progressive fibrosis, termed “progressive fibrosing phenotype”. Indeed, antifibrotic treatment has shown to be beneficial in ILDs characterized by the progressive fibrosing phenotype. This narrative review summarizes current knowledge in the field of progressive fibrosing ILDs. Here, we discuss the clinical characteristics and pathogenesis of lung fibrosis and highlight relevant literature concerning the mechanisms underlying progressive fibrosing ILDs. We also summarize current diagnostic approaches and the available treatments of progressive fibrosing ILDs and address the optimization of treating progressive fibrosing ILDs with antifibrotics in clinical practice.

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Circulating lung biomarkers in idiopathic lung fibrosis and interstitial lung diseases associated with connective tissue diseases: Where do we stand?

Seminars in Arthritis and Rheumatism ◽

10.1016/j.semarthrit.2020.01.006 ◽

2020 ◽

Vol 50 (3) ◽

pp. 480-491 ◽

Cited By ~ 4

Author(s):

Muriel Elhai ◽

Jérôme Avouac ◽

Yannick Allanore

Keyword(s):

Connective Tissue ◽

Lung Fibrosis ◽

Lung Diseases ◽

Connective Tissue Diseases ◽

Interstitial Lung Diseases

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Endotoxin markers in bronchoalveolar lavage fluid of patients with interstitial lung diseases

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2012.641 ◽

2012 ◽

Vol 7 ◽

Author(s):

Bogumiła Szponar ◽

Lennart Larsson ◽

Joanna Domagała-Kulawik

Keyword(s):

Bronchoalveolar Lavage ◽

Cell Count ◽

Lung Fibrosis ◽

Lung Diseases ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Carbon Chain ◽

Interstitial Lung Diseases ◽

Indoor Environments ◽

Eosinophilic Disorders

Background: Exposure to inhaled endotoxins (lipopolysaccharides, LPS) of Gram-negative bacteria commonly found in indoor environments and assessed in secondary tobacco smoke, has been associated with airway inflammation and asthma exacerbation. The bronchoalveolar lavage fluid (BALf) from patients with interstitial lung diseases (sarcoidosis, lung fibrosis, smoking-related ILD, eosinophilic disorders) was analyzed for the markers of lipopolysaccharide (LPS, endotoxin). Methods: BALf was obtained from patients with diffuse lung diseases: idiopathic pulmonary fibrosis (n = 42), sarcoidosis (n = 22), smoking-related-ILD (n = 11) and eosinophilic disorders (n = 8). Total cell count and differential cell count were performed. In addition, samples were analyzed for 3-hydroxy fatty acids (3-OHFAs) of 10–18 carbon chain lengths, as markers of LPS, by gas chromatography-tandem mass spectrometry. Results: The highest LPS concentration was found in patients with eosinophilic disorders and the lowest in patients with sarcoidosis (p< 0.05) followed by the lung fibrosis and the sr-ILD patients. The difference between LPS in BALf with extremely high eosinophil proportion (> 25%) and those with lower proportion was also significant (p = 0.014). A significant correlation was found between LPS and eosinophils, but not between LPS and lymphocytes, neutrophils, or macrophages count. Conclusions: A positive relationship of LPS and eosinophilic pulmonary disorders may be linked to a persistent eosinophil activation mediated by Th2 pathway: chronic endotoxin exposure would intensify Th2 pathway resulting in fibrosis and, at the same time, eosinophil stimulation, and hence in eosinophilic pulmonary disorders.

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Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00210.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. L736-L748 ◽

Cited By ~ 31

Author(s):

Rebecca Lee ◽

Charles Reese ◽

Michael Bonner ◽

Elena Tourkina ◽

Zoltan Hajdu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Disease ◽

Lung Fibrosis ◽

Lung Diseases ◽

Interstitial Lung Diseases ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Dermal Fibrosis ◽

Direct Model ◽

Entire Lung

The interstitial lung diseases (ILD) include a large number of chronic, progressive, irreversible respiratory disorders involving pulmonary fibrosis, the most common of which are idiopathic pulmonary fibrosis and scleroderma lung disease (SSc ILD). Because bleomycin causes lung fibrosis when used in cancer chemotherapy, it is used to model human ILD in rodents. In most studies, bleomycin has been delivered directly into the lung by intratracheal or intraoral administration. Here we have compared the effects in mice of bleomycin delivered directly into the lungs (direct model) or systemically using osmotic minipumps (pump model) to determine which more closely resembles human ILD. The pump model is more similar to human SSc ILD in that: 1) lung injury/fibrosis is limited to the subpleural portion of the lung in the pump model and in SSc ILD, whereas the entire lung is affected in the direct model; 2) conversely, there is massive inflammation throughout the lung in the direct model, whereas inflammation is limited in the pump model and in SSc ILD; 3) hypertrophic type II alveolar epithelial cells are present at high levels in SSc ILD and in the pump model but not in the direct model; and 4) lung fibrosis is accompanied by dermal fibrosis. The pump model is also move convenient and humane than the direct model because there is less weight loss and mortality.

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