CD206 macrophages are relevant non-invasive imaging biomarkers and therapeutic targets in experimental lung fibrosis.

Background: Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline.

Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases.

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-β.

Therapeutic strategies targeting pro-fibrotic macrophages in interstitial lung disease.

Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis.

Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis.

Neighbourhood disadvantage impacts on pulmonary function in patients with sarcoidosis.

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes.

Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide ( ) and linear mixed effects models for associations with rate of FVC or decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation.

Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease.

Importance: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.

Neighborhood-Level Disadvantage Impacts on Patients with Fibrotic Interstitial Lung Disease.

Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada.

Connective-Tissue Growth Factor Contributes to TGF-β1-induced Lung Fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and in the lung. Connective-tissue growth factor (CTGF) exacerbates pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we demonstrate upregulation of CTGF in a rat lung fibrosis model induced by an adenovirus vector encoding active TGF-β1 (AdTGF-β1). We show that CTGF is also upregulated in patients with idiopathic pulmonary fibrosis.

Emerging therapeutic targets for idiopathic pulmonary fibrosis: preclinical progress and therapeutic implications.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high associated morbidity and mortality. The therapeutic landscape has significantly changed in the last 20 years with two drugs currently approved that have demonstrated the ability to slow disease progression. Despite these developments, survival in IPF is limited, so there is a major interest in therapeutic targets which could serve to open up new therapeutic avenues.

Mouse Models of Lung Fibrosis.

The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease.

FK506-Binding Protein 13 Expression Is Upregulated in Interstitial Lung Disease and Correlated with Clinical Severity. A Potentially Protective Role.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects.

Progressive fibrosing interstitial lung disease: treatable traits and therapeutic strategies.

Purpose Of Review: In this review, the authors describe therapeutic strategies for a disease group called progressive fibrosing interstitial lung disease (PF-ILD) and highlight the importance of the definition of progression, prognosis, and treatment response.

Recent Findings: Although it is a relatively new concept, the term PF-ILD has been increasingly applied in clinical research and practice. Three domains commonly used to detect the disease progression include clinical symptoms, rate of forced vital capacity (FVC) decline and the extent of fibrosis on imaging.

The importance of interventional timing in the bleomycin model of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5-7 days.

Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis.

Background: The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown.

Objectives: We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis.

Results: In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60% View Article and Find Full Text PDF

Therapeutic targets and early stage clinical trials for pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive, and irreversible fatal interstitial lung disease. Although many drugs have failed in clinical trials, these failures improved the understanding of the pathogenesis of IPF. Currently, there are two drugs approved for IPF that slow the progression of the disease.

Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis.

Although recent evidence indicates that gp130 cytokines, Oncostatin M (OSM) and IL-6 are involved in alternative programming of macrophages, their role in lung fibrogenesis is poorly understood. Here, we investigated the effect of transient adenoviral overexpression of OSM or IL-6 in mice during bleomycin-induced lung fibrosis. Lung fibrosis and M2-like macrophage accumulation were assessed by immunohistochemistry, western blotting, gene expression and flow cytometry.

Platelet derived growth factor-evoked Ca2+ wave and matrix gene expression through phospholipase C in human pulmonary fibroblast.

The primary role of fibroblasts is production and degradation of extracellular matrix, and thus it helps in the structural framework of tissues. The close relation between fibroblast malfunction and many diseases such as chronic obstructive pulmonary disease, asthma, and fibrosis is widely accepted. Fibroblasts are known to respond to different growth factors and cytokines including platelet-derived growth factors (PDGF).

Transforming growth factor-β evokes Ca2+ waves and enhances gene expression in human pulmonary fibroblasts.

Fibroblasts maintain the structural framework of animal tissue by synthesizing extracellular matrix molecules. Chronic lung diseases are characterized in part by changes in fibroblast numbers, properties, and more. Fibroblasts respond to a variety of growth factors, cytokines, and proinflammatory mediators.