scholarly journals The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

2020 ◽  
Author(s):  
Dan JK Yombo ◽  
Nishanth Gupta ◽  
Anil G. Jegga ◽  
Satish K Madala
Keyword(s):  
T Cells ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Gene Networks ◽  
Pulmonary Inflammation ◽  
Collagen Deposition ◽  
Lung Function Decline ◽  
Elevated Expression ◽  
Fibrotic Lung Disease

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

scholarly journals The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan J. K. Yombo ◽  
Varshini Odayar ◽  
Nishant Gupta ◽  
Anil G. Jegga ◽  
Satish K. Madala
Keyword(s):  
T Cells ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Gene Networks ◽  
Therapeutic Potential ◽  
Pulmonary Inflammation ◽  
Protective Effects ◽  
Collagen Deposition ◽  
Lung Function Decline

Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.

scholarly journals Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
D. J. Leeming ◽  
F. Genovese ◽  
J. M. B. Sand ◽  
D. G. K. Rasmussen ◽  
C. Christiansen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Extracellular Matrix ◽  
Wound Healing ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Interstitial Lung Diseases ◽  
Lessons Learned ◽  
Lung Function Decline ◽  
Tissue Remodelling

AbstractPulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor’s consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.

scholarly journals Potential role of senescent macrophages in radiation-induced pulmonary fibrosis

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Lulu Su ◽  
Yinping Dong ◽  
Yueying Wang ◽  
Yuquan Wang ◽  
Bowen Guan ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Pulmonary Fibrosis ◽  
Late Toxicity ◽  
Airway Epithelial ◽  
Tnf Α ◽  
Elevated Expression ◽  
Radiation Induced ◽  
Therapeutic Radiation ◽  
Tgf Β1

AbstractRadiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal+ senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

scholarly journals Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Duncan C. Humphries ◽  
Ross Mills ◽  
Ross Dobie ◽  
Neil C. Henderson ◽  
Tariq Sethi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Respir Crit ◽  
Pulmonary Inflammation ◽  
Myeloid Cell ◽  
Clinical Development ◽  
Galectin 3 ◽  
Direct Targeting

Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury.Methods:LgalS3fl/fl mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre+/-/LgalS3fl/fl and Pdgfrb-cre+/-/LgalS3fl/fl mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3−/− mice.Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre+/-/LgalS3fl/flmice.Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.

scholarly journals Asthma progression and mortality: the role of inhaled corticosteroids

2019 ◽  
Vol 54 (1) ◽  
pp. 1900491 ◽  
Author(s):  
Paul O'Byrne ◽  
Leonardo M. Fabbri ◽  
Ian D. Pavord ◽  
Alberto Papi ◽  
Stefano Petruzzelli ◽  
...  
Keyword(s):  
Lung Function ◽  
Pulmonary Function ◽  
Inhaled Corticosteroids ◽  
Administrative Databases ◽  
Rapid Decline ◽  
Lung Function Decline ◽  
The Impact ◽  
Asthma Mortality

Overall, asthma mortality rates have declined dramatically in the last 30 years, due to improved diagnosis and to better treatment, particularly in the 1990s following the more widespread use of inhaled corticosteroids (ICSs). The impact of ICS on other long-term outcomes, such as lung function decline, is less certain, in part because the factors associated with these outcomes are incompletely understood. The purpose of this review is to evaluate the effect of pharmacological interventions, particularly ICS, on asthma progression and mortality. Furthermore, we review the potential mechanisms of action of pharmacotherapy on asthma progression and mortality, the effects of ICS on long-term changes in lung function, and the role of ICS in various asthma phenotypes.Overall, there is compelling evidence of the value of ICS in improving asthma control, as measured by improved symptoms, pulmonary function and reduced exacerbations. There is, however, less convincing evidence that ICS prevents the decline in pulmonary function that occurs in some, although not all, patients with asthma. Severe exacerbations are associated with a more rapid decline in pulmonary function, and by reducing the risk of severe exacerbations, it is likely that ICS will, at least partially, prevent this decline. Studies using administrative databases also support an important role for ICS in reducing asthma mortality, but the fact that asthma mortality is, fortunately, an uncommon event makes it highly improbable that this will be demonstrated in prospective trials.

scholarly journals Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial

2021 ◽  
pp. 2001518
Author(s):  
Imre Noth ◽  
Vincent Cottin ◽  
Nazia Chaudhuri ◽  
Tamera J Corte ◽  
Kerri A Johannson ◽  
...  
Keyword(s):  
Lung Function ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Pearson Correlation ◽  
Correlation Coefficients ◽  
Strong Correlations ◽  
Lung Function Decline ◽  
Open Label ◽  
Rates Of Change ◽  
Rate Of Decline

Data from the INMARK trial were used to investigate the feasibility and validity of home spirometry as a measure of lung function decline in patients with idiopathic pulmonary fibrosis (IPF).Subjects with IPF and preserved forced vital capacity (FVC) were randomised to receive nintedanib or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Clinic spirometry was conducted at baseline and weeks 4, 8, 12, 16, 20, 24, 36 and 52. Subjects were asked to perform home spirometry at least once a week and ideally daily. Correlations between home- and clinic-measured FVC and rates of change in FVC were assessed using Pearson correlation coefficients.In total, 346 subjects were treated. Mean adherence to weekly home spirometry decreased over time but remained above 75% in every 4-week period. Over 52 weeks, mean adherence was 86%. Variability in change from baseline in FVC was greater when measured by home rather than clinic spirometry. Strong correlations were observed between home- and clinic-measured FVC at all time-points (r=0.72 to 0.84), but correlations between home- and clinic-measured rates of change in FVC were weak (r=0.26 for rate of decline in FVC over 52 weeks).Home spirometry was a feasible and valid measure of lung function in patients with IPF and preserved FVC, but estimates of the rate of FVC decline obtained using home spirometry were poorly correlated with those based on clinic spirometry.

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