IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

AbstractIdiopathic pulmonary fibrosis (IPF) remains a progressive disease despite best medical management. We previously identified IL-11 as a critical factor for cardiovascular fibrosis and examine here its role in pulmonary fibrosis.IL-11is consistently upregulated in IPF genomic datasets, which we confirmed by histology. Pulmonary fibroblasts stimulated with IL-11 transform into invasive myofibroblasts whereas fibroblasts fromIl11radeleted mice did not respond to pro-fibrotic stimuli. In the mouse, injection of recombinant Il-11 or fibroblast-specific expression of Il-11 caused pulmonary fibrosis. We then generated a neutralising IL-11 binding antibody that blocks lung fibroblast activation across species. In a mouse model of IPF, anti-IL-11 therapy attenuated lung fibrosis and specifically blocked Erk activation. These data prioritise IL-11 as an accessible drug target in IPF.One Sentence SummaryNon-canonical IL-11 signalling is a central hallmark of idiopathic pulmonary fibrosis and represents a novel target for antibody therapies.

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Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis

Respiratory Research ◽

10.1186/s12931-021-01801-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

H. Jessen ◽

N. Hoyer ◽

T. S. Prior ◽

P. Frederiksen ◽

M. A. Karsdal ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Progression ◽

Real World ◽

Progressive Disease ◽

Type Iii Collagen ◽

Type I ◽

Collagen Turnover ◽

Baseline Levels ◽

Longitudinal Biomarker

Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF. Methods Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not. Results Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics. Conclusion Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

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Dynamic contrast-enhanced magnetic resonance imaging of the lung reveals important pathobiology in idiopathic pulmonary fibrosis

ERJ Open Research ◽

10.1183/23120541.00907-2020 ◽

2021 ◽

pp. 00907-2020

Author(s):

Sydney B. Montesi ◽

Iris Zhou ◽

Lloyd L. Liang ◽

Subba R. Digumarthy ◽

Sarah Mercaldo ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Extracellular Space ◽

Progressive Disease ◽

Functional Information ◽

Dce Mri ◽

Dynamic Contrast Enhanced ◽

Peak Enhancement ◽

Contrast Enhanced

IntroductionEvidence suggest that abnormalities occur in the lung microvasculature in idiopathic pulmonary fibrosis (IPF). We hypothesized that dynamic contrast-enhanced (DCE)-MRI could detect alterations in permeability, perfusion, and extracellular extravascular volume in idiopathic pulmonary fibrosis thus providing in vivo regional functional information not otherwise available.MethodsHealthy controls and IPF subjects underwent DCE-MRI of the thorax using a dynamic volumetric radial sampling sequence and administration of gadoterate meglumine at a dose of 0.1 mmol·kg−1 at 2 mL·s−1. Model-free analysis of signal intensity versus time curves in regions of interest from a lower, middle, and upper axial plane and a posterior coronal plane yielded parameters reflective of perfusion and permeability (peak enhancement and rate of contrast arrival, kwashin) and the extracellular extravascular space (rate of contrast clearance, kwashout). These imaging parameters were compared between IPF and healthy control subjects, and between fast/slow IPF progressors.ResultsIPF subjects (n=16, M=56%, age=67.5 (range 60–79)) had significantly reduced peak enhancement and slower kwashin in all measured lung regions compared to the healthy volunteers (n=17, M=65%, age=58 (range 51–63)) on unadjusted analyses consistent with microvascular alterations. kwashout, as a measure of the extravascular extracellular space, was significantly slower in the lower lung and posterior coronal regions in the IPF subjects consistent with an increased extravascular extracellular space. All estimates were attenuated after adjusting for age. Similar trends were observed, but only the associations with kwashin remained statistically significant. Among IPF subjects, kwashout rates nearly perfectly discriminated between those with rapidly progressive disease versus those with stable/slowly progressive disease.ConclusionsDCE-MRI detects changes in the microvasculature and extravascular extracellular space in IPF thus providing in vivo regional functional information.

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Cardiovascular Fibrosis in Idiopathic Pulmonary Fibrosis

Case Medical Research ◽

10.31525/ct1-nct04177251 ◽

2019 ◽

Author(s):

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cardiovascular Fibrosis

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Idiopathic pulmonary fibrosis: airway volume measurement identifies progressive disease on computed tomography scans

ERJ Open Research ◽

10.1183/23120541.00290-2019 ◽

2020 ◽

Vol 6 (1) ◽

pp. 00290-2019 ◽

Cited By ~ 2

Author(s):

Thomas McLellan ◽

Peter M. George ◽

Paul Ford ◽

Jan De Backer ◽

Cedric Van Holsbeke ◽

...

Keyword(s):

Computed Tomography ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Progressive Disease ◽

Volume Measurement ◽

Computed Tomography Scans

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Longitudinal serological assessment of type VI collagen turnover is related to progression in a real-world cohort of idiopathic pulmonary fibrosis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01684-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Henrik Jessen ◽

Nils Hoyer ◽

Thomas S. Prior ◽

Peder Frederiksen ◽

Sarah R. Rønnow ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Progression ◽

Real World ◽

Progressive Disease ◽

Degradation Products ◽

Serum Levels ◽

Average Difference ◽

Type Vi Collagen ◽

Collagen Formation

Abstract Background Remodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients. Methods Two serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies. Results Patients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3–22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI − 0.005–27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI − 0.07–47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib. Conclusions Type VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF.

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S139 The K+ channel KCa3.1 is a novel target for the treatment of idiopathic pulmonary fibrosis

Thorax ◽

10.1136/thx.2010.150946.40 ◽

2010 ◽

Vol 65 (Suppl 4) ◽

pp. A63-A63

Author(s):

M. C. Shepherd ◽

S. R. Sabir ◽

C. McSharry ◽

H. Wulff ◽

P. Bradding

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

K Channel ◽

Novel Target

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The K+ Channel KCa3.1 As A Novel Target For Idiopathic Pulmonary Fibrosis

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1952 ◽

2012 ◽

Author(s):

Katy M. Roach ◽

Malcolm C. Shepherd ◽

Sumir R. Sabir ◽

Heike Wulff ◽

William Coward ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

K Channel ◽

Novel Target

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Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

Journal of Clinical Medicine ◽

10.3390/jcm9061993 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1993

Author(s):

Canay Caliskan ◽

Benjamin Seeliger ◽

Benedikt Jäger ◽

Jan Fuge ◽

Tobias Welte ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Progressive Disease ◽

Progression Free Survival ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Free Survival ◽

Antifibrotic Therapy ◽

Level Measurement ◽

Chemokine Ligand

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts.

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Epithelial–Mesenchymal Transition: A Major Pathogenic Driver in Idiopathic Pulmonary Fibrosis?

Medicina ◽

10.3390/medicina56110608 ◽

2020 ◽

Vol 56 (11) ◽

pp. 608

Author(s):

Francesco Salton ◽

Barbara Ruaro ◽

Paola Confalonieri ◽

Marco Confalonieri

Keyword(s):

Respiratory Failure ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Progressive Disease ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lungs that leads to parenchymal scarring and death due to respiratory failure within a few years despite the recent therapeutic advances [...]

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