Novel differences in gene expression and functional capabilities of myofibroblast populations in idiopathic pulmonary fibrosis

Walsh, S.; Worrell, Julie C.; Fabre, Aurélie; Hinz, Boris; Kane, Rosemary; Keane, Michael P.

doi:10.1152/ajplung.00543.2017

Cited by 23 publications

(16 citation statements)

References 39 publications

(55 reference statements)

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“…The fibrocyte, a specialized cell derived from the monocyte cell lineage, has been postulated to be a precursor of the myofibroblast and has been implicated in the pathogenesis of IPF ( 45 , 46 ). In patients with IPF, higher concentrations of circulating fibrocytes may be predictive of a worse prognosis in terms of disease progression and have shown to be markedly elevated in acute exacerbations of IPF ( 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…In patients with IPF, higher concentrations of circulating fibrocytes may be predictive of a worse prognosis in terms of disease progression and have shown to be markedly elevated in acute exacerbations of IPF ( 46 , 47 ). C-C motif chemokine ligand 18, produced by fibrocytes and, to a greater extent, by alveolar macrophages, has shown potential as a serum biomarker of disease progression and mortality in IPF ( 45 , 48 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

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Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis

Kreuter

Lee

Tzouvelekis

et al. 2021

Am J Respir Crit Care Med

128

102

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Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2,067 patients stratified by monocyte count (at baseline: <0.60 × 10 9 cells/L [ n = 1,609], 0.60 to <0.95 × 10 9 cells/L [ n = 408], and ≥0.95 × 10 9 cells/L [ n = 50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60 to <0.95 × 10 9 cells/L or ≥0.95 × 10 9 cells/L versus <0.60 × 10 9 cells/L experienced IPF progression ( P = 0.016 and P = 0.002, respectively), all-cause hospitalization ( P = 0.030 and P = 0.003, respectively), and all-cause mortality ( P = 0.005 and P < 0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment. Conclusions: In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis

Kreuter

Lee

Tzouvelekis

et al. 2021

Am J Respir Crit Care Med

128

102

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“…A commercial ELISA does exist for Gremlin-1 but we are yet to be convinced of its specificity. Significantly elevated levels of Gremlin-1 has been demonstrated in renal fibroblasts and in idiopathic pulmonary fibrosis (Walsh et al, 2018). It could be that the mRNA expression is unchanged in the SSc samples but the protein level is much increased.…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis

Duffy

Henderson

Brown

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveSystemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis.MethodsDermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed.ResultsOverexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice.ConclusionGremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc.

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“…Consistent with prior knowledge, blood vessels have been shown to be enriched in aggrecan (ACAN), elastin (ELN), emilin (EMIL1), lumican (LUM), tenascin (TNC), von Willebrand factor (VWF), nidogen (NID1), and collagen VIII (CO8A2) which are shown in the volcano plot [44]. Similarly, ECM proteins MMP9, MUC1, PSPB (surfactant protein B), S100A8/A9, ANXA2, and collagen VI are all known to be enriched in lung epithelium in the context of IPF pathogenesis which are shown in the volcano plot [45][46][47][48][49][50]. Together, these data further support that our microproteomics protocol, using multiple techniques to process samples, may be useful to delineate the ECM composition between distinct regions.…”

Section: The Ecm Comprising Morphologically Normal Human Lung Alveolimentioning

confidence: 99%

Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues

et al. 2020

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Background: Haematoxylin and eosin (H&E)-which respectively stain nuclei blue and other cellular and stromal material pink-are routinely used for clinical diagnosis based on the identification of morphological features. A richer characterization can be achieved by laser capture microdissection coupled to mass spectrometry (LCM-MS), giving an unbiased assay of the proteins that make up the tissue. However, the process of fixing and H&E staining of tissues provides challenges with standard sample preparation methods for mass spectrometry, resulting in low protein yield. Here we describe a microproteomics technique to analyse H&E-stained, formalin-fixed paraffin-embedded (FFPE) tissues. Methods: Herein, we utilize heat extraction, physical disruption, and in column digestion for the analysis of H&E stained FFPE tissues. Micro-dissected morphologically normal human lung alveoli (0.082 mm 3) and human lung blood vessels (0.094 mm 3) from FFPE-fixed H&E-stained sections from Idiopathic Pulmonary Fibrosis (IPF) specimens (n = 3 IPF specimens) were then subject to a qualitative and then quantitative proteomics approach using BayesENproteomics. In addition, we tested the sensitivity of this method by processing and analysing a range of micro-dissected human lung blood vessel tissue volumes. Results: This approach yields 1252 uniquely expressed proteins (at a protein identification threshold of 3 unique peptides) with 892 differentially expressed proteins between these regions. In accord with prior knowledge, our methodology approach confirms that human lung blood vessels are enriched with smoothelin, CNN1, ITGA7, MYH11, TAGLN, and PTGIS; whereas morphologically normal human lung alveoli are enriched with cytokeratin-7,-8,-18,-19, 14, and-17. In addition, we identify a total of 137 extracellular matrix (ECM) proteins and immunohistologically validate that laminin subunit beta-1 localizes to morphologically normal human lung alveoli and tenascin localizes to human lung blood vessels. Lastly, we show that this micro-proteomics technique can be applied to tissue volumes as low as 0.0125 mm 3 .

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Novel differences in gene expression and functional capabilities of myofibroblast populations in idiopathic pulmonary fibrosis

Cited by 23 publications

References 39 publications

Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis

Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis

Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis

Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues

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