Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes

Clarke, D. S.; Carruthers, Alan; Mustelin, Tomas; Murray, Lynne A.

doi:10.1186/1755-1536-6-20

Cited by 92 publications

(76 citation statements)

References 96 publications

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“…Collagen 1a1 and fibronectin are the main components of ECM that participate in tissue and vascular remodeling. Increased collagen 1a1 and fibronectin expression is consistently associated with pulmonary fibrosis (29,30). We showed that treatment with ICG001 did not affect β-catenin nuclear translocation index but drastically downregulated cyclin D1, collagen Iα1, and fibronectin expression in CTGF transgenic lungs.…”

Section: Discussionmentioning

confidence: 73%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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Section: Discussionmentioning

confidence: 73%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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“…IL-13 promotes fibrosis by stimulating collagen accumulation, downregulating MMPs and recruiting pro-fibrotic innate immune cells 83 . IL-13 also promotes the differentiation of fibroblasts into myofibroblasts and increases TGFβ expression 84 . How these cytokines and growth factors are upregulated in different tissues remains to be elucidated.…”

Section: Aberrant Ecm Remodelling In Diseasementioning

confidence: 99%

Remodelling the extracellular matrix in development and disease

Bonnans

Chou

Werb

2014

Nat Rev Mol Cell Biol

3,435

2,877

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The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

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“…Thus, there is agreement that resident fibroblasts contribute to myofibroblasts in fibrosis, but the role of other cell types is controversial. The resident fibroblasts turn into myofibroblasts which produce excessive extracellular matrix components, especially collagen-I [10].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis

Cai

Song

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause that typically leads to respiratory failure and death within 3-5years of diagnosis. TGF-β1 is considered a major profibrotic factor. However, TGF-β1 is necessary but not sufficient to the pathogenesis of fibrotic lesion of the lungs. Recent observations have revealed that calpain, a calcium dependent protease, plays a pivotal role in tissue remodeling and fibrosis. However, the mechanism of calpain mediating pulmonary fibrosis is not understood. Calpain conditional knockout (ER-Cre(+/-)capns1(flox/flox)) mice and primary human lung fibroblasts (HLFs) were used here to investigate the relationship between calpain and TGF-β1. Calpain knockout mice were protected from fibrotic effects of bleomycin. Bleomycin induced increases in TGF-β1 via calpain activation in HLFs. Moreover, TGF-β1 also activated calpain. This crosstalk between calpain activation and TGF-β1 triggered the downstream signaling pathway including TGF-β1 Smad2/3 and non-Smad (Akt) pathways, as well as collagen-I synthesis. Taken together, our data indicate that the crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in HLFs and in pulmonary fibrosis. Intervention in the crosstalk between calpain activation and TGF-β1 is a novel potential strategy to prevent pulmonary fibrosis.

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Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes

Cited by 92 publications

References 96 publications

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Remodelling the extracellular matrix in development and disease

Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis

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