Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

Effendi, Wiwin Is; Nagano, Tatsuya

doi:10.3390/ijms23116064

Cited by 33 publications

(20 citation statements)

References 179 publications

(192 reference statements)

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“…integrins, heparan sulfate proteoglycans, LRPs, and TrkA). The consequences of Ctgf binding are multifaceted, including effects on the extracellular matrix (ECM), endothelial-mesenchymal transition, macrophage polarization, autophagy, and senescence-associated metabolic disruption [35]. It is responsible for the direct binding of cytokines and mediates ECM-related proteins, in addition to regulating growth factor and cytokine activity by modulating crosstalk between signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes

Nelson,

Eadie,

Madhu

et al. 2024

Preprint

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Myocardial infarction and reperfusion is a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling that is essential to cardiac development also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. Yap, not Taz, patterns of expression differ in post-myocardial infarct compared to peri-infarct tissue suggesting cell-specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were most sensitive to nutrient deprivation compared to other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, dominantly L-isoleucine, and influences the expression of Ctgf, a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation.

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Section: Discussionmentioning

confidence: 99%

Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes

Nelson,

Eadie,

Madhu

et al. 2024

Preprint

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“…CTFG is a protein that modulates signaling pathways in myofibroblast activation, ECM deposition, and remodeling [ 60 ]. It is the primary mediator of TGF-β and is overexpressed in areas of fibrotic lesions in major organs including the lungs of IPF patients [ 61 , 62 , 63 ]. In 2019, the phase 2 PRAISE trial demonstrated that intravenous pamrevlumab successfully decreased the decline in FVC by approximately 70% in IPF patients at 48 weeks compared to the placebo group [ 64 ].…”

Section: Novel Treatmentmentioning

confidence: 99%

Trials and Treatments: An Update on Pharmacotherapy for Idiopathic Pulmonary Fibrosis

Thong

McElduff

Henry

2023

Life

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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial lung disease that occurs predominantly in the older population. There is increasing incidence and prevalence in IPF globally. The emergence of anti-fibrotic therapies in the last decade have improved patient survival though a cure is yet to be developed. In this review article, we aim to summarize the existing and novel pharmacotherapies for the treatment of IPF (excluding treatments for acute exacerbations), focusing on the current knowledge on the pathophysiology of the disease, mechanism of action of the drugs, and clinical trials.

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“…Connective tissue growth factor (CTGF) is an essential downstream mediator of various regulatory modulators, such as transforming growth factor-β (TGF-β). [7][8][9] CTGF expression is elevated in activated fibroblasts and alveolar epithelial cells in patients with IPF. 10,11 The interaction of CTGF and TGF-β can mediate cell adhesion and migration, myofibroblast activation, and extracellular matrix deposition and remodeling, leading to tissue remodeling and fibrosis, which is an important mechanism leading to IPF.…”

Section: Introductionmentioning

confidence: 97%

“…Connective tissue growth factor (CTGF) is an essential downstream mediator of various regulatory modulators, such as transforming growth factor‐β (TGF‐β) 7–9 . CTGF expression is elevated in activated fibroblasts and alveolar epithelial cells in patients with IPF 10,11 .…”

Section: Introductionmentioning

confidence: 99%

A first‐in‐human phase I study of SHR‐1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants

Song,

Zhou,

et al. 2023

Clinical Translational Sci

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New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR‐1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR‐1906 in healthy participants. This was a randomized, double‐blind, placebo‐controlled, dose‐escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR‐1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment‐related treatment‐emergent adverse events occurred in 25 participants (46.3%) in the SHR‐1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14–0.63 mL/h/kg, the geometric mean volume of distribution at steady‐state was 47.4–75.5 mL/kg, and the terminal elimination half‐life was 51.9–349 h. SHR‐1906 showed nonlinear PKs. The peak concentration increased in a dose‐proportional manner, whereas the area under the concentration–time curve showed a greater than dose‐proportional increase. Anti‐drug antibodies of SHR‐1906 were detected in nine of 54 participants (16.7%). A single dose of SHR‐1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR‐1906 were evaluated, supporting further clinical development.

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Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

Cited by 33 publications

References 179 publications

Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes

Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes

Trials and Treatments: An Update on Pharmacotherapy for Idiopathic Pulmonary Fibrosis

A first‐in‐human phase I study of SHR‐1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants

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