Connective-Tissue Growth Factor Contributes to TGF-β1–induced Lung Fibrosis

Yanagihara, Toyoshi; Tsubouchi, Kazuya; Gholiof, Mahsa; Chong, Sy Giin; Lipson, Kenneth E.; Zhou, Quan; Scallan, Ciaran; Upagupta, Chandak; Tikkanen, Jussi; Keshavjee, Shaf; Ask, Kjetil; Kolb, Martin

doi:10.1165/rcmb.2020-0504oc

Cited by 62 publications

(33 citation statements)

References 38 publications

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“…Due to adverse effects of currently drugs for IPF and there is no effective cure, IPF research is increasingly focused on developing new molecular targets and treatment options. As mentioned above, CTGF is an important pro-fibrotic growth factor associated with extracellular matrix secretion and abnormal tissue repair ( Yanagihara et al, 2021 ). A recent phase II clinical trial has confirmed that treatment of pamrevlumab, which is a fully human recombinant monoclonal antibody against CTGF, can significantly reduce the decline of FVC and attenuate the progression of IPF.…”

Section: Treatmentsmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.

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Section: Treatmentsmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

et al. 2022

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“…TCP is a very rigid matrix, similar to tendon or bone, with a tensile strength of 10 6 kPa (23). The level of COL1A1, one of the fibrotic markers, was highest in TCP, followed by 50 kPa compared to 1 kPa (Figure 7D), suggesting stiffness around the fibroblasts induces a fibrotic phenotype, similar to other pro-fibrotic markers, such as CTGF (24). The level of GREM1 was greatly upregulated on 50 kPa compared to 1 kPa, but no difference between 50 kPa and TCP (Figure 7E).…”

Section: Gremlin Regulation By Tgfβ Il-1β and Stiffness Around Cellsmentioning

confidence: 92%

Intrinsic BMP inhibitor Gremlin regulates lung alveolar progenitor cell proliferation and differentiation

Yanagihara

Zhou

Tsubouchi

et al. 2022

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Type 1 alveolar epithelial cells (AT1s) and type 2 alveolar epithelial cells (AT2s) regulate the structural integrity and function of alveoli. AT1s mediate gas exchange, whereas AT2s serve multiple functions, including surfactant secretion and alveolar repair through proliferation and differentiation into AT1s as progenitors. However, mechanisms regulating AT2 proliferation and differentiation remain unclear. Here we demonstrate that Gremlin, an intrinsic inhibitor of bone morphogenetic protein (BMP), induces AT2 proliferation and differentiation. Transient overexpression of Gremlin in rat lungs by adenovirus vector delivery suppressed BMP signaling, induced proliferation of AT2s and the production of Bmp2, which in turn led to the recovery of BMP signaling and induced AT2 differentiation into AT1s. Gremlin was upregulated in a bleomycin-induced lung injury model. TGF-β and IL-1β induced Gremlin expression in fibroblasts. Taken together, our findings implicate that Gremlin expression during lung injury leads to precisely timed inhibition of BMP signaling and activates AT2s, leading to alveolar repair.

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“…A new research has confirmed the synergistic effect of CTGF and TGF-β1 (33). Intriguingly, single nucleotide polymorphisms (SNPs) in CTGF have been found to associate with the process of PF (34).…”

Section: Interference With Ctgf Detained the Development Of Pf In Vivomentioning

confidence: 93%

Interference with connective tissue growth factor attenuated fibroblast-to-myofibroblast transition and pulmonary fibrosis

et al. 2022

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Background: The aberrant activation and phenotype shift of resident fibroblasts in lung tissues via fibroblast-to-myofibroblast transition (FMT) is considered a pivotal step in pulmonary fibrogenesis, resulting in excessive extracellular matrix (ECM) production and deposition. However, the molecular mechanisms regulating FMT and lung fibrosis are still unclear. Connective tissue growth factor (CTGF) has been reported to be both an ECM protein and a versatile signaling molecule that is involved in multiple pathophysiological contexts, especially fibrosis. The relationship between CTGF, FMT, and lung fibrosis has not yet been well defined.Methods: In this study, a pulmonary fibrosis (PF) rat model and FMT cell model induced by paraquat (PQ) were established to explore the relevant regulatory mechanisms in vivo and in vitro. Results:The results showed that the CTGF was highly activated and was a mediator of canonical Wnt signaling during FMT and PF. The inhibition of the CTGF by small-interfering ribonucleic acid decreased the expression of FMT markers, including α-smooth muscle actin, vimentin, and collagen I, inhibited the activated Wnt signaling pathway, and ameliorated lung fibrosis.Conclusions: Our findings showed that CTGF was the key effector of the FMT and fibrotic changes, and emphasized the therapeutic potential of the inhibitor or monoclonal antibody against CTGF for PF.

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Connective-Tissue Growth Factor Contributes to TGF-β1–induced Lung Fibrosis

Cited by 62 publications

References 38 publications

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

Intrinsic BMP inhibitor Gremlin regulates lung alveolar progenitor cell proliferation and differentiation

Interference with connective tissue growth factor attenuated fibroblast-to-myofibroblast transition and pulmonary fibrosis

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