Specific Features of Fibrotic Lung Fibroblasts Highly Sensitive to Fibrotic Processes Mediated via TGF-β–ERK5 Interaction

Kadoya, Kotaro; Togo, Shinsaku; Tulafu, Miniwan; Namba, Yukiko; Iwai, Moe; Watanabe, Junko; Okabe, Takahiro; Jin, Jin; Kodama, Yuzo; Kitamura, Hideya; Ogura, Takashi; Kitamura, Norikazu; Ikeo, Kazuho; Takeda, Tomomi; Kondo, Naoto; Takahashi, Kazuhisa

doi:10.33594/000000057

Cited by 10 publications

(10 citation statements)

References 39 publications

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“…However, CTHRC1 and FHL2 levels in the normal control fibroblast did not change upon TGF-β1 stimulation (CTHRC1: control, P = 0.109 versus lung fibrosis, P = 0.003; FHL2: control, P = 0.360 versus lung fibrosis, P = 0.006; Fig. 3A, B), which suggested that fibrotic fibroblasts specifically responded to TGF-β1 stimulation as previously described [11]. As CTHRC1 is a secreted protein, and a previous report showed that CTHRC1 was present in patient plasma [29], we measured release of CTHRC1 from human lung fibroblasts using enzyme-linked immunosorbent assay (ELISA).…”

Section: Resultssupporting

confidence: 77%

“…In addition, rhCTHRC1 stimulated lung fibroblast-mediated gel contraction and migration toward fibronectin, and CTHRC1 knockdown functionally suppressed lung fibroblasts-mediated migration and gel contraction and blocked the TGF-β1 stimulation. Pirfenidone restored TGF-β1- and rhCTHRC1-dependent suppression of BMP4 expression, which was previously reported to reduce proliferation and TGF-β1-induced migration toward fibronectin and synthesis of ECM components, including fibronectin, in lung fibroblast [11, 45, 46]. In the present study, pirfenidone also reduced the levels of the BMP4 antagonist Gremlin1, which was previously implicated in the development of lung fibrosis [47], when stimulated by TGF-β1 and rhCTHRC1.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, pirfenidone also suppressed FHL-2-mediated fibroblast migration. Furthermore, we previously demonstrated that the high response of fibrotic fibroblasts to TGF-β1 [11] suggested resulting in the high response of TGF-β1–induced CTHRC1 and FHL2 expression, which in turn elicited elevated response to pirfenidone treatment in fibrotic fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…The two wells of the Boyden blind well chamber were separated by an 8-μM pore filter (Nucleopore, Pleasanton, CA, USA). The chambers were incubated at 37 °C in a humid atmosphere containing 5% CO 2 for 8 h, after which the cells on top of the filter were removed by scraping [8, 11, 23]. The cells that had migrated through the filter were then fixed, stained with DiffQuick Sysmex (16920), and mounted on glass microscope slides.…”

Section: Methodsmentioning

confidence: 99%

“…We demonstrated that fibrotic fibroblasts, characterized by high response to TGF-β1, stimulated TGF-β1-induced contraction of collagen gels, fibroblast migration, and expression of α-smooth muscle actin and fibronectin. The ERK5 inhibitor blocked these responses more in fibrotic fibroblasts than in normal lung fibroblasts [11]. These observations suggest that fibrotic fibroblasts respond specifically to fibroblast-mediated fibrotic processes and anti-fibrotic compounds.…”

Section: Introductionmentioning

confidence: 99%

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Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

et al. 2019

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Background Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. Methods The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. Results Compared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. Conclusions Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1093-z) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 77%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

et al. 2019

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Cancer‐associated fibroblast migration in non‐small cell lung cancers is modulated by increased integrin α11 expression

et al. 2021

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Cancer-associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer-stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non-small cell lung cancer (NSCLC), and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC-associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer-stroma interactions may serve as a novel, promising anti-tumor strategy.

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Oral Papillary Squamous Cell Carcinoma and Oral Squamous Cell Carcinoma: A Histopathological and Immunohistochemical Comparative Study

Mahmoud,

Abdellatif,

Mahmoud

2024

Head and Neck Pathol

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Purpose The aim of the study is to investigate the immunohistochemical expression of both Alpha smooth muscle actin and Transforming Growth Factor beta and compare their expression in oral papillary squamous cell carcinoma with their expression in different histological grades of oral squamous cell carcinoma. A correlation between these immuno-histochemical expressions and histological findings will then be performed. The research question is “Do the percentages of α-SMA and TGF-β immune-expression in OPSCC differ from that in the conventional OSCC?”. Methods This will be achieved by collecting archival blocks of oral papillary squamous cell carcinoma and different grades of oral squamous cell carcinoma, staining the specimens with Transforming Growth Factor beta and alpha smooth muscle actin, then measuring the mean staining index of expression in each group and the area percent of both markers. Results Results revealed that transforming growth factor beta expression in the epithelium was high in all cases of well-differentiated squamous cell carcinoma, most oral papillary squamous cell carcinoma, and poorly differentiated oral squamous cell carcinoma. On the other hand, different grades of oral squamous cell carcinoma showed a high staining index of alpha smooth muscle actin expression in the stroma. While cases of oral papillary squamous cell carcinoma were either moderate or low-staining. Conclusions Oral papillary squamous cell carcinoma has a favourable prognosis compared to different histological grades, and the prognosis does not depend only on histological grade but also on other prognostic factors.

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Specific Features of Fibrotic Lung Fibroblasts Highly Sensitive to Fibrotic Processes Mediated via TGF-β–ERK5 Interaction

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 10 publications

References 39 publications

Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1

Cancer‐associated fibroblast migration in non‐small cell lung cancers is modulated by increased integrin α11 expression

Oral Papillary Squamous Cell Carcinoma and Oral Squamous Cell Carcinoma: A Histopathological and Immunohistochemical Comparative Study

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