Insulin-Like Growth Factor-Binding Protein-5 Induces Pulmonary Fibrosis and Triggers Mononuclear Cellular Infiltration

Yasuoka, Hidekata; Zhou, Zhihong; Pilewski, Joseph M.; Oury, Tim D.; Choi, Augustine M.K.; Feghali‐Bostwick, Carol

doi:10.2353/ajpath.2006.060501

Cited by 74 publications

(103 citation statements)

References 42 publications

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“…19 This was due, in part, to induction of cell migration by IGFBP-5. 19 To determine whether Egr-1 modulates the migratory activity of IGFBP-5, we compared the migration of fibroblasts and splenocytes from wild-type and Egr-1 KO mice. IGFBP-5-treated wild-type fibroblasts exhibited significantly increased migration ( Figure 10A and B).…”

Section: Igfbp-5-induced Cell Migration Is Regulated By Egr-1mentioning

confidence: 99%

“…[17][18][19] We examined whether IGFBP-5-induced fibronectin expression was regulated by Egr-1. As shown in Figures 9A and B, baseline and IGFBP-5-induced expression of fibronectin was suppressed in Egr-1 KO mouse fibroblasts, as compared with wild-type mouse fibroblasts.…”

Section: Egr-1 Regulates Fibronectin Expression But Not Translocationmentioning

confidence: 99%

“…19 To determine whether primary human and mouse lung fibroblasts respond similarly to IGFBP-5 stimulation in vitro, we expressed IGFBP-5 in primary lung fibroblasts from wildtype mice. Using immunofluorescence, we demonstrate that the distribution of IGFBP-5 and Egr-1 in mouse fibroblasts ( Figure 8A and B) is comparable with that seen in human fibroblasts (Figure 7).…”

Section: Response Of Wild-type and Egr-1 Ko Mouse Fibroblasts To Igfbmentioning

confidence: 99%

“…The chemoattractant activity of IGFBP-5 was assessed using splenocytes 19 and primary lung fibroblasts from wild-type and Egr-1 KO mice. Chemoattractant activity was assessed in a 24-well Trans-well cell culture dish with 5-m pore-size polycarbonate filters for splenocytes and 8-m pore size filters for fibroblasts.…”

Section: Migration Assaymentioning

confidence: 99%

“…19 Briefly, 8-week old wild-type C57BL/6J mice were intratracheally injected with PBS, or 10 9 Pfu cAd or Ad-IGFBP-5 in a 55-l volume. Mice were sacrificed 3 days after adenoviral administration.…”

Section: Mice and Adenoviral Administrationmentioning

confidence: 99%

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The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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We have previously shown that insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that

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Section: Igfbp-5-induced Cell Migration Is Regulated By Egr-1mentioning

confidence: 99%

Section: Egr-1 Regulates Fibronectin Expression But Not Translocationmentioning

confidence: 99%

Section: Response Of Wild-type and Egr-1 Ko Mouse Fibroblasts To Igfbmentioning

confidence: 99%

Section: Migration Assaymentioning

confidence: 99%

Section: Mice and Adenoviral Administrationmentioning

confidence: 99%

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The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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Clinical, Histologic, and Transcriptomic Evaluation of Sequential Fat Grafting for Morphea

Liu,

Wang,

Zhang

et al. 2024

JAMA Dermatol

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ImportanceMorphea is a rare disease of unknown etiology without satisfactory treatment for skin sclerosis and soft tissue atrophy.ObjectiveTo provide clinical, histologic, and transcriptome evidence of the antisclerotic and regenerative effects of sequential fat grafting with fresh fat and cryopreserved stromal vascular fraction gel (SVF gel) for morphea.Design, Setting, and ParticipantsThis single-center, nonrandomized controlled trial was conducted between January 2022 and March 2023 in the Department of Plastic and Reconstructive Surgery of Nanfang Hospital, Southern Medical University and included adult participants with early-onset or late-onset morphea who presented with varying degrees of skin sclerosis and soft tissue defect.InterventionsGroup 1 received sequential grafting of fresh fat and cryopreserved SVF gel (at 1 and 2 months postoperation). Group 2 received single autologous fat grafting. All patients were included in a 12-month follow-up.Main Outcome and MeasuresThe primary outcome included changes in the modified Localized Scleroderma Skin Severity Index (mLoSSI) and Localized Scleroderma Skin Damage Index (LoSDI) scores as evaluated by 2 independent blinded dermatologists. The histologic and transcriptome changes of morphea skin lesions were also evaluated.ResultsOf 44 patients (median [IQR] age, 26 [23-33] years; 36 women [81.8%]) enrolled, 24 (54.5%) were assigned to group 1 and 20 (45.5%) to group 2. No serious adverse events were noted. The mean (SD) mLoSSI scores at 12 months showed a 1.6 (1.50) decrease in group 1 and 0.9 (1.46) in group 2 (P = .13), whereas the mean (SD) LoSDI scores at 12 months showed a 4.3 (1.34) decrease in group 1 and 2.1 (1.07) in group 2 (P &lt; .001), indicating that group 1 had more significant improvement in morphea skin damage but not disease activity compared with group 2. Histologic analysis showed improved skin regeneration and reduced skin sclerosis in group 1, whereas skin biopsy specimens of group 2 patients did not show significant change. Transcriptome analysis of skin biopsy specimens from group 1 patients suggested that tumor necrosis factor α signaling via NFκB might contribute to the immunosuppressive and antifibrotic effect of sequential fat grafting. A total of 15 hub genes were captured, among which many associated with morphea pathogenesis were downregulated and validated by immunohistochemistry, such as EDN1, PAI-1, and CTGF.Conclusions and RelevanceThe results of this nonrandomized trial suggest that sequential fat grafting with fresh fat and cryopreserved SVF gel was safe and its therapeutic effect was superior to that of single autologous fat grafting with improved mLoSSI and LoSDI scores. Histological and transcriptomic changes further support the effectiveness after treatment.Trial RegistrationChinese Clinical Trial Registry identifier: ChiCTR2200058003

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Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation

Lagares¹,

Busnadiego²,

García‐Fernández³

et al. 2012

Arthritis & Rheumatism

154

121

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Objective Enhanced adhesive signaling including activation of the focal adhesion kinase (FAK) is a hallmark of fibroblasts from lung fibrosis patients, and FAK has been therefore hypothesized to be a key mediator of this disease. This study was undertaken to characterize the contribution of FAK to the development of pulmonary fibrosis both in vivo and in vitro. Methods FAK expression and activity were analyzed in lung tissue samples from lung fibrosis patients by immunohistochemistry. Mice orally treated with the FAK inhibitor, PF-562,271, or with siRNA-mediated silencing of FAK, were exposed to intratracheally instilled bleomycin to induce lung fibrosis, and the lungs were harvested for histological and biochemical analysis. Using endothelin-1 (ET-1) as stimulus, cell adhesion and contraction, as well as profibrotic gene expression were studied in fibroblasts isolated from wild type and FAK-deficient mouse embryos. ET-1-mediated FAK activation and gene expression were studied in primary mouse lung fibroblasts, as well as in wild type and integrin β1-deficient fibroblasts. Results Increased FAK expression and activity are upregulated in fibroblast foci and remodeled vessels in lung fibrosis patients. Pharmacological or siRNA-mediated targeting of FAK resulted in marked abrogation of bleomycin-induced lung fibrosis. Loss of FAK impaired the acquisition of a profibrotic phenotype in response to ET-1. Profibrotic gene expression leading to myofibroblast differentiation required cell adhesion, and was driven by Jun N-terminal kinase activation through integrin β1/FAK signaling. Conclusion These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases.

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Insulin-Like Growth Factor-Binding Protein-5 Induces Pulmonary Fibrosis and Triggers Mononuclear Cellular Infiltration

Cited by 74 publications

References 42 publications

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Clinical, Histologic, and Transcriptomic Evaluation of Sequential Fat Grafting for Morphea

Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation

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