Role of insulin like growth factor axis in the bleomycin induced lung injury in rats

Kotarkonda, Lakshmi Kanth; Kulshrestha, Ritu; Ravindran, Krishnan

doi:10.1016/j.yexmp.2017.01.004

Cited by 12 publications

(9 citation statements)

References 39 publications

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“…Furthermore, these studies not only confirmed the presence of elevated levels of IGF-1 in BLM-induced murine lung fibrosis ( Figure 2B,C), 29,69 but showed (1) an increase in IGF-1R-phosphorylation ( Figure 2D,E); (2) that animals treated with Imatinib (PDGFR and cAbl inhibitor) + Lapatinib (EGFR inhibitor), previously shown to ameliorate murine lung fibrosis, 23 had decreased IGF-1 expression and IGF-1R activation ( Figure 2); and (3) an analogous increase in IGF-1 ligand and IGF-1R-phosphorylation in IPF lung tissue (Figure 4). This latter finding was of particular interest as there is conflicting evidence as to whether IGF-1 is upregulated 30,31 or downregulated 82 in IPF and historic immunohistochemical evidence from IPF tissue implies IGF-1 is localized only to injured alveolar epithelia 72 and inflammatory cells. 83 To further address these issues we, first, determined that IGF-1 gene expression in IPF compared to normal primary fibroblasts is a time sensitive response to TGFβ that is masked by the lack of active TGFβ in cell culture medium compared to that in vivo ( Figure 3C); second, evaluated three different patient cohorts and determined that IGF-1 was increased in all three and positively correlated with TGFβ and decreased pulmonary function associated with increased severity of IPF ( Figure 3C-E); and, third, focused our investigations on the proliferating fibroblasts found in IPF fibroblastic foci which showed an enrichment of IGF-1 and IGF-1R-phosphorylation ( Figure 4).…”

Section: Discussionmentioning

confidence: 99%

IPF pathogenesis is dependent upon TGFβ induction of IGF‐1

et al. 2020

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Pathogenic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), have some of the worst prognoses and affect millions of people worldwide. With unclear etiology and minimally effective therapies, two‐thirds of IPF patients die within 2‐5 years from this progressive interstitial lung disease. Transforming Growth Factor Beta (TGFβ) and insulin‐like growth factor‐1 (IGF‐1) are known to promote fibrosis; however, myofibroblast specific upregulation of IGF‐1 in the initiation and progression of TGFβ‐induced fibrogenesis and IPF have remained unexplored. To address this, the current study (1) documents the upregulation of IGF‐1 via TGFβ in myofibroblasts and fibrotic lung tissue, as well as its correlation with decreased pulmonary function in advanced IPF; (2) identifies IGF‐1's C1 promoter as mediating the increase in IGF‐1 transcription by TGFβ in pulmonary fibroblasts; (3) determines that SMAD2 and mTOR signaling are required for TGFβ‐dependent Igf‐1 expression in myofibroblasts; (4) demonstrates IGF‐1R activation is essential to support TGFβ‐driven profibrotic myofibroblast functions and excessive wound healing; and (5) establishes the effectiveness of slowing the progression of murine lung fibrosis with the IGF‐1R inhibitor OSI‐906. These findings expand our knowledge of IGF‐1's role as a novel fibrotic‐switch, bringing us one step closer to understanding the complex biological mechanisms responsible for fibrotic diseases and developing effective therapies.

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Section: Discussionmentioning

confidence: 99%

IPF pathogenesis is dependent upon TGFβ induction of IGF‐1

et al. 2020

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“…IGF-1 may induce epithelial-mesenchymal transition (EMT) of ATII cells, an important process forming fibroblast-like, ECM-producing cells in pulmonary fibrosis [ 108 ]. IGF-1 and IGFBP-5 expressions are significantly reduced in ATII cells in a rat model of bleomycin-induced pulmonary fibrosis [ 109 ]. This is accompanied by an increase in surface protein C (SPC) and α -SMA expression and their colocalization in ATII cells, which suggests the involvement of IGF-1 signaling in EMT of ATII cells during the process of lung injury and fibrosis [ 109 ].…”

Section: Igf-1 In Fibrotic Lung Diseasesmentioning

confidence: 99%

“…IGF-1 and IGFBP-5 expressions are significantly reduced in ATII cells in a rat model of bleomycin-induced pulmonary fibrosis [ 109 ]. This is accompanied by an increase in surface protein C (SPC) and α -SMA expression and their colocalization in ATII cells, which suggests the involvement of IGF-1 signaling in EMT of ATII cells during the process of lung injury and fibrosis [ 109 ]. IGF-1 induces MMP-2 and MMP-9 expression in alveolar epithelial cells through ERK signaling [ 110 ].…”

Section: Igf-1 In Fibrotic Lung Diseasesmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

Wang

Guo

et al. 2018

BioMed Research International

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Insulin-like growth factor-1 (IGF-1) was firstly identified as a hormone that mediates the biological effects of growth hormone. Accumulating data have indicated the role of IGF-1 signaling pathway in lung development and diseases such as congenital disorders, cancers, inflammation, and fibrosis. IGF-1 signaling modulates the development and differentiation of many types of lung cells, including airway basal cells, club cells, alveolar epithelial cells, and fibroblasts. IGF-1 signaling deficiency results in alveolar hyperplasia in humans and disrupted lung architecture in animal models. The components of IGF-1 signaling pathways are potentiated as biomarkers as they are dysregulated locally or systemically in lung diseases, whereas data may be inconsistent or even paradoxical among different studies. The usage of IGF-1-based therapeutic agents urges for more researches in developmental disorders and inflammatory lung diseases, as the majority of current data are collected from limited number of animal experiments and are generally less exuberant than those in lung cancer. Elucidation of these questions by further bench-to-bedside researches may provide us with rational clinical diagnostic approaches and agents concerning IGF-1 signaling in lung diseases.

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“…Although IGFBPs can regulate IGF activity, they also have IGF-independent effects ( 7 ). IGFBP-5 is the most conserved member of the IGFBP family and binds IGF-1 with high affinity ( 7 , 8 ). Similar to other IGFBPs, IGFBP-5 also exerts both IGF-dependent and -independent effects ( 7 , 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…We further showed that IGFBP-5 induced a fibrotic phenotype in vitro in primary human pulmonary fibroblasts, in vivo in mouse skin and lung, and ex vivo in human skin maintained in organ culture ( 7 , 10 – 15 ). Furthermore, the expression of IGFBP-5 is increased in bleomycin-induced pulmonary fibrosis in rats ( 8 ). Taken together, these findings suggest that IGFBP-5 levels are elevated in the setting of tissue fibrosis and that IGFBP-5 can promote the development of fibrosis.…”

Section: Introductionmentioning

confidence: 99%

IGFBP-5 Promotes Fibrosis via Increasing Its Own Expression and That of Other Pro-fibrotic Mediators

et al. 2018

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Pulmonary fibrosis is a hallmark of diseases such as systemic sclerosis (SSc, scleroderma) and idiopathic pulmonary fibrosis (IPF). To date, the therapeutic options for patients with pulmonary fibrosis are limited, and organ transplantation remains the most effective option. Insulin-like growth factor-binding protein 5 (IGFBP-5) is a conserved member of the IGFBP family of proteins that is overexpressed in SSc and IPF. In this study, we demonstrate that both exogenous and adenovirally expressed IGFBP-5 promote fibrosis by increasing the production of extracellular matrix (ECM) genes and the expression of pro-fibrotic genes in primary human lung fibroblasts. IGFBP-5 increased expression of the pro-fibrotic growth factor CTGF and levels of the matrix crosslinking enzyme lysyl oxidase (LOX). Silencing of IGFBP-5 had different effects in lung fibroblasts from normal donors and patients with SSc or IPF. Moreover, we show that IGFBP-5 increases expression of ECM genes, CTGF, and LOX in human lung tissues maintained in organ culture. Together, our data extend our previous findings and demonstrate that IGFBP-5 exerts its pro-fibrotic activity by directly inducing expression of ECM and pro-fibrotic genes. Further, IGFBP-5 promotes its own expression, generating a positive feedback loop. This suggests that IGFBP-5 likely acts in concert with other growth factors to drive fibrosis and tissue remodeling.

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Role of insulin like growth factor axis in the bleomycin induced lung injury in rats

Cited by 12 publications

References 39 publications

IPF pathogenesis is dependent upon TGFβ induction of IGF‐1

IPF pathogenesis is dependent upon TGFβ induction of IGF‐1

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

IGFBP-5 Promotes Fibrosis via Increasing Its Own Expression and That of Other Pro-fibrotic Mediators

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