Roles for Insulin-Like Growth Factor I and Transforming Growth Factor-β in Fibrotic Lung Disease

doi:10.1378/chest.122.6_suppl.289S

Chest

Volume 122, Issue 6, Supplement, December 2002, Pages 289S-293S

https://doi.org/10.1378/chest.122.6_suppl.289S Get rights and content

Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-β, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-β production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-β in cell migration, proliferation, and ECM synthesis in patients with IPF.

Section snippets

IGF-I

IGF-I is a 70-amino acid, 7.6-kd, single-chain nonglycosylated polypeptide with structural similarity to insulin. IGF-I has a broad range of physiologic functions including the stimulation of cell division, differentiation, migration, growth, inhibition of apoptosis, and the regulation of gene transcription. The actions of IGF-I occur primarily via the IGF-I receptor (IGF-IR), a tetrameric, type-1 surface receptor that is composed of two α-chains and two β-chains that are joined by disulfide

TGF-β

TGF-β consists of a family of several peptide members secreted in a latent form that must be activated by cleavage for function. TGF-β binds a heterodimeric receptor on the surface of target cells and stimulates cells via its receptor serine/threonine kinase activity and signal transduction cascades, including the SMAD and mitogen-activated protein kinase pathways.²⁰ TGF-β stimulates several processes that are critical to wound repair following lung injury, including serving to reduce

Divergent Roles of TGF-β and IGF-I

Studies in our laboratory have shown that bone marrow-derived macrophages in the presence of TGF-β have reduced basal IGF-I messenger RNA production and, when stimulated with TNF-α, macrophages, have been unable to enhance IGF-I messenger RNA production (Fig 1). Therefore, TGF-β inhibits the ability of the macrophage to express IGF-I directly, by repressing IGF-I messenger RNA expression, and indirectly, by reducing proinflammatory cytokine production. Interestingly, Homma et al¹³ showed large

Conclusion

Inflammation has been shown to occur in the early stages of IPF, presumably in response to damage to the respiratory epithelium and the subsequent recruitment of leukocytes. While arguments persist as to whether fibrosis is a result of inflammation or whether fibrosis occurs without significant inflammation, we argue that inflammation and the subsequent local production of IGF-I are required for the efficient repair of epithelial injury. In the absence of inflammation or with the premature

References (23)

H Olbruck et al.
Supernatants from quartz dust treated human macrophages stimulate cell proliferation of different human lung cells as well as collagen-synthesis of human diploid lung fibroblasts in vitro
Toxicol Lett
(1998)
MA Guvakova et al.
The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin
Exp Cell Res
(1999)
M Selman et al.
Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy
Ann Intern Med
(2001)
PM Krein et al.
Growth factor regulation and manipulation in wound repair: to scar or not to scar, that is the question
Expert Opin Ther Patients
(2001)
JA Lasky et al.
Interstitial fibrosis and growth factors
Environ Health Perspect
(2000)
Y Miyazaki et al.
Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis
J Clin Invest
(1995)
J-Y Liu et al.
Increased TGF-beta1 in the lungs of asbestos-exposed rats and mice: reduced expression in TNF-alpha receptor knockout mice
J Environ Pathol Toxicol Oncol
(2001)
PJ Sime et al.
Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung
J Clin Invest
(1997)
J Gauldie et al.
Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis
Curr Topics Pathol
(1999)
IY Adamson et al.
Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis
Am J Pathol
(1988)

G Raghu et al.

Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs

Am Rev Respir Dis

(1988)

Cited by (106)

Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review
2023, International Journal of Biological Macromolecules
Liver fibrosis is a wound-healing response due to persistent liver damage and it may progress to cirrhosis and even liver cancer if no intervention is given. In the current cognition, liver fibrosis is reversible. So, it is of great significance to explore the related gene targets or biomarker for anti-fibrosis of liver. Insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) are mainly expressed in the liver tissues and play critical roles in the liver function. The present review summarized the role of IGF1/IGF1R and its signaling system in liver fibrosis and illustrated the potential mechanisms including DNA damage repair, cell senescence, lipid metabolism and oxidative stress that may be involved in this process according to the studies on the fibrosis of liver or other organs. In particular, the roles of IGF1 and IGF1R in DNA damage repair were elaborated, including membrane-localized and nucleus-localized IGF1R. In addition, for each of the potential mechanism in anti-fibrosis of liver, the signaling pathways of the IGF1/IGF1R mediated and the cell species in liver acted by IGF1 and IGF1R under different conditions were included. The data in this review will support for the study about the effect of IGF1/IGF1R on liver fibrosis induced by various factors, meanwhile, provide a basis for the study of liver fibrosis to focus on the communications between the different kinds of liver cells.
Exosomal let-7i-5p from three-dimensional cultured human umbilical cord mesenchymal stem cells inhibits fibroblast activation in silicosis through targeting TGFBR1
2022, Ecotoxicology and Environmental Safety
Citation Excerpt :
It is notably challenging to identify the mechanism of PF. The following cytokines and fibrogenic factors have been shown to contribute to the pathogenesis of PF in many patients: insulin-like growth factor-1, TGFβ1, tumor necrosis factor-1, and platelet derived growth factor (Krein and Winston, 2002; Correa-Costa et al., 2014) Changes in apoptosis (Jiang, 2018), matrix metalloproteinases (Winkler and Fowlkes, 2002), the presence of myofibroblasts (Wijsenbeek and Cottin, 2020) and cell adhesion molecules (Shimbori et al., 2016), changes in abnormal epithelial cell function (Ballester et al., 2019), excessive procoagulant activity (Lin et al., 2016) and mast cell function (Guzy, 2020). All of these studies offer promising opportunities for therapeutic interventions.
Silicosis of pulmonary fibrosis (PF) is related to long-term excessive inhalation of silica. The activation of fibroblasts into myofibroblasts is the main terminal effect leading to lung fibrosis, which is of great significance to the study of the occurrence and development of silicosis fibrosis and its prevention and treatment. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) are considered to be a potential therapy of silica-induced PF, however, their exact mechanism remains unknown. Therefore, this study aims to explore whether hucMSC-Exos affect the activation of fibroblasts to alleviate PF. In this study, a three-dimensional (3D) method was applied to culture hucMSCs and MRC-5 cells (human embryonic lung fibroblasts), and exosomes were isolated from serum-free media, identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blotting analysis. Then, the study used an animal model of silica-induced PF to observe the effects of hucMSC-Exos and MRC-5-Exos on activation of fibroblasts. In addition, the activation of fibroblasts was analyzed by Western blotting analysis, wound healing, and migration assay with the treatment of hucMSC-Exos and MRC-5-Exos in NIH-3T3 cells (mouse embryonic fibroblasts). Furthermore, differential expression of microRNAs (DE miRNAs) was measured between hucMSCs-Exos and MRC-5-Exos by high throughput sequence. HucMSC-Exos inhibited the activation of fibroblasts in mice and NIH-3T3 cells. Let-7i-5p was significantly up-regulated in hucMSCs-Exos compared to MRC-5-Exos, which was related to silica-induced PF. Let-7i-5p of hucMSCs-Exos was responsible for the activation of fibroblasts by targeting TGFBR1. Meanwhile, Smad3 was also an important role in the activation of fibroblasts. The study demonstrates that hucMSCs-Exos act as a mediator that transfers let-7i-5p to inhibit the activation of fibroblasts, which alleviates PF through the TGFBR1/Smad3 signaling pathway. The mechanism has potential value for the treatment of silica-induced PF.
Role of insulin like growth factor axis in the bleomycin induced lung injury in rats
2017, Experimental and Molecular Pathology
Alveolar epithelial cell injury has been proposed as a causative factor for the onset and progression of pulmonary fibrosis. However, the role of type II alveolar epithelial cells (AECs) in the epithelial mesenchymal transition (EMT) is controversial.
The present study performed in rats instilled with bleomycin investigated a) the expressions of the insulin growth factor (IGF-1) and insulin growth factor binding protein 5 (IGFBP-5) and transforming growth factor (TGF-β1) in the type II AECs, b) the role of type II AECs in EMT and extracellular matrix (ECM) formation and, c) the effect of pioglitazone on all the above parameters.
Male Wistar rats were divided into three Groups: Group I (saline control), Group II (Bleomycin, given as a single intratracheal instillation, 7 U/kg) and Group III (Bleomycin + Pioglitazone (40 mg/kg/day orally, starting 7 days post bleomycin instilled as in Group II). From lung tissues, the protein expressions of IGF-1, IGFBP-5, TGF-β1, surfactant protein C (SP-C, as a marker for type II AECs) and α-smooth muscle actin (α-SMA, as a marker for EMT), were determined on day 7 in Groups I and II and on days 14, 21 and 35 in all the three groups.
IGFBP-5 and IGF-1 expressions were reduced significantly and TGF-β1 expression increased significantly in type II AECs in Group II from day 7 till day 35 as compared to Group I. An increase in SP-C and α-SMA expression and their co-localization were seen in the type II AECs undergoing EMT from day 7 till day 35. A concomitant remodeling and laying down of ECM was observed also. In Group III, with pioglitazone, there was a reversal with significant up-regulation in IGFBP-5 and IGF-1 expressions and down-regulation of TGF-β1 in the type II AECs along with a significant decrease in the solid area fraction, EMT and ECM in the lung tissue.
IGFBP-5, IGF-1 and TGF-β1 in the type II AECs play a key role in lung injury caused by bleomycin and pioglitazone attenuates the lung injury/fibrosis by restoring IGFBP-5 and IGF-1 and decreasing TGF-β1 expressions in the type II AECs.
MicroRNAs-mediated epithelial-mesenchymal transition in fibrotic diseases
2017, European Journal of Pharmacology
MicroRNAs (miRNAs), a large family of small and highly conserved non-coding RNAs, regulate gene expression through translational repression or mRNA degradation. Aberrant expression of miRNAs underlies a spectrum of diseases including organ fibrosis. Recent evidence suggests that miRNAs contribute to organ fibrosis through mediating epithelial-mesenchymal transition (EMT). Alleviation of EMT has been proposed as a promising strategy against fibrotic diseases given the key role of EMT in fibrosis. miRNAs impact the expression of specific ligands, receptors, and signaling pathways, thus modulating EMT and consequently influencing fibrosis. This review summarizes the current knowledge concerning how miRNAs regulate EMT and highlights the specific roles that miRNAs-regulated EMT plays in fibrotic diseases as diverse as pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis. It is desirable that a more comprehensive understanding of the functions of miRNAs-regulated EMT will facilitate the development of novel diagnostic and therapeutic strategies for various debilitating organ fibrosis.
Gene expression profiling reveals novel protective effects of Aminaphtone on ECV304 endothelial cells
2016, European Journal of Pharmacology
Citation Excerpt :
IGF-1, the insulin growth factor 1, exerts pleiotropic antioxidant and anti-inflammatory effects, which together may reduce atherosclerotic burden and vascular injury (Shai et al., 2011), and has a protective role in the pulmonary fibrotic process. High IGF-1 levels are, in fact, dosed in patients affected by idiopathic pulmonary fibrosis and are correlated with a better healing because of its property in the induction of epithelialization repair in post-inflammation tissue (Krein and Winston, 2002; Muguerza et al., 2001). Thus, IGF-1 up-regulation induced by Aminaphtone could have a therapeutic role in many inflammatory disorders, as it is shown to be a protective anti-fibrotic factor.
Aminaphtone, a drug used in the treatment of chronic venous insufficiency (CVI), showed a remarkable role in the modulation of several vasoactive factors, like endothelin-1 and adhesion molecules. We analysed in vitro the effects of Aminaphtone on whole-genome gene expression and production of different inflammatory proteins. ECV-304 endothelial cells were stimulated with IL-1β 100 U/ml in the presence or absence of Aminaphtone 6 μg/ml. Gene expression profiles were compared at 1, 3, and 6 h after stimulation by microarray. Supernatants of ECV-304 cultures were analysed at 3, 6, 12, and 24 h by multiplex ELISA for production of several cytokine and chemokines. Microarrays showed a significant down-regulation at all times of a wide range of inflammatory genes. Aminaphtone appeared also able to modulate the regulation of immune response process (down-regulating cytokine biosynthesis, transcripts involved in lymphocyte differentiation and cell proliferation, and cytokine-cytokine receptor interaction) and to regulate genes engaged in homeostasis, secretion, body fluid levels, response to hypoxia, cell division, and cell-to-cell communication and signalling. Results were confirmed and extended analysing the secretome, which showed significant reduction of the release of 14 cytokines and chemokines. These effects are predicted to be mediated by interaction with different transcription factors.
Aminaphtone was able to modulate the expression of inflammatory molecules relevant to the pathogenesis of several conditions in which the endothelial dysfunction is the main player and early event, like scleroderma, lung fibrosis, or atherosclerosis.
Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation
2016, Environmental Research
Citation Excerpt :
Membrane damage also not only acts as a cause of inflammation, but also facilitates the transfer of nanoparticles into other organs (Kagan et al., 2005; Tahara et al., 2012). Additionally, TGF-β stimulates processes to repair lung injury, including reducing pro-inflammatory cytokine production from macrophages, promoting the recruitment of fibroblasts, and stimulating the production of extracellular matrix proteins (Davies, 2009; Halwani et al., 2011; Park et al., 2013; Krein and Winston, 2002; Lohcharoenkal et al., 2013). Therefore, we hypothesize that SWCNTs may cause systemic health effects with a local immune response, translocating freely or at state engulfed by phagocytes into other organs for a long time (Bhattacharya et al., 2013; Ong et al., 2016).
Due to their unique physicochemical properties, the potential health effects of single-walled carbon nanotubes (SWCNTs) have attracted continuous attention together with their extensive application. In this study, we aimed to identify local and systemic health effects following pulmonary persistence of SWCNTs. As expected, SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation (50, 100, and 200 μg/kg). In the lung, the total number of cells and the percentages of lymphocytes and neutrophils significantly increased at 200 μg/kg compared to the control, and the Th1-polarized immune response was induced accompanying enhanced expression of tissue damage-related genes and increased release of chemokines. Additionally, SWCNTs enhanced the expression of antigen presentation-related proteins on the surface of antigen-presenting cells, however, maturation of dendritic cells was inhibited by their persistence. As compared to the control, a significant increase in the percentage of neutrophils and a remarkable decrease of BUN and potassium level were observed in the blood of mice treated with the highest dose. This was accompanied by the down-regulation of the expression of antigen presentation-related proteins on splenocytes. Moreover, protein and glucose metabolism were disturbed with an up-regulation of fatty acid β-oxidation. Taken together, we conclude that SWCNTs may induce adverse health effects by disturbing immune and metabolic regulation functions in the body. Therefore, careful application of SWCNTs is necessary for the enforcement of safety in nano-industries.

View all citing articles on Scopus

: Dr. Winston was supported by a Canadian Institutes of Health Research (Medical Research Council of Canada) Scholarship, an Alberta Lung Association Operating Grant, and an Alberta Heritage Foundation for Medical Research Clinical Investigator Grant. Mr. Krein was supported by an Alberta Heritage Foundation for Medical Research Studentship Award.

View full text

Article preview

Chest

Section snippets

IGF-I

TGF-β

Divergent Roles of TGF-β and IGF-I

Conclusion

References (23)

Supernatants from quartz dust treated human macrophages stimulate cell proliferation of different human lung cells as well as collagen-synthesis of human diploid lung fibroblasts in vitro

Toxicol Lett

The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin

Exp Cell Res

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

Growth factor regulation and manipulation in wound repair: to scar or not to scar, that is the question

Expert Opin Ther Patients

Interstitial fibrosis and growth factors

Environ Health Perspect

Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis

J Clin Invest

Increased TGF-beta1 in the lungs of asbestos-exposed rats and mice: reduced expression in TNF-alpha receptor knockout mice

J Environ Pathol Toxicol Oncol

Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung

J Clin Invest

Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis

Curr Topics Pathol

Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis

Am J Pathol

Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs

Am Rev Respir Dis

Cited by (106)

Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review

Exosomal let-7i-5p from three-dimensional cultured human umbilical cord mesenchymal stem cells inhibits fibroblast activation in silicosis through targeting TGFBR1

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

MicroRNAs-mediated epithelial-mesenchymal transition in fibrotic diseases

Gene expression profiling reveals novel protective effects of Aminaphtone on ECV304 endothelial cells

Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation

Chest

Roles for Insulin-Like Growth Factor I and Transforming Growth Factor-β in Fibrotic Lung Disease*

Section snippets

IGF-I

TGF-β

Divergent Roles of TGF-β and IGF-I

Conclusion

Toxicol Lett

Exp Cell Res

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

Growth factor regulation and manipulation in wound repair: to scar or not to scar, that is the question

Expert Opin Ther Patients

Interstitial fibrosis and growth factors

Environ Health Perspect

Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis

J Clin Invest

Increased TGF-beta1 in the lungs of asbestos-exposed rats and mice: reduced expression in TNF-alpha receptor knockout mice

J Environ Pathol Toxicol Oncol

Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung

J Clin Invest

Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis

Curr Topics Pathol

Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis

Am J Pathol

Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs

Am Rev Respir Dis

Roles for Insulin-Like Growth Factor I and Transforming Growth Factor-β in Fibrotic Lung Disease^*