Insulin-Like Growth Factor Binding Proteins 3 and 5 Are Overexpressed in Idiopathic Pulmonary Fibrosis and Contribute to Extracellular Matrix Deposition

Pilewski, Joseph M.; Liu, Lixin; Henry, Adam C.; Knauer, Alycia V.; Feghali‐Bostwick, Carol

doi:10.1016/s0002-9440(10)62263-8

Cited by 212 publications

(317 citation statements)

References 35 publications

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“…MMP-19 is able to hydrolyze diverse components of the ECM, such as aggrecan, cartilage oligomeric matrix protein (COMP), fibronectin, and the basement membrane proteins laminin-5g2, nidogen, and collagen type IV (30,37), all found in fibrotic matrix. MMP-19 has been shown to cleave IGFBP3 (38), a molecule increased in IPF as well as other fibrotic disorders (39), as well as to cleave tenascin-C, an ECM component required for lung fibrosis in the bleomycin model (40). Similar to our observation in MMP19 2/2 mice exposed to bleomycin, exaggerated tenascin C accumulation was observed in MMP-19-deficient mice exposed to a murine model of asthma.…”

Section: Discussionsupporting

confidence: 86%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycininduced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19 2/2 mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19 2/2 mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

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Section: Discussionsupporting

confidence: 86%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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“…Among the 30 most consistently up-regulated genes were several proteins previously associated with IPF, such as several extracellular matrix proteins and IGFBP-5 (Table 1). 19 One of the most consistently upregulated genes was twist1 (Table 2 and Figure 1A). Interestingly, although earlier gene expression profiling studies of this disease did not identify twist1 as being up-regulated, 20 -22 a recent reanalysis of microarray data did identify twist1 as being-up-regulated, although this result was not explored further.…”

Section: Gene Expression Profiling Identifies Twist1 As the Most Consmentioning

confidence: 99%

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

Bridges

Kass

Loh

et al. 2009

The American Journal of Pathology

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Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into IPF pathogenesis, we performed gene expression profiling of IPF lungs. Twist1, a basic helix-loop-helix protein, was found among the most consistently and highly up-regulated genes and was expressed in nuclei of type II epithelial cells, macrophages, and fibroblasts in IPF lungs. We studied the function of Twist1 in fibroblasts further, because they are the major effector cells in this disease and persist despite an ambient proapoptotic environment. Twist1 was induced by the profibrotic growth factors (GFs) basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor in primary rat lung fibroblasts (RLFs). Suppression of Twist1 expression resulted in decreased RLF accumulation due to increased apoptosis, whereas Twist1 overexpression protected RLFs against several apoptotic stimuli. Addition of platelet-derived growth factor in combination with other GFs led to an increase in proliferation. When Twist1 was depleted, GFs continued to act as mitogens but caused a marked increase in cell death. The increase in apoptosis under basal or growth factorstimulated conditions was partly mediated by up-regulation of the proapoptotic Bcl-2 family members, Bim and PUMA. These findings indicate that Twist1 promotes survival and accumulation of fibroblasts by shaping their responsiveness to growth factor stimulation. We propose that Twist1 represents one of the factors that promotes pathogenic accumulation of fibroblasts in fibrotic lung disease. (Am J Pathol

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“…13 Briefly, the full-length cDNAs of human IGFBP-3 and -5 were obtained by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA extracted from primary human lung fibroblasts. The cDNAs were subcloned into the shuttle vector pAdlox and used for the preparation of replication-deficient adenovirus serotype 5 expressing IGFBP-3 (Ad3), IGFBP-5 (Ad5), or no cDNA (cAd) in the Vector Core Facility at the University of Pittsburgh.…”

Section: Adenovirus Construct Preparationmentioning

confidence: 99%

“…ECM was harvested as we have previously described. 13 Samples were analyzed by Western blot analysis using one of the following antibodies: anti-human IGFBP-3 (Santa Cruz Biotechnology, Santa Cruz, CA), anti-IGFBP-5 (Gropep Ltd., Thebarton, Australia), anti-fibronectin (Santa Cruz Biotechnology), or anti-␣-smooth muscle actin (␣-SMA) (Sigma-Aldrich). Signals were detected after incubation with horseradish peroxidase-conjugated secondary antibody and chemiluminescence (Perkin Elmer Life Sciences, Inc., Boston, MA).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…13 In addition, we have shown that overexpression of IGFBP-5 in normal primary fibroblasts increases collagen and fibronectin deposition in the extracellular milieu. 13 In this study, we report the in vivo effects of human IGFBP-5 expression in the mouse. Expression of IGFBP-5 induced prominent inflammatory changes and fibrosis resembling human fibrotic disease states.…”

mentioning

confidence: 92%

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

Yasuoka

Zhou

Pilewski

et al. 2006

The American Journal of Pathology

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Insulin-Like Growth Factor Binding Proteins 3 and 5 Are Overexpressed in Idiopathic Pulmonary Fibrosis and Contribute to Extracellular Matrix Deposition

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown etiology that results in

Cited by 212 publications

References 35 publications

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

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

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