Pathogenesis of fibrosis: role of TGF-β and CTGF

Ihn, Hironobu

doi:10.1097/00002281-200211000-00009

Cited by 303 publications

(227 citation statements)

References 67 publications

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“…Superoxide has been shown previously to induce proliferation of cardiac fibroblasts [25]. The most abundant growth factor detected was connective tissue growth factor which has been ascribed a role in the pathogenesis of fibrosis [26]. At the time of resubmission of our manuscript, a paper was published showing that cGK I inhibits the fibrogenic potential of high glucose by repressing thrombospondin 1 -dependent transforming growth factor-beta activation; both of these proteins are also expressed in cardiac fibroblasts (Table 4) [27].…”

Section: Expression Of Extracellular Matrix Proteins and Growth Factorsmentioning

confidence: 87%

Quantitative analysis of the cardiac fibroblast transcriptome—implications for NO/cGMP signaling

et al. 2004

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SummaryCardiac fibroblasts regulate tissue repair and remodeling in the heart. To quantify transcript levels in these cells we performed a comprehensive gene expression study using serial analysis of gene expression (SAGE). Among 110,169 sequenced tags we could identify 30,507 unique transcripts. A comparison of SAGE data from cardiac fibroblasts with data derived from total mouse heart revealed a number of fibroblast-specific genes. Cardiac fibroblasts expressed a specific collection of collagens, matrix proteins and metalloproteinases, growth factors, and components of signalling pathways. The NO/cGMP signalling pathway was represented by the mRNAs for α 1 and β 1 subunits of guanylyl cyclase, cGMP-dependent protein kinase type I (cGK I) and interestingly the G-kinase anchoring protein GKAP42. The expression of cGK I was verified by RT-PCR and Western Blot. To establish a functional role for cGK I in cardiac fibroblasts we studied its effect on cell proliferation. Selective activation of cGK I with a cGMP-analog inhibited the proliferation of serum-stimulated cardiac fibroblasts which express cGK I, but not higher passage fibroblasts which contain no detectable cGK I. Currently, our data suggest that cGK I mediates the inhibitory effects of the NO/cGMP pathway on cardiac fibroblast growth.Furthermore the SAGE library of transcripts expressed in cardiac fibroblasts provides a basis for future investigations into the pathological regulatory mechanisms underlying cardiac fibrosis.

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Section: Expression Of Extracellular Matrix Proteins and Growth Factorsmentioning

confidence: 87%

Quantitative analysis of the cardiac fibroblast transcriptome—implications for NO/cGMP signaling

et al. 2004

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“…In murine models, overexpression of the gene for TGF-b1 (TGFB1) leads to increased airway inflammation and subepithelial fibrosis (8,9). Alternatively, recent data suggest that TGF-b1 antagonism results in a marked increase in airway responsiveness in mice with chronic airway inflammation induced by exposure to dust mite allergen, suggesting a potential role for gene-by-environment interactions (10).…”

mentioning

confidence: 99%

Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma

Sharma¹,

Raby²,

Hunninghake³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Polymorphisms in the gene for transforming growth factor-b1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma. Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood. Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity. Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P 5 0.0006) and CAMP (P 5 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P < 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P 5 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P 5 0.009) and CAMP (P 5 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts. Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.

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“…Because high levels of CTGF are observed during wound healing and in fibrotic lesions, and CTGF induces the synthesis of extracellular matrix proteins, it is believed to play a role in the pathogenesis of fibrosis (5). The fibrogenic growth factor transforming growth factor ␤ (TGF␤) is one of the major inducers of CTGF expression, but other mediators implicated in organ injury and wound healing such as lysophosphatidic acid (LPA), serotonin, or angiotensin II can also directly increase CTGF levels (e.g.…”

mentioning

confidence: 99%

Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton

Ott

Iwanciw

Graneß

et al. 2003

Journal of Biological Chemistry

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Modulation of the cytoskeletal architecture was shown to regulate the expression of CTGF (connective tissue growth factor, CCN2). The microtubule disrupting agents nocodazole and colchicine strongly up-regulated CTGF expression, which was prevented upon stabilization of the microtubules by paclitaxel. As a consequence of microtubule disruption, RhoA was activated and the actin stress fibers were stabilized. Both effects were related to CTGF induction. Overexpression of constitutively active RhoA induced CTGF synthesis. Interference with RhoA signaling by simvastatin, toxinB, C3 toxin, and Y27632 prevented up-regulation of CTGF. Likewise, direct disintegration of the actin cytoskeleton by latrunculin B interfered with nocodazolemediated up-regulation of CTGF expression. Disassembly of actin fibers by cytochalasin D, however, unexpectedly increased CTGF expression indicating that the content of F-actin per se was not the major determinant for CTGF gene expression. Given the fact that cytochalasin D sequesters G-actin, a decrease in G-actin increased CTGF, while increased levels of Gactin corresponded to reduced CTGF expression. These data link alterations in the microtubule and actin cytoskeleton to the expression of CTGF and provide a molecular basis for the observation that CTGF is up-regulated in cells exposed to mechanical stress.

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Pathogenesis of fibrosis: role of TGF-β and CTGF

Cited by 303 publications

References 67 publications

Quantitative analysis of the cardiac fibroblast transcriptome—implications for NO/cGMP signaling

Quantitative analysis of the cardiac fibroblast transcriptome—implications for NO/cGMP signaling

Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma

Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton

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