Back to the Future

Noble, Paul W.; Homer, Robert J.

doi:10.1165/rcmb.f301

Cited by 81 publications

(20 citation statements)

References 44 publications

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“…Major key pathophysiological events in IPF currently discussed include repetitive alveolar epithelial cell injuries, in the presence or absence of local inflammation, impaired epithelial-mesenchymal crosstalk, and subsequent fibroblast to myofibroblast activation [10], [18]–[20]. These mechanisms are mediated by aberrantly activated signaling molecules that drive the fibrotic process, such as TGF-β, IGF, PDGF, or TNF-α [9], [20].…”

Section: Discussionmentioning

confidence: 99%

“…The occurrence of fibroblast foci represents an important prognostic factor, since their numbers have been correlated with survival in IPF [8]. Fibroblast foci occur in subepithelial layers, close to areas of alveolar epithelial cell injury and repair, suggesting that impaired epithelial-mesenchymal crosstalk contributes to the pathobiology of IPF [8], [9]. Indeed, it is well accepted that repetitive injury and subsequent repair of alveolar epithelial type II (ATII) cells, in the presence or absence of local inflammation, represent a key pathogenic mechanism in IPF, which leads to aberrant growth factor activation and perpetuation of fibrotic transformation [10].…”

Section: Introductionmentioning

confidence: 99%

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Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

et al. 2008

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease, characterized by distorted lung architecture and loss of respiratory function. Alveolar epithelial cell injury and hyperplasia, enhanced extracellular matrix deposition, and (myo)fibroblast activation are features of IPF. Wnt/β-catenin signaling has been shown to determine epithelial cell fate during development. As aberrant reactivation of developmental signaling pathways has been suggested to contribute to IPF pathogenesis, we hypothesized that Wnt/β-catenin signaling is activated in epithelial cells in IPF. Thus, we quantified and localized the expression and activity of the Wnt/β-catenin pathway in IPF.Methodology/Principal FindingsThe expression of Wnt1, 3a, 7b, and 10b, the Wnt receptors Fzd1-4, Lrp5-6, as well as the intracellular signal transducers Gsk-3β, β-catenin, Tcf1, 3, 4, and Lef1 was analyzed in IPF and transplant donor lungs by quantitative real-time (q)RT-PCR. Wnt1, 7b and 10b, Fzd2 and 3, β-catenin, and Lef1 expression was significantly increased in IPF. Immunohistochemical analysis localized Wnt1, Wnt3a, β-catenin, and Gsk-3β expression largely to alveolar and bronchial epithelium. This was confirmed by qRT-PCR of primary alveolar epithelial type II (ATII) cells, demonstrating a significant increase of Wnt signaling in ATII cells derived from IPF patients. In addition, Western blot analysis of phospho-Gsk-3β, phospho-Lrp6, and β-catenin, and qRT-PCR of the Wnt target genes cyclin D1, Mmp 7, or Fibronectin 1 demonstrated increased functional Wnt/β-catenin signaling in IPF compared with controls. Functional in vitro studies further revealed that Wnt ligands induced lung epithelial cell proliferation and (myo)fibroblast activation and collagen synthesis.Conclusions/SignificanceOur study demonstrates that the Wnt/β-catenin pathway is expressed and operative in adult lung epithelium. Increased Wnt/β-catenin signaling may be involved in epithelial cell injury and hyperplasia, as well as impaired epithelial-mesenchymal cross-talk in IPF. Thus, modification of Wnt signaling may represent a therapeutic option in IPF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

et al. 2008

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“…IPF is a severe fibrotic disorder limited to the lung, the complex pathogenesis of which is still unclear. It seems to depend principally on an altered mechanism of wound repair in which epithelial cells and fibroblasts play a major role, but other cells and many mediators are involved [34,73,75]. SSc is a connective tissue disease in which lung involvement with interstitial inflammatory infiltration and progressive fibrosis frequently occurs [76].…”

Section: Interstitial Lung Diseasesmentioning

confidence: 99%

Proteome analysis of bronchoalveolar lavage in lung diseases

et al. 2006

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The proteomic approach is complementary to genomics and enables protein composition to be investigated under various clinical conditions. Its application to the study of bronchoalveolar lavage (BAL) is extremely promising. BAL proteomic studies were initially based on two-dimensional electrophoretic separation of complex protein samples and subsequent identification of proteins by different methods. With the techniques available today it is possible to attain many different research objectives. BAL proteomics can contribute to the identification of proteins in alveolar spaces with possible insights into pathogenesis and clinical application for diagnosis, prognosis and therapy. Many proteins with different functions have already been identified in BAL. Some could be biomarkers that need to be individually confirmed by correlation with clinical parameters and validation by other methods on larger cohorts of patients. The standardization of BAL sample preparation and processing for proteomic studies is an important goal that would promote and facilitate clinical applications. Here, we review the principal literature on BAL proteomic analysis applied to the study of lung diseases.

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“…During the remodeling phase, myofibroblasts produce ECM and promote tissue contraction, which will ultimately lead to resolution of the damage. The current dogma is that ongoing microinjury within an organ induces an imbalance in ECM homeostasis and subsequently leads to fibrosis ( 2 , 3 ). In most organs, ECM-producing myofibroblasts are found in close proximity with macrophages, and there is increasing evidence that suggests that normally these two cell types interact in many ways to control ECM homeostasis and that these interactions may be dysregulated in fibrosis ( 3 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

The Elusive Antifibrotic Macrophage

et al. 2015

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Fibrotic diseases, especially of the liver, the cardiovascular system, the kidneys, and the lungs, account for approximately 45% of deaths in Western societies. Fibrosis is a serious complication associated with aging and/or chronic inflammation or injury and cannot be treated effectively yet. It is characterized by excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts and impaired degradation by macrophages. This ultimately destroys the normal structure of an organ, which leads to loss of function. Most efforts to develop drugs have focused on inhibiting ECM production by myofibroblasts and have not yielded many effective drugs yet. Another option is to stimulate the cells that are responsible for degradation and uptake of excess ECM, i.e., antifibrotic macrophages. However, macrophages are plastic cells that have many faces in fibrosis, including profibrotic behavior-stimulating ECM production. This can be dependent on their origin, as the different organs have tissue-resident macrophages with different origins and a various influx of incoming monocytes in steady-state conditions and during fibrosis. To be able to pharmacologically stimulate the right kind of behavior in fibrosis, a thorough characterization of antifibrotic macrophages is necessary, as well as an understanding of the signals they need to degrade ECM. In this review, we will summarize the current state of the art regarding the antifibrotic macrophage phenotype and the signals that stimulate its behavior.

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Back to the Future

Cited by 81 publications

References 44 publications

Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

Functional Wnt Signaling Is Increased in Idiopathic Pulmonary Fibrosis

Proteome analysis of bronchoalveolar lavage in lung diseases

The Elusive Antifibrotic Macrophage

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