Fibrogenic Reactions in Lung Disease
Division of Respiratory Disease, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan. Annual Review of Pathology Mechanisms of Disease
(Impact Factor: 18.75).
02/2010; 5(1):77-98. DOI: 10.1146/annurev.pathol.4.110807.092217
Fibrogenic lung reactions occur as a common phenotype shared among disorders of heterogeneous etiologies. Even with a common etiology, the extent and pattern of fibrosis vary greatly among individuals, even within families, suggesting complex gene-environment interactions. The search for mechanisms shared among all fibrotic lung diseases would represent a major advance in the identification of therapeutic targets that could have a broad impact on lung health. Although it is difficult to grasp all of the complexities of the varied cell types and cytokine networks involved in lung fibrogenic responses, and to predict the biologic responses to the overexpression or deficiency of individual cytokines, a large body of evidence converges on a single common theme: the central importance of the transforming growth factor beta (TGF-beta) pathway. Therapies that act upstream or downstream of TGF-beta activation have the therapeutic potential to treat all fibrogenic responses in the lung.
Available from: Bart G J Dekkers
- "Although this review will focus on novel targets for anti-fibrotic therapy, many of these targets mediate their effects by modulating the synthesis or activation of the potent pro-fibrotic cytokine TGFb. TGFb is a member of the TGFb superfamily, a highly conserved group of cytokines of which there are three mammalian isoforms (TGFb1, b2 and b3), with the role of TGFb1 in pulmonary fibrosis being the best characterized   . TGFb1 is a ubiquitously expressed pleiotropic cytokine which has profound effects on epithelial cells, airway smooth muscle cells and fibroblasts, all of which play a key role in the development of fibrosis within the lung. "
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ABSTRACT: Within the lungs, fibrosis can affect both the parenchyma and the airways. Fibrosis is a hallmark pathological change in the parenchyma in patients with idiopathic pulmonary fibrosis (IPF), whilst in asthma or chronic obstructive pulmonary disease (COPD) fibrosis is a component of the remodelling of the airways. In the past decade, significant advances have been made in understanding the disease behaviour and pathogenesis of parenchymal and airway fibrosis and as a result a variety of novel therapeutic targets for slowing or preventing progression of these fibrotic changes have been identified. This review highlights a number of these targets and discusses the potential for treating parenchymal or airway fibrosis through these mediators/pathways in the future.
Available from: Olivier Durupthy
- "However, the data here did not indicate any myofibroblastic differentiation. These findings could be explained by the absence of TGF-ß production in NP-exposed macrophage supernatant, as TGF-ß is the main cytokine involved in fibroblasts differentiation . Moreover, one can’t rule out the influence of kinetic aspects of our experimental set-up, where macrophages were exposed for 48 hours, leading to a M1-like pro-inflammatory phenotype, without the possibility of developing a later M2 phenotype, where macrophages could act as the primary effectors of later stages of repair and/or later proliferative and remodeling phases. "
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Although major concerns exist regarding the potential consequences of human exposure to nanoparticles (NP), no human toxicological data is currently available. To address this issue, we took welders, who present various adverse respiratory outcomes, as a model population of occupational exposure to NP.The aim of this study was to evaluate if welding fume-issued NP could be responsible, at least partially, in the lung alterations observed in welders.
A combination of imaging and material science techniques including ((scanning) transmission electron microscopy ((S)TEM), energy dispersive X-ray (EDX), and X-ray microfluorescence (μXRF)), was used to characterize NP content in lung tissue from 21 welders and 21 matched control patients. Representative NP were synthesized, and their effects on macrophage inflammatory secretome and migration were evaluated, together with the effect of this macrophage inflammatory secretome on human lung primary fibroblasts differentiation.
Welding-related NP (Fe, Mn, Cr oxides essentially) were identified in lung tissue sections from welders, in macrophages present in the alveolar lumen and in fibrous regions. In vitro macrophage exposure to representative NP (Fe2O3, Fe3O4, MnFe2O4 and CrOOH) induced the production of a pro-inflammatory secretome (increased production of CXCL-8, IL-1ß, TNF-α, CCL-2, -3, -4, and to a lesser extent IL-6, CCL-7 and -22), and all but Fe3O4 NP induce an increased migration of macrophages (Boyden chamber). There was no effect of NP-exposed macrophage secretome on human primary lung fibroblasts differentiation.
Altogether, the data reported here strongly suggest that welding-related NP could be responsible, at least in part, for the pulmonary inflammation observed in welders. These results provide therefore the first evidence of a link between human exposure to NP and long-term pulmonary effects.
Available from: Paul Stoll
- "The majority (> 95%) of circulating BDNF is stored in alpha granules of the platelets, together with Transforming Growth Factor-β1 (TGF-β1). TGF-β1 has been reported to play a major role in the pathogenesis of fibrosis and emphysema in COPD
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Chronic Obstructive Pulmonary Disease (COPD) is characterised by complex inflammatory, neuronal and fibrotic changes. Brain-derived Neurotrophic Factor (BDNF) is a key regulator of neuronal plasticity, whereas Transforming Growth Factor-β1 (TGF-β1) plays a crucial role in tissue repair and emphysema pathogenesis. Both mediators are stored in platelets and released from platelets in inflammatory conditions and during serum preparation. In patients with asthma, it was previously shown that elevated serum BDNF concentrations correlate with disease severity, whereas TGF-β1 concentrations were normal.
In the present study, 63 patients with stable COPD (spirometric GOLD stages 2–4) and 17 age- and comorbidity-matched controls were studied. Lung function, smoking history, medication, platelet concentrations in peripheral blood and serum concentrations of BDNF, TGF-β1 and Serotonin (5-HT) were assessed in all participants.
Serum levels of both BDNF and TGF-β1 (but not concentrations of platelets in peripheral blood) were significantly elevated in all stages of COPD as compared to controls. Highest BDNF concentrations were found in spirometric GOLD stage 3, whereas highest TGF-β1 serum levels were found in spirometric GOLD stage 4. There were specific, stage-dependent correlations of these mediators with lung function parameters of the patients.
Taken together, we show that, in contrast to asthma, COPD is characterised by elevated concentrations of both BDNF and TGF-β1 in serum. The stage-dependent association with lung function supports the hypothesis that these platelet mediators may play a role in the pathogenesis of COPD.
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