Mechanisms of fibrosis in coal workers' pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta and relationship to disease severity.

Vanhée, Dominique; Gosset, P.; Wallaert, B; Voisin, C; Tonnel, A.-B.

doi:10.1164/ajrccm.150.4.7921435

Cited by 82 publications

(56 citation statements)

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“…All the mitogens are present in the airways (4,15,24). However, their levels in the airways of asthmatics are likely to vary depending on the degree of inflammatory cell activation and vascular leakage occurring locally.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Lalor¹,

Truong²,

Henness³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammation and vascular leakage are prevalent in asthma. This study aimed to elucidate the mechanisms involved in serum potentiation of cytokine-induced granulocyte macrophage colony stimulating factor (GM-CSF) production by human airway smooth muscle cells and to identify possible factors responsible. Serum-deprived cells at low density were stimulated with TNF-α and IL-1β for 24 h. Human AB serum (10%), inhibitors of RNA and protein synthesis or specific signaling molecules, or known smooth muscle mitogens were then added for 24 h. Culture supernatants were analyzed for GM-CSF levels, and cells were harvested to assess viability, cell cycle progression, GM-CSF-specific mRNA content, and p38 phosphorylation. Serum potentiated GM-CSF release when added before, together with (maximal), or after the cytokines. The potentiation involved both new GM-CSF-specific mRNA production and protein synthesis. The mitogens IGF, PDGF, and thrombin all potentiated GM-CSF release, and neutralizing antibodies for EGF, IGF, and PDGF reduced the serum potentiation. Inhibitor studies ruled as unlikely the involvement of p70S6kinase and the MAPK p42/p44, two signaling pathways implicated in proliferation, and the involvement of the MAPK JNK, while establishing roles for p38 MAPK and NF-κB in the potentiation of GM-CSF release. Detection of significant p38 phosphorylation in response to serum stimulation, through Western blotting, further demonstrated the involvement of p38. These studies have provided evidence to support p38 being targeted to interrupt the cycle of inflammation, vascular leakage and cytokine production in asthma.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Lalor¹,

Truong²,

Henness³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It has been well demonstrated in both experimental and human studies that lung fibrosis, and silicosis in particular, is characterized by an alveolar macrophage-dominant alveolitis. The numerous and activated macrophages present in fibrotic lesions release exaggerated amounts of mediators capable of injuring lung parenchymal cells (e.g., superoxide anion and hydrogen peroxide) (41), recruiting neutrophils (TNF-␣, IL-1, and IL-8) (42,43), or promoting the growth and/or collagen production of mesenchymal cells (fibronectin, TGF-␤, TNF-␣, PDGF, and insulin-like growth factor-1) (43)(44)(45)(46). On the basis of this recognized key role of macrophages, we suggest that excessive IL-12p40 found in silicatreated mice can induce selective macrophage accumulation in tissue and airspace compartments, and thus sustain its detrimental activity in the lung fibrotic process.…”

Section: Discussionmentioning

confidence: 99%

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

Huaux

Arras²,

Tomasi³

et al. 2002

The Journal of Immunology

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The p40 subunit of IL-12 (IL-12p40), but not the heterodimeric form IL-12p70, is secreted during the development of silica-induced lung fibrosis in C57BL/6 mice. To delineate the contribution of IL-12p40 to the lung inflammatory and fibrotic processes, we compared the pulmonary responses with silica particles of IL-12p35-deficient mice (IL-12p35−/−, able to produce IL-12p40) and IL-12p40-deficient mice (IL-12p40−/−). IL-12p35−/− and IL-12p40−/− animals developed strikingly contrasting responses to silica in comparison with wild-type C57BL/6 mice. Although the IL-12p40−/− mice exhibited limited inflammatory and fibrotic reactions, the IL-12p35−/− mice presented a robust and well-developed pulmonary inflammation and fibrosis. Furthermore, the silica-induced increase in lung IL-12p40 content was significantly higher in IL-12p35−/− mice than in wild-type controls, and was associated with extensive lung fibrosis and pulmonary macrophage infiltration. The contrasting responses observed between these two IL-12 subunit-deficient murine strains were not accompanied by a strict type 1 or type 2 polarization as estimated by the measurements of lung IFN-γ/IgG2a and IL-4/IgG1 content. In vitro proliferation, type I collagen expression, as well as myofibroblast differentiation of purified pulmonary fibroblasts were not affected by treatment with exogenous rIL-12p40. In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40−/− mice, and also promoted fibrosis and macrophage influx in wild-type mice. Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment.

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“…Once PMNs are recruited into the alveolar spaces, several inflammatory cytokines act (124) have been reported to increase fibroblast proliferation. PDGF and fibronectin are competence factors, whereas alveolar macrophage-derived growth factor is a progression factor for proliferation of fibroblasts.…”

Section: Stimulation Ofinflammatory Cytokine Releasementioning

confidence: 99%

“…In contrast, IL-6 exhibits antifibrotic activity (128). Prostaglandin E2 and transforming growth factor beta (TGF-P) exhibit a depressive effect on cell growth (122,124). However, under certain conditions, TGF-P can stimulate collagen synthesis in vitro (129).…”

Section: Stimulation Ofinflammatory Cytokine Releasementioning

confidence: 99%

Silicosis and coal workers' pneumoconiosis.

Castranova

Vallyathan

2000

Environ Health Perspect

306

176

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Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and progression of pulmonary fibrosis. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; o) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms.

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Mechanisms of fibrosis in coal workers' pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta and relationship to disease severity.

Cited by 82 publications

References 0 publications

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

Silicosis and coal workers' pneumoconiosis.

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