Abstract
BackgroundIt has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged.MethodsUsing biochemical, histological, immunohistochemistry, and cellular analyses, we compared the lung responses (inflammation and fibrosis) to fibrogenic silica particles (2.5 and 25 mg/g lung) in Sprague-Dawley rats and NMRI mice.ResultsRats treated with silica particles developed chronic and progressive inflammation accompanied by an overproduction of TNF-α as well as an intense lung fibrosis. Dexamethasone or pioglitazone limited the amplitude of the lung fibrotic reaction to silica in rats, supporting the paradigm that inflammation drives lung fibrosis.In striking contrast, in mice, silica induced only a limited and transient inflammation without TNF-α overproduction. However, mice developed lung fibrosis of a similar intensity than rats. The fibrotic response in mice was accompanied by a high expression of the anti-inflammatory and fibrotic cytokine IL-10 by silica-activated lung macrophages. In mice, IL-10 was induced only by fibrotic particles and significantly expressed in the lung of silica-sensitive but not silica-resistant strains of mice. Anti-inflammatory treatments did not control lung fibrosis in mice.ConclusionThese results indicate that, beside chronic lung inflammation, a pronounced anti-inflammatory reaction may also contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis.
Highlights
It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged
Anti-inflammatory treatments did not control lung fibrosis in mice. These results indicate that, beside chronic lung inflammation, a pronounced antiinflammatory reaction may contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis
Pulmonary inflammation induced by silica particles was persistent in rats but limited in mice Lactate dehydrogenase (LDH) activity, protein levels and neutrophil numbers measured in BALF were used to estimate the amplitude of pulmonary inflammation induced by silica particles both in rats and mice (2.5 and 25 mg/g of lung) (Figure 1)
Summary
It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged. Lung inflammatory cells are a source of growth factors [7], cytokines [8] and chemokines [9] that amplify and maintain alveolitis and activate fibroblasts It has been demonstrated, for instance, that macrophages obtained from animal models of silicosis [10] or from patients with lung fibrosis [11] overproduce pro-inflammatory cytokines and growth factors such as TNF-α, IL-1, PDGF and TGF-β. For instance, that macrophages obtained from animal models of silicosis [10] or from patients with lung fibrosis [11] overproduce pro-inflammatory cytokines and growth factors such as TNF-α, IL-1, PDGF and TGF-β All these mediators clearly possess strong stimulating activities on fibroblasts [4,12]
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