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Mitogenic activity for fibroblasts induced by silica and titanium dioxide particles in vitro and in vivo
Abstract:
Experimental studies on particle-induced pulmonary fibrosis have not provided consistent evidence for the specific induction of fibroblast-regulating cytokines by pulmonary macrophages in response to fibrogenic as compared to non-fibrogenic particles. Using an optimized, wholly serum-free bioassay, we assessed mitogenic activity for pulmonary fibroblasts in supernatants of short-term cultures of alveolar macrophages exposed to either fibrogenic silica or non-fibrogenic titanium dioxide ducts. The responses to these supernatants were influenced by the replicative status of the target cells, in that samples which stimulated non-cycling fibroblasts caused inhibition of DNA synthesis by cycling cells when tested at the same concentration. However, both silica and titanium dioxide elicited comparable secretion of growth factor activity by macrophages, following either in-vitro or in-vivo administration of particles. In contrast, bronchoalveolar lavage fluids from animals that received intratracheal injections of silica, but not from those that received titanium dioxide, exhibited a sustained reduction in fibroblast-stimulating activity. We conclude that secretion of growth factor activity by alveolar macrophages in culture is induced by particles in a non-specific manner. However, alterations in mitogenic activity in bronchoalveolar lavage fluid may constitute a biological marker of the pattern of pulmonary injury which progresses to fibrosis.
Insights
Particle exposure non-specifically stimulates macrophages to release growth factors. However, changes in bronchoalveolar lavage fluid mitogenic activity may indicate fibrotic pulmonary injury patterns.
Area of Science:
- Pulmonary immunology
- Cell biology
- Toxicology
Background:
- Particle-induced pulmonary fibrosis lacks consistent evidence on specific cytokine induction by macrophages.
- Pulmonary macrophages play a role in regulating fibroblast activity during fibrosis.
Purpose of the Study:
- To investigate the mitogenic activity of alveolar macrophage supernatants on pulmonary fibroblasts after exposure to fibrogenic (silica) and non-fibrogenic (titanium dioxide) particles.
- To determine if particle-induced growth factor secretion by macrophages is specific or non-specific.
- To explore bronchoalveolar lavage fluid (BALF) mitogenic activity as a potential marker for fibrotic lung injury.
Main Methods:
- Utilized a serum-free bioassay to assess fibroblast mitogenesis in response to alveolar macrophage supernatants.
- Exposed macrophages in vitro and in vivo to silica and titanium dioxide particles.
- Analyzed BALF from particle-exposed animals for fibroblast-stimulating activity.
Main Results:
- Both silica and titanium dioxide induced comparable growth factor secretion by macrophages, indicating non-specific responses.
- Macrophage supernatant activity varied based on the replicative status of target fibroblasts (stimulation vs. inhibition).
- Silica, but not titanium dioxide, exposure led to a sustained reduction in BALF fibroblast-stimulating activity.
Conclusions:
- Macrophage secretion of growth factors is induced non-specifically by particle exposure.
- Reduced mitogenic activity in BALF following particle instillation may serve as a biological marker for fibrotic pulmonary injury patterns.