Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Identification, development and validation of early biological markers of lung disease caused by environmental and industrial pollutants

The objectives of this research were to develop integrated experimental procedures, taking advantage of modern methods in physicochemistry, and cell and molecular biology for the identification of early biological markers of lung toxicity.

The most significant results can be summarized as follows:

The physicochemical features that determine the pathogenicity of a given particle are more than one and, beside gravimetric dose, other parameters such as particle number, shape, size, hydrophilicity, surface reactivity, surface charge or surface area should be considered. The experimental data obtained indicate that for insoluble particles, the dose should be expressed in surface area than in the usual gravimetric terms.

A novel mechanism of interaction between metallic particles, which is responsible for the lung toxicity of hard metal dust was discovered. This mechanism represents the first demonstration of a toxicological interaction between solid particles (cobalt metal and tungsten carbide), and opens a new avenue of research to understand the toxicity of complex metallic dusts.

An in vitro model of alveolar macrophage using differentiated U937 human cells has been validated. This model offers the possibility to test the biological reactivity of inhaled particles (eg in terms of cytokine expression or sialidase alterations).

Two candidate biomarkers are proposed to assess the progression to lung fibrosis upon inhalation of particles.

Alterations in cytokine networks have been evidenced in response to inhaled toxic particles. The demonstration of the profibrotic activity of interleukin-10, together with the fact that alterations can be detected in the serum of experimental animals, indicate a possible practical usefulness of this parameter for monitoring populations exposed to toxic particles.

Urokinase, which is a main component of the fibrinolytic system, is upregulated in response to toxic particles and possesses an antifibrotic activity. The value of this parameter was confirmed in a clinical study in patients with fibrotic lung diseases, which demonstrated that reduced fibrinolytic activity paralleled the intensity of the interstitial decease. In addition, the demonstration of alterations of the lung fibrinolytic system upon exposure to toxic particles provides some support to the suggestion that alterations in blood coagulability might be involved in the excess cardiovascular mortality associated with urban air particulate pollution.