Variability of biological effects of silicas: different degrees of activation of the fifth component of complement by amorphous silicas.

A biogenic and a pyrogenic amorphous silica were incubated in normal human plasma and compared on a per unit surface basis for their ability to split C5 molecules and yield small C5a peptides. Since C5a peptides induce selective chemotactic attraction of polymorphonuclear leukocytes (PMN), measurement of PMN-induced chemotaxis was used as an index of C5 activation. Though to a lesser extent than the crystalline forms, amorphous silicas can promote the cleavage of C5 protein and generation of C5a-like fragment. The biogenic silica, which differs from the pyrogenic variety in particle shape, level of contaminants, and degree of surface hydrophilicity, besides specific surface, induced a greater response. Both silicas activated C5 through a process which seems to involve multiple events similar to those induced by crystalline silica. C5 molecules are adsorbed and hydroxyl radicals are generated through Haber Weiss cycles catalyzed by the redox-active iron present at the particle surface either as trace impurities or chelated from plasma by silanol groups. In turn, these radicals convert native C5 to an oxidized C5-like form C5(H2O2). Finally, C5(H2O2) is cleaved by protease enzymatic action of plasma kallikrein activated by the same silica dusts, yielding a product, C5a(H2O2), having the same functional characteristic as C5a.

[The in vitro release of hydroxyl radicals from dust containing fluoro-edenite fibers identified in the volcanic rocks of Biancavilla (eastern Sicily)]. / Studio del rilascio in vitro di radicali ossidrile (HO.) da parte di polveri contenenti fibre di fluoro-edenite identificate nella roccia lavica di Biancavilla (Sicilia orientale).

BACKGROUND: Epidemiological studies revealed an unusually high incidence of malignant pleural mesothelioma in Biancavilla, a town in eastern Sicily located in a volcanic area. In the absence of occupational risk factors connected with asbestos inhalation, a nearby stone quarry, which has long been providing most of the local building materials (e.g. plaster), was suspected to be the source of mineral fibres. These fibres had never been studied before and were identified as fluoro-edenite. OBJECTIVE: To investigate the ability of the fluoro-edenite fibres present in mineral dusts and house plaster to release hydroxyl radicals in vitro. METHODS: After fibre characterisation and the determination of particulate specific surface, the ability of quarry rock dust and house plaster dust to generate hydroxyl radicals was measured in vitro using the deoxyribose degradation assay. Treatment with 1,3-dimethyl-2-thiourea (DMTU), a hydroxyl radical scavenger, or deferoxamine (DFX), an iron chelator, was performed to confirm hydroxyl radical production and study the role of iron. Crocidolite (UICC) was used as positive control. RESULTS: The rocks were found to contain fibrous amphiboles, identified as fluoro-edenite, which are chemically similar to tremolite. All samples generated hydroxyl radicals, with rocks yielding consistently higher values than plaster. Treatment of the dusts with DMTU or DFX significantly reduced hydroxyl radical production by both samples. The type of biological reactivity observed with these fluoro-edenite fibres resembled that of asbestos fibres. CONCLUSIONS: The hydroxyl radicals generated by asbestos fibres have long been known to mediate inflammatory fibrosis of the lung and DNA damage that may ultimately result in lung carcinoma and mesothelioma.

Cleavage of the fifth component of human complement and release of a split product with C5a-like activity by crystalline silica through free radical generation and kallikrein activation.

The effects of the same form of crystalline silica variously modified were compared to investigate the mechanisms by which silica activates C5 molecules. After incubation in human plasma, silica generated C5a-type fragments that stimulated polymorphonuclear leukocyte chemotaxis. This activity was totally abolished when plasma, adsorbed with antiserum against C5a or thermally inactivated, was used. Pretreatment of plasma with deferoxamine, 1,3 dimethyl-2-thiourea, or aprotinin markedly inhibited or totally abolished C5 activation. Finally, a significant increase in kallikrein activity was detected after incubation of silica particles in plasma. The results seem to indicate that the activation of C5 by crystalline silica occurs through a complex mechanism: the redox-active iron possibly present at the silica surface catalyzes, via Haber-Weiss cycles, the production of hydroxyl radicals, which in turn convert native C5 to an oxidized C5-like form. This product is then cleaved by kallikrein, activated by the same silica particles, yielding oxidized C5a with the same functional properties as C5a. The different types of the same form of silica exhibited different reactivity. Two separate properties of the dusts seem to contribute to C5 activation: the potential to release hydroxyl radicals and the extent of C5 adsorption at the surface. The degree of surface hydrophobicity/hydrophilicity appeared sufficient to explain the different responses.