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

• Published in: Toxicology and applied pharmacology 2002-03, Vol.179 (3), p.129-136
• Main Authors: Governa, Mario, Fenoglio, Ivana, Amati, Monica, Valentino, Matteo, Bolognini, Lucia, Coloccini, Sabrina, Volpe, Anna Rita, Carmignani, Marco, Fubini, Bice
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; C5 activation; Chemical and industrial products toxicology. Toxic occupational diseases; Chemotaxis - drug effects; complement; Complement Activation - drug effects; Complement C5 - antagonists & inhibitors; Complement C5 - metabolism; Complement C5a - metabolism; crystalline silica; Deferoxamine - pharmacology; Female; Free Radical Scavengers - pharmacology; Humans; Hydroxyl Radical - metabolism; Inorganic dusts (pneumoconiosises) and organic dusts (byssinosis etc.); Iron - pharmacology; Iron Chelating Agents - pharmacology; kallikrein; Kallikreins - blood; Male; Medical sciences; Middle Aged; Neutrophils - drug effects; Quartz - pharmacology; Quartz - toxicity; silicon dioxide; Thiourea - analogs & derivatives; Thiourea - pharmacology; Toxicology; Zymosan - pharmacology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2002.9351

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.