1 (Nano)Particle Exposure, Acute Phase Response and Cardiovascular Disease

Abstract Particle inhalation is linked to diseases including cancer, COPD, fibrosis and cardiovascular disease. We propose a biological mechanism-of-action for particle-induced cardiovascular disease causally linking particle exposure to induction of acute phase response, which in turn is a known risk factor for atherosclerosis and cardiovascular disease. Inhalation and pulmonary deposition of particles induce inflammation, which is proportional to the total surface area of the pulmonary-deposited particles. In mice, inflammation is accompanied by an acute phase response, which is long-lasting for insoluble particles. Acute phase protein Serum Amyloid A (SAA) is among the most differentially expressed genes in lung tissue following particle exposure. SAA is causally implicated in atherosclerosis and both overexpression and pulmonary dosing of SAA promote plaque formation in ApoE-/- mice. In mice, we show that both soluble and insoluble metal fume particles induce acute phase response but with different time-dependence. Neutrophil influx, pulmonary Saa expression and SAA blood levels are highly correlated in mice and may be used as biomarkers of each other. In humans, controlled exposure to metal oxides and combustion particles induces dose-dependent increases in blood levels of SAA and C-reactive protein. Blood levels of acute phase proteins SAA and C-reactive protein are risk factors for cardiovascular disease in prospective, epidemiological studies. Nanoparticles have a higher specific surface area than larger particles with similar chemical composition, and consequently, nanoparticles are more hazardous than larger particles of similar chemical composition in relation to cardiovascular disease. This underscores cardiovascular disease as a particle-induced occupational disease.