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WIREs Nanomed Nanobiotechnol
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Particle‐induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease

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Inhalation of ambient and workplace particulate air pollution is associated with increased risk of cardiovascular disease. One proposed mechanism for this association is that pulmonary inflammation induces a hepatic acute phase response, which increases risk of cardiovascular disease. Induction of the acute phase response is intimately linked to risk of cardiovascular disease as shown in both epidemiological and animal studies. Indeed, blood levels of acute phase proteins, such as C‐reactive protein and serum amyloid A, are independent predictors of risk of cardiovascular disease in prospective epidemiological studies. In this review, we present and review emerging evidence that inhalation of particles (e.g., air diesel exhaust particles and nanoparticles) induces a pulmonary acute phase response, and propose that this induction constitutes the causal link between particle inhalation and risk of cardiovascular disease. Increased levels of acute phase mRNA and proteins in lung tissues, bronchoalveolar lavage fluid and plasma clearly indicate pulmonary acute phase response following pulmonary deposition of different kinds of particles including diesel exhaust particles, nanoparticles, and carbon nanotubes. The pulmonary acute phase response is dose‐dependent and long lasting. Conversely, the hepatic acute phase response is reduced relative to lung or entirely absent. We also provide evidence that pulmonary inflammation, as measured by neutrophil influx, is a predictor of the acute phase response and that the total surface area of deposited particles correlates with the pulmonary acute phase response. We discuss the implications of these findings in relation to occupational exposure to nanoparticles. WIREs Nanomed Nanobiotechnol 2014, 6:517–531. doi: 10.1002/wnan.1279 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Characteristic patterns of change in plasma concentrations of some acute‐phase proteins after a moderate inflammatory stimulus. (Reprinted with permission from Ref . Copyright 1999, Massachusetts Medical Society)
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The proposed mechanism of action of particle‐induced cardiovascular disease. Inhalation of particles (indicated by 1 in the figure) leads to a pulmonary acute phase response (2). The accumulation of SAA in lungs leads to attraction of neutrophils. SAA is incorporated into HDL (3), replacing APO‐A1 and goes into systemic circulation. SAA‐HDL is deficient in reverse cholesterol transport and promotes foam cell formation from macrophages, leading to plaque progression.
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Change in plasma total cholesterol (solid squares), free cholesterol (open squares), and cholesterol esters (solid circles) concentrations following the induction of an acute subcutaneous inflammatory reaction with 2% silver nitrate. Values are the mean ± SEM, n = 12. (Reprinted with permission from Ref . Copyright 1997, Elsevier)
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Correlation between neutrophil influx and total surface area of deposited nanoparticles. Doses of 0, 18, 54, or 162 µg/mouse carbon black or TiO2 nanoparticles were deposited in lungs of mice by intratracheal instillation and the number of neutrophils in bronchial lavage fluid was determined as described previously. N = 6 per group, except for vehicle controls where n = 22: (a) 24 h after instillation and (b) 28 days post exposure.
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Correlation between neutrophil influx and normalized Saa3 mRNA levels in lung tissue 1–28 days following instillation or inhalation of various nanomaterials or dust collected at a biofuel plant. Saa3 mRNA levels were quantified by real‐time PCR and normalized to 18S. Exposures include inhalation of carbon black and TiO2 nanoparticles (open squares), instillation of carbon black and TiO2 nanoparticles (filled diamonds), instillation of carbon nanotubes (filled circles), instillation of biofuel dust (filled triangles), instillation of vehicle (negative control) (filled squares). (Reprinted with permission from Ref . Copyright 2013 under Creative Commons Attribution License)
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Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease

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