Resolution Mediators in Pulmonary Inflammation Induced by Multi‐walled Carbon Nanotubes and Fullerenes in Mice

Abstract

Exposure to certain nanoparticles can cause fibrosis and cancer as a result of unresolved inflammation. Inflammation resolution is largely mediated through specialized pro‐resolving mediators (SPMs). To understand the mechanism by which nanoparticle‐induced pulmonary inflammation is resolved, we analyzed and compared the inflammatory and pro‐resolving responses to fibrogenic multi‐walled carbon nanotubes (MWCNTs) and low‐toxicity fullerenes (C60F). Pharyngeal aspiration of MWCNTs at 40 μg/mouse or C60F at doses larger than 640 μg/mouse elicited pulmonary effects in B6C3F1 mice. Histopathology showed that both particles stimulated acute inflammation, predominated by neutrophils and macrophages, in the lung on day 1, which transitioned to histiocytic inflammation by day 7, and to granuloma and interstitial fibrosis by day 28 in MWCNTs, and to a much lesser extent, C60F exposed mice. Flow cytometric profiling of bronchoalveolar lavage fluid (BALF) cells revealed that neutrophil infiltration peaked at day 1 and declined to 36.6% for MWCNTs‐ and 16.8% for C60F (1,280 μg/mouse)‐treated mice by day 7, and to basal levels by day 28 in both groups, suggesting a rapid initiation phase and an extended resolution phase in both groups. Additionally, MWCNTs stimulated dynamic changes in eosinophils, bone marrow‐derived inflammatory macrophages, monocyte‐derived dendritic cells, and T lymphocytes, indicating distinctive patterns of immune cell infiltration in the BAL in response to nanoparticles. MWCNTs stimulated high levels of pro‐inflammatory lipid mediators, including leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), on day 1. At the same time, MWCNTs induced high levels of SPMs, including resolvin D1 (RvD1) and E1 (RvE1) and lipoxin A4 (LXA4), on day 1, which continued to rise and peaked on day 7, creating a high RvD1/LTB4 or RvD1/PGE2 ratio. C60F stimulated a similar pattern of changes in the mediators but to a much lesser extent. Together, these findings suggest that MWCNTs at a low dose and fullerenes at a high dose induce time‐dependent progression from type 1 to type 2 inflammation with an extended resolution phase mediated through SPMs.Support or Funding InformationThis work was funded by grant 09390BN5 (DWP and QM) and grant 09390BMX (QM) from the Health Effects Laboratory Division, the Nanotechnology Research Center, and the NORA Research Program at the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, USA.