Pulmonary DWCNT exposure causes sustained local and low-level systemic inflammatory changes in mice

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 84; no. 2; pp. 412 - 420
• Main Authors: Tian, Furong, Habel, Nunja C., Yin, Renfu, Hirn, Stephanie, Banerjee, Atrayee, Ercal, Nuran, Takenaka, Shinji, Estrada, Giovani, Kostarelos, Kostas, Kreyling, Wolfgang, Stoeger, Tobias
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2013
• Subjects: Animals; Antioxidants - metabolism; Bronchoalveolar Lavage Fluid; Carbon nanotubes; Cytokines; Cytokines - blood; Cytokines - metabolism; DWCNT; Female; Glutathione; Glutathione - metabolism; Granulocytes - cytology; Lung - drug effects; Macrophages, Alveolar - cytology; Mice; Mice, Inbred BALB C; Nanotubes, Carbon; Neutrophils - cytology; Neutrophils - metabolism; Phagocytosis; Pneumonia - chemically induced; Pulmonary Alveoli - drug effects; Pulmonary inflammation Systemic inflammation Phagocytosis; Reactive Oxygen Species; DWCNT; Carbon nanotubes; Pulmonary inflammation Systemic inflammation Phagocytosis; Cytokines; Glutathione
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2013.03.008

Carbon nanotubes (CNTs) represent promising vectors to facilitate cellular drug delivery and to overcome biological barriers, but some types may also elicit persistent pulmonary inflammation based on their fibre characteristics. Here, we show the pulmonary response to aqueous suspensions of block copolymer dispersed, double-walled carbon nanotubes (DWCNT, length 1–10μm) in mice by bronchoalveolar lavage (BAL) analysis, and BAL and blood cytokine and lung antioxidant profiling. The intratracheally instilled dose of 50μg DWCNT caused significant pulmonary inflammation that was not resolved during a 7-day observation period. Light microscopy investigation of the uptake of DWCNT agglomerates revealed no particle ingestion for granulocytes, but only for macrophages. Accumulating macrophage, multinucleated macrophage and lymphocyte numbers in the alveolar region further indicated ineffective resolution with chronification of the inflammation. The local inflammatory impairment of the lung was accompanied by pulmonary antioxidant depletion and haematological signs of systemic inflammation. While the observed inflammation during its acute phase was dominated by neutrophils and neutrophil recruiting cytokines, the contribution of macrophages and lymphocytes with related cytokines became more significant after day 3 of exposure. This study confirms that acute pulmonary toxicity can occur on exposure of high doses of DWCNT agglomerates and offers further insight for improved nanotube design parameters to avoid potential long-term toxicity.