The pulmonary inflammatory response to multiwalled carbon nanotubes is influenced by gender and glutathione synthesis

Abstract

Inhalation of multiwalled carbon nanotubes (MWCNTs) during their manufacture or incorporation into various commercial products may cause lung inflammation, fibrosis, and oxidative stress in exposed workers. Some workers may be more susceptible to these effects because of differences in their ability to synthesize the major antioxidant and immune system modulator glutathione (GSH). Accordingly, in this study we examined the influence of GSH synthesis and gender on MWCNT-induced lung inflammation in C57BL/6 mice. GSH synthesis was impaired through genetic manipulation of Gclm, the modifier subunit of glutamate cysteine ligase, the rate-limiting enzyme in GSH synthesis. Twenty-four hours after aspirating 25 µg of MWCNTs, all male mice developed neutrophilia in their lungs, regardless of Gclm genotype. However, female mice with moderate (Gclm heterozygous) and severe (Gclm null) GSH deficiencies developed significantly less neutrophilia. We found no indications of MWCNT-induced oxidative stress as reflected in the GSH content of lung tissue and epithelial lining fluid, 3-nitrotyrosine formation, or altered mRNA or protein expression of several redox-responsive enzymes. Our results indicate that GSH-deficient female mice are rendered uniquely susceptible to an attenuated neutrophil response. If the same effects occur in humans, GSH-deficient women manufacturing MWCNTs may be at greater risk for impaired neutrophil-dependent clearance of MWCNTs from the lung. In contrast, men may have effective neutrophil-dependent clearance, but may be at risk for lung neutrophilia regardless of their GSH levels.

Airway Exposure to Modified Multi-walled Carbon Nanotubes Perturbs Cardiovascular Adenosinergic Signaling in Mice

“…Both studies showed that N-doped exposure increased cellularity and neutrophilia compared to the Vehicle instillation. This type of cellularity/neutrophilia has also been demonstrated with MWCNT exposure in mice [32] and rats [33]. One contrast between our two studies were that CD-1 mice did not present with increased BALF protein concentration after N-doped exposure, as was seen with the C57BL/6 mice [5].…”

Materials for Immunotherapy

“…Further, CNTs reduced the expression of CD69 (marker of NK cell activation), CD107a, NK1.1, TNF‐α, IFN‐γ, and reduced the cytotoxicity of NK cells . In some contexts, however, CNTs have been found to be potently inflammatory (e.g., generating pulmonary inflammation and fibrosis via inhalation) . When cultured on sheets of CNTs, dendritic cells were less capable of inducing T cell proliferation or performing pinocytosis, produced less IL‐6 and IL‐10, downregulated CD80, and yet increased secretion of TNF‐α .…”

Mechanisms of carbon nanotube‐induced pulmonary fibrosis: a physicochemical characteristic perspective

“…Therefore, strain susceptibility to pulmonary fibrosis may depend on the agent used to induce fibrosis. Of interest, the sex of mice has also been linked to the inflammatory response experienced by mice following MWCNT aspiration exposure where female mice, especially those with reduced glutathione levels, have reduced neutrophilia and MWCNT clearance from their lungs 110 . Currently, there is a lack of information on sex differences in response to pulmonary exposure to CNTs.…”