The pulmonary inflammatory response to multiwalled carbon nanotubes is influenced by gender and glutathione synthesis.
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 25µg 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.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Megan M
MM
Cartwright
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Stefanie C
SC
Schmuck
Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA.
Charlie
C
Corredor
Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Bingbing
B
Wang
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
David K
DK
Scoville
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Claire R
CR
Chisholm
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Hui-Wen
HW
Wilkerson
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Zahra
Z
Afsharinejad
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Theodor K
TK
Bammler
Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA; Department of Mechanical Engineering, University of Washington, Seattle, WA 98195, USA.
Jonathan D
JD
Posner
Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Vaithiyalingam
V
Shutthanandan
Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Donald R
DR
Baer
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ 07102, USA.
Somenath
S
Mitra
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
William A
WA
Altemeier
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: tjkav@uw.edu.
Terrance J
TJ
Kavanagh
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D037742:Nanotubes, Carbon / Q000009:adverse effects*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011014:Pneumonia / Q000209:etiology* / Q000378:metabolism*; D012737:Sex Factors
D016207:Cytokines; D018836:Inflammation Mediators; D037742:Nanotubes, Carbon; D005978:Glutathione
Gender differences; Glutathione; Inflammation; Multiwalled carbon nanotubes; Nanotoxicology; Oxidative stress