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Pathologic and molecular profiling of rapid-onset fibrosis and inflammation induced by multi-walled carbon nanotubes

  • Organ Toxicity and Mechanisms
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Abstract

Multi-walled carbon nanotubes (MWCNT) are new materials with a wide range of industrial and commercial applications. However, their nano-scaled size and fiber-like shape render them respirable and potentially fibrogenic if inhaled into the lungs. To understand MWCNT fibrogenesis, we analyzed the pathologic and molecular aspects of the early phase response to MWCNT in mouse lungs. MWCNT induced rapid and pronounced lesions in the lungs characterized by increased cellularity and formation of fibrotic foci, most notably near where MWCNT deposited, within 14 days post-exposure. Deposition of collagen fibers was markedly increased in the alveolar septa and fibrotic foci, accompanied by elevated expression of fibrotic genes Col1a1, Col1a2, and Fn1 at both mRNA and protein levels. Fibrosis was induced rapidly at 40 μg, wherein fibrotic changes were detected on day 1 and reached a maximal intensity on day 7 through day 14. Induction of fibrosis was dose-dependent at the dose range of 5–40 μg, 7 days post-exposure. MWCNT elicited rapid and prominent infiltrations of neutrophils and macrophages alongside fibrosis implicating acute inflammation in the fibrotic response. At the molecular level, MWCNT induced elevated expression of proinflammatory cytokines TNFα, IL1α, IL1β, IL6, and CCL2 in lung tissues as well as the bronchoalveolar lavage fluid, in a dose- and time-dependent manner. MWCNT also increased the expression of fibrogenic growth factors TGF-β1 and PDGF-A in the lungs significantly. These findings underscore the interplay between acute inflammation and the early fibrotic response in the initiation and propagation of pulmonary fibrosis induced by MWCNT.

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Abbreviations

BAL:

Bronchoalveolar lavage

CNT:

Carbon nanotubes

DM:

Dispersion medium

Gapdh :

Glyceraldehyde 3-phosphate dehydrogenase

IL:

Interleukin

LDH:

Lactate dehydrogenase

MWCNT:

Multi-walled carbon nanotubes

PBS:

Phosphate-buffered saline

PDGF:

Platelet-derived growth factor

SWCNT:

Single-walled carbon nanotubes

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

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Acknowledgments

The study was supported by a grant to QM from National Institute for Occupational Safety and Health, Health Effects Laboratory Division. The anti-MBP antibody was kindly offered by Drs. Nancy A. Lee and James J. Lee at Mayo Clinic (Scottsdale, AZ, USA).

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical standard

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Authors and Affiliations

  1. Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Mailstop 3014, Morgantown, WV, 26505, USA

    Jie Dong & Qiang Ma

  2. Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV, 26505, USA

    Dale W. Porter, Lori A. Batteli & Michael G. Wolfarth

  3. Pathology Core, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Morgantown, WV, 26505, USA

    Diana L. Richardson

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  1. Jie Dong
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  2. Dale W. Porter
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  3. Lori A. Batteli
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  4. Michael G. Wolfarth
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  6. Qiang Ma
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Correspondence to Qiang Ma.

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The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

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Dong, J., Porter, D.W., Batteli, L.A. et al. Pathologic and molecular profiling of rapid-onset fibrosis and inflammation induced by multi-walled carbon nanotubes. Arch Toxicol 89, 621–633 (2015). https://doi.org/10.1007/s00204-014-1428-y

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  • DOI: https://doi.org/10.1007/s00204-014-1428-y

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