Bacterial Lipopolysaccharide Enhances PDGF Signaling and Pulmonary Fibrosis in Rats Exposed to Carbon Nanotubes

Abstract

Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later. Pulmonary fibrosis was observed 21 days after MWCNT exposure, but not with CB. LPS alone caused no fibrosis but enhanced MWCNT-induced fibrosis. LPS plus CB did not significantly increase fibrosis. MWCNT increased platelet-derived growth factor-AA (PDGF-AA), a major mediator of fibrosis. PDGF-AA production in response to MWCNT, but not CB, was synergistically enhanced by LPS. Immunostaining showed PDGF-AA in bronchiolar epithelial cells and macrophages. Since macrophages engulfed MWCNT, were positive for PDGF-AA, and mediate fibroblast responses, experiments were performed with rat lung macrophages (NR8383 cells) and rat lung fibroblasts in vitro. LPS exposure increased PDGF-A mRNA levels in NR8383 cells and enhanced MWCNT-induced PDGF-A mRNA levels. Moreover, LPS increased MWCNT-or CB-induced PDGF receptor-a (PDGF-Ra) mRNA in fibroblasts. Our data suggest that LPS exacerbates MWCNT-induced lung fibrosis by amplifying production of PDGF-AA in macrophages and epithelial cells, and by increasing PDGF-Ra on pulmonary fibroblasts. Our findings also suggest that individuals with pre-existing pulmonary inflammation are at greater risk for the potential adverse effects of MWCNT.

Nickel Nanoparticles Enhance Platelet-Derived Growth Factor–Induced Chemokine Expression by Mesothelial Cells via Prolonged Mitogen-Activated Protein Kinase Activation

“…During the pathogenesis of fibrosis, PDGF contributes to the production and deposition of collagen by driving myofibroblast proliferation and chemotaxis (33,34). After exposure to MWCNTs, mice have increased levels of PDGF throughout the lung that could be available to mesothelial cells in vivo (8,9). Alveolar macrophages are a major source of PDGF-BB in the lungs, whereas PDGF-AA is mainly produced by fibroblasts and epithelial cells (10,35).…”

“…Platelet-derived growth factor (PDGF) is a key mediator of fibrogenesis, and is increased in the lungs of mice that are exposed to Ni-containing MWCNTs (8,9). PDGF is a family of polypeptides (AA, BB, AB, CC, DD) that bind and dimerize cell surface receptors, termed PDGF receptor (PDGF-R) a and PDGF-Rb, to form dimeric aa, ab, or bb receptors with tyrosine kinase activity.…”

Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells

“…IL-6 stimulates the acutephase reaction, which enhances the innate immune system and protects against tissue damage [23]. MWCNTs represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung [24]. MacNee et al reported that IL-8 is a chemoattractant chemokine that plays a role in the initiation of airway inflammation [25].…”

Direct Leukocyte Migration across Pulmonary Arterioles and Venules into the Perivascular Interstitium of Murine Lungs during Bleomycin Injury and Repair

“…50 Tissues were first deparaffinized in xylene and rehydrated through graded ethanol. Endogenous peroxidase was blocked by immersing slides in 3% H 2 O 2 for 15 minutes.…”