Role of Signal Transducer and Activator of Transcription 1 in Murine Allergen–Induced Airway Remodeling and Exacerbation by Carbon Nanotubes

Thompson, Elizabeth A.; Sayers, Brian C.; Glista-Baker, Ellen E.; Shipkowski, Kelly A.; Ihrie, Mark D.; Duke, Katherine S.; Taylor, Alexia J.; Bonner, James C.

doi:10.1165/rcmb.2014-0221oc

Cited by 36 publications

(51 citation statements)

References 50 publications

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“…40 Moreover, our in vitro doses of 25–50 μ g/mL (5–10 μ g/cm 2 ) are comparable with mouse exposure doses previously reported in the literature. 10,25,34 …”

Section: Resultsmentioning

confidence: 99%

“…41 A significant increase in IL-1 β has already been reported after exposure to CNTs. 9,10,34,42,43 MWCNT exposure, similar to asbestos, can induce inflammasome activation in the lungs, leading to IL-1 β secretion. 42 We previously reported IL-1 β secretion from primary human bronchial epithelial cells after MWCNT exposure via activation of the inflammasome that contributed to increased profibrotic gene expression in human fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

“…62 MWCNTs are associated with MCM development in the exposed lungs. 34,35,43,63,64 In order to evaluate the impact of HA functionalization in MW-induced MCM development, we analyzed mucus-producing goblet cells in lung sections and quantified chemical mediators involved in the MCM phenotype. Scoring criteria were based on published methodology and are detailed in Supporting Information methods.…”

Section: Resultsmentioning

confidence: 99%

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Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury

Hussain

Taylor

et al. 2016

ACS Nano

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Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air–liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury.

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“…40 Moreover, our in vitro doses of 25–50 μ g/mL (5–10 μ g/cm 2 ) are comparable with mouse exposure doses previously reported in the literature. 10,25,34 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury

Hussain

Taylor

et al. 2016

ACS Nano

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“…Recent reports also show that OPN was induced by chronic exposure to CNTs including both SWCNTs and MWCNTs of various types [35–40]. In view of the anticipated multifold functions of OPN in fibrosis development, a comprehensive profiling of OPN expression in the lungs exposed to CNTs is warranted but was lacking.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiation

Dong

2017

Part Fibre Toxicol

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Background: Carbon nanotubes (CNTs) have been used in a variety of applications because of their unique properties and functions. However, many CNTs have been shown to induce lung fibrosis in experimental animals with some at a potency greater than that of silica, raising concern over possible toxic effects of CNT exposure in humans. Research into the mechanisms by which CNTs induce pulmonary fibrosis is warranted in order to facilitate the understanding, monitoring, and treatment of CNT-induced lung lesions that might occur in exposed populations. The current study focuses on investigating the role of osteopontin (OPN) in the development of lung fibrosis upon exposure to multiwalled carbon nanotubes (MWCNTs). Methods: C57BL/6J (WT) and Opn knockout (KO) mice were exposed to MWCNTs by pharyngeal aspiration to examine the acute and chronic effects of MWCNT exposure. The role of OPN and its mode of action in lung fibrosis development were analyzed at the cellular and molecular levels in vivo and in vitro. Results: OPN was highly and persistently induced in both the acute and chronic phases of the response to MWCNT exposure in mouse lungs. Comparison between WT and Opn KO mice revealed that OPN critically regulated MWCNT-induced lung fibrosis as indicated by reduced fibrotic focus formation and myofibroblast accumulation in Opn KO lungs. At the molecular level, OPN promotes the expression and activation of TGF-β1, stimulates the differentiation of myofibroblasts from fibroblasts, and increases the production of fibrous matrix proteins in lungs and cultured lung cells exposed to MWCNTs. Conclusion: OPN is highly induced in CNT-exposed lungs and plays critical roles in TGF-β1 signaling activation and myofibroblast differentiation to promote fibrosis development from MWCNT exposure. This study reveals an OPN-dependent mechanism to promote MWCNT-induced lung fibrosis. The findings raise the possibility of using OPN as a biomarker to monitor CNT exposure and as a drug target to halt fibrosis development.

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“…Stat1 −/− mice exhibit increased fibrosis following exposure to the chemotherapeutic drug bleomycin compared to wild type ( Stat1 +/+ ) mice, demonstrating that STAT1 is protective against fibrogenesis [19]. Also, ovalbumin sensitized Stat1 −/− mice that were subsequently challenged with tMWCNTs by oropharyngeal aspiration exhibit greater airway fibrosis than Stat1 +/+ mice, indicating that STAT1 plays a role in the immune response to tMWCNTs and allergens [11]. Moreover, fibroblasts isolated from lungs of Stat1 −/− mice are more responsive in vitro to exogenous transforming growth factor (TGF)-β1, produce more collagen than Stat1 +/+ fibroblasts treated with TGF-β1 and display an increased proliferative response in vitro to PDGF or EGF compared to Stat1 +/+ fibroblasts [19].…”

Section: Introductionmentioning

confidence: 99%

STAT1-dependent and -independent pulmonary allergic and fibrogenic responses in mice after exposure to tangled versus rod-like multi-walled carbon nanotubes

et al. 2017

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BackgroundPulmonary toxicity of multi-walled carbon nanotubes (MWCNTs) is influenced by physicochemical characteristics and genetic susceptibility. We hypothesized that contrasting rigidities of tangled (t) versus rod-like (r) MWCNTs would result in differing immunologic or fibrogenic responses in mice and that these responses would be exaggerated in transgenic mice lacking the signal transducer and activator of transcription-1 (STAT1), a susceptible mouse model of pulmonary fibrosis.MethodsMale wild type (Stat1 +/+) and STAT1-deficient (Stat1 −/−) mice were exposed to 4 mg/kg tMWCNTs, rMWCNTs, or vehicle alone via oropharyngeal aspiration and evaluated for inflammation at one and 21 days post-exposure via histopathology, differential cell counts, and cytokine levels in bronchoalveolar lavage fluid (BALF). Granuloma formation, mucous cell metaplasia, and airway fibrosis were evaluated by quantitative morphometry. Airway epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation. Cytokine protein levels in BALF and serum IgE levels were measured by ELISA. Lung protein Smad2/3 levels and activation were measured by Western blot. Lung mRNAs were measured by PCR.ResultsThere was a 7-fold difference in rigidity between tMWCNTs and rMWCNTs as determined by static bending ratio. Both MWCNT types resulted in acute inflammation (neutrophils in BALF) after one-day post-exposure, yet only rMWCNTs resulted in chronic inflammation at 21 days as indicated by neutrophil influx and larger granulomas. Both MWCNTs induced BrdU uptake in airway epithelial cells, with the greatest proliferative response observed in rMWCNT-exposed mice after one-day. Only rMWCNTs induced mucous cell metaplasia, but this index was not different between genotypes. Stat1 −/− mice had higher levels of baseline serum IgE than Stat1 +/+ mice. Greater airway fibrosis was observed with rMWCNTs compared to tMWCNTs, and exaggerated airway fibrosis was seen in the Stat1 −/− mouse lungs with rMWCNTs but not tMWCNTs. Increased fibrosis correlated with elevated levels of TGF-β1 protein levels in the BALF of Stat1 −/− mice exposed to rMWCNTs and increased lung Smad2/3 phosphorylation.ConclusionsRigidity plays a key role in the toxicity of MWCNTs and results in increased inflammatory, immunologic, and fibrogenic effects in the lung. STAT1 is an important protective factor in the fibroproliferative response to rMWCNTs, regulating both induced TGF-β1 production and Smad2/3 phosphorylation status. Therefore, both rigidity and genetic susceptibility should be major considerations for risk assessment of MWCNTs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-017-0207-3) contains supplementary material, which is available to authorized users.

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Role of Signal Transducer and Activator of Transcription 1 in Murine Allergen–Induced Airway Remodeling and Exacerbation by Carbon Nanotubes

Cited by 36 publications

References 50 publications

Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury

Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury

Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiation

STAT1-dependent and -independent pulmonary allergic and fibrogenic responses in mice after exposure to tangled versus rod-like multi-walled carbon nanotubes

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