Carbon Nanotube-Induced Pulmonary Granulomatous Disease: Twist1 and Alveolar Macrophage M1 Activation

Barna, Barbara P.; Huizar, Isham; Malur, Anagha; McPeek, Matthew; Marshall, Irene; Jacob, Mark; Dobbs, Larry; Kavuru, Mani S.; Thomassen, Mary Jane

doi:10.3390/ijms141223858

Cited by 25 publications

(20 citation statements)

References 44 publications

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“…Aliquots of BAL cells were centrifuged and frozen for qPCR evaluation as previously described [23]. Total RNA was extracted from BAL cells by RNeasy protocol (Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease

Malur¹,

Barna²

2015

J Nanomed Nanotechnol

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Recent studies suggest additive effects of environmental pollutants and microbial antigens on respiratory disease. We established a granuloma model in which instilled multiwall carbon nanotubes (MWCNT) elicit granulomatous pathology. We hypothesized that mycobacterial antigen ESAT-6, a T cell activator associated with tuberculosis and sarcoidosis, might alter pathology. Wild-type C57Bl/6 mice received MWCNT with or without ESAT-6 peptide. Controls received vehicle (surfactant-PBS) or ESAT-6 alone. Mice were evaluated 60 days later for granulomas, fibrosis, and bronchoalveolar lavage (BAL) cell expression of inflammatory mediators (CCL2, MMP-12, and Osteopontin). Results indicated increased granulomas, fibrosis, and inflammatory mediators in mice receiving the combination of MWCNT+ESAT-6 compared to MWCNT or vehicle alone. ESAT-6 alone showed no significant effect on these pathological endpoints. However, CD3 (+) lymphocyte infiltration of lung tissue increased with MWCNT+ESAT-6 versus MWCNT alone. Findings suggest that concurrent exposure to microbial antigen and MWCNT exacerbates chronic pulmonary disease.

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“…Aliquots of BAL cells were centrifuged and frozen for qPCR evaluation as previously described [23]. Total RNA was extracted from BAL cells by RNeasy protocol (Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease

Malur¹,

Barna²

2015

J Nanomed Nanotechnol

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“…HP has been reported in metalworkers that were exposed to nontuberculous mycobacteria in contaminated metalworking fluid, providing an interesting example of a different pathogenic outcome from exposure to these organisms that results in a form of granulomatous inflammation in the lung [64]. Recent studies demonstrate that carbon nanotubes can induce some features of a sarcoidosis-like granulomatous reaction when injected into the lungs of mice, but fail to recapitulate the clinical features of sarcoidosis [65][66][67]. Whether the definition of sarcoidosis should include granulomatous responses in the lung induced by exposure to such known inorganic or organic agents remains a contested issue [68].…”

Section: Environmental Studies Of Sarcoidosis Etiologymentioning

confidence: 99%

Etiologies of Sarcoidosis

Chen

Möller

2015

Clinic Rev Allerg Immunol

122

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Since sarcoidosis was first described more than a century ago, the etiologic determinants causing this disease remain uncertain. Studies suggest that genetic, host immunologic, and environmental factors interact together to cause sarcoidosis. Immunologic characteristics of sarcoidosis include non-caseating granulomas, enhanced local expression of T helper-1 (and often Th17) cytokines and chemokines, dysfunctional regulatory T-cell responses, dysregulated Toll-like receptor signaling, and oligoclonal expansion of CD4+ T cells consistent with chronic antigenic stimulation. Multiple environmental agents have been suggested to cause sarcoidosis. Studies from several groups implicate mycobacterial or propionibacterial organisms in the etiology of sarcoidosis based on tissue analyses and immunologic responses in sarcoidosis patients. Despite these studies, there is no consensus on the nature of a microbial pathogenesis of sarcoidosis. Some groups postulate sarcoidosis is caused by an active viable replicating infection while other groups contend there is no clinical, pathologic, or microbiologic evidence for such a pathogenic mechanism. The authors posit a novel hypothesis that proposes that sarcoidosis is triggered by a hyperimmune Th1 response to pathogenic microbial and tissue antigens associated with the aberrant aggregation of serum amyloid A within granulomas, which promotes progressive chronic granulomatous inflammation in the absence of ongoing infection.

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“…Furthermore, PPARγ ligands inhibit TGF-β-induced myofibroblast differentiation in a dose dependent manner through the P13K/AKT pathway 124,125 . PPARγ knockout mice have higher expression of Twist1 , a transcription factor responsive to classical M1 and not M2 macrophage stimulation 126 . Alveolar macrophages from mice 60 days post-MWCNT exposure exhibit a decrease in PPARγ expression and knockout mice exposed this way experience increased inflammation and larger granuloma formation 120 .…”

Section: Genetic Susceptibility To Pulmonary Fibrosismentioning

confidence: 99%

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

Duke

Bonner

2017

WIREs Nanomed Nanobiotechnol

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Carbon nanotubes (CNTs) are engineered nanomaterials (ENMs) with numerous beneficial applications. However, they could pose a risk to human health from occupational or consumer exposures. Rodent models demonstrate that exposure to CNTs via inhalation, instillation, or aspiration results in pulmonary fibrosis. The severity of the fibrogenic response is determined by various physicochemical properties of the nanomaterial such as residual metal catalyst content, rigidity, length, aggregation status, or surface charge. CNTs are also increasingly functionalized post-synthesis with organic or inorganic agents to modify or enhance surface properties. The mechanisms of CNT-induced fibrosis involve oxidative stress, innate immune responses of macrophages, cytokine and growth factor production, epithelial cell injury and death, expansion of the pulmonary myofibroblast population, and consequent extracellular matrix accumulation. A comprehensive understanding of how physicochemical properties affect the fibrogenic potential of various types of CNTs should be considered in combination with genetic variability and gain or loss of function of specific genes encoding secreted cytokines, enzymes, or intracellular cell signaling molecules. Here, we cover the current state of the literature on mechanisms of CNT-exposed pulmonary fibrosis in rodent models with a focus on physicochemical characteristics as principal drivers of the mechanisms leading to pulmonary fibrosis. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

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Carbon Nanotube-Induced Pulmonary Granulomatous Disease: Twist1 and Alveolar Macrophage M1 Activation

Cited by 25 publications

References 44 publications

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease

Etiologies of Sarcoidosis

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

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