Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

Broström, Julia M.; Ye, Zhiwei; Axmon, Anna; Littorin, Margareta; Tinnerberg, Håkan; Lindh, Christian; Zheng, Huiyuan; Ghalali, Aram; Stenius, Ulla; Jönsson, Bo; Högberg, Johan

doi:10.1016/j.taap.2015.06.006

Cited by 14 publications

(19 citation statements)

References 52 publications

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“…Further work showed that P2X4 and P2X7 co-localize in response to TDI, and that ATX is rapidly concentrated in plasma membrane vesicles, presumably as a step preceding the secretion of ATX. Our data also show that the cytokine MCP-1 (also referred to as CCL2) affect the purinergic receptors so that vesicle formation and ATX secretion was facilitated [9] . The low concentrations of TDI needed for ATX activation in our cell models suggested that workers exposed to TDI in their work environment should exhibit signs of increased ATX activity.…”

Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"supporting

confidence: 57%

“…For example, increased levels of IgE are found in most cases of allergic asthma but relatively rarely in diisocyanate asthma patients, and this lack of IgE antibodies has puzzled researchers for many years [11] . We find that two purinergic receptors, P2X4 and P2X7, are needed for TDI-induced ATX secretion and a subsequent de novo synthesis of ATX in lung epithelial cells [9] . How the initial secretion relates to the subsequent protein synthesis is not known, but our data suggest not yet described control mechanisms for ATX expression; previous work indicate an inhibitory feedback loop between LPA and ATX in e.g.…”

Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"mentioning

confidence: 81%

“…We show that nano-molar concentrations of toluene diisocyanate (TDI) [9] , a notorious lung toxicant and respiratory sensitizer [10] , induce a sudden release of ATX from lung epithelial cells and we couple ATX to TDI toxicity [9] .…”

Section: Research Highlightmentioning

confidence: 99%

“…The low concentrations of TDI needed for ATX activation in our cell models suggested that workers exposed to TDI in their work environment should exhibit signs of increased ATX activity. Although TDI air levels in industry are restricted by very low occupational exposure limits (OELs), it is possible that TDI in blood might rise to nM concentrations [9] . It is also possible that aerosol droplets, which reach epithelial surfaces in the respiratory tree, might contain much higher concentrations of diisocyanates [12] .…”

Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"mentioning

confidence: 99%

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Autotaxin signaling, purinergic receptors and lung damage

Högberg

2015

Inflamm Cell Signal

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ATX is a secreted enzyme that produces lysophosphatindic acid (LPA) in plasma. For several years investigators have characterized endogenous factors that regulate ATX expression and compartmentalization. However many questions remain unanswered and this article highlights our recent finding that autotaxin (ATX) is readily induced by toxic environmental chemicals. LPA binds G-protein coupled receptors that affect basic cell functions. The interest in the ATX-LPA axis stems from its role in embryogenesis and its association to diseases such as allergic asthma, idiopathic lung fibroses, rheumatoid arthritis, wound healing and several common types of cancer. In our study we used toluene diisocyanate (TDI) and other diisocyanates. Diisocyanates are low-molecular weight industrial chemicals notorious for being respiratory sensitizers and lung toxicants. Mechanisms behind these effects are not sufficiently characterized. We mainly used TDI and found that TDI in the nM range induced a rapid secretion of ATX from respiratory epithelial cells. Two purinergic receptors, P2X4 and P2X7, were implicated in this effect of TDI, suggesting that there is a "P2X-ATX axis" in bronchial epithelium that is sensitive to diisocyanates. We also showed associations between TDI exposures, LPA levels in plasma and symptoms reported by exposed individuals. Thus, our data support a role for the ATX-LPA axis in TDI toxicity. Furthermore, they suggest novel ways to study the regulation of ATX expression. Of particular interest is to understand how ATX expression is affected by purinergic receptors, and to investigate a possible involvement of ATX in asthma induced by diisocyanates and perhaps other low-molecular weight environmental chemicals. Our study also raises questions about current occupational exposure limits for diisocyanates.

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Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"supporting

confidence: 57%

Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"mentioning

confidence: 81%

Section: Research Highlightmentioning

confidence: 99%

Section: Proof Of Principal: Tdi Is a Potent Activator Of A "P2x-atx"mentioning

confidence: 99%

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Autotaxin signaling, purinergic receptors and lung damage

Högberg

2015

Inflamm Cell Signal

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“…In ovalbumin-sensitized mice, intratracheally instilled magnetic iron oxide nanoparticles triggered release of EV that promote dendritic cell maturation and T cell activation (Zhu et al 2012). Brostrom et al (2015) found that treatment of pulmonary epithelial cells with the occupational respiratory toxicant toluene diisocyanate initiated release of autotaxin via EV, an enzyme that has been implicated in allergic airway inflammation.…”

Section: Allergic Inflammationmentioning

confidence: 99%

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

Benedikter

Wouters

Savelkoul

et al. 2018

Journal of Toxicology and Environmental Health, Part B

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Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.

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The impact of environmental contaminants on extracellular vesicles and their key molecular regulators: A literature and database‐driven review

Carberry

Rager

2022

Environ and Mol Mutagen

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Exposure to environmental chemicals is now well recognized as a significant factor contributing to the global burden of disease; however, there remain critical gaps in understanding the types of biological mechanisms that link environmental chemicals to adverse health outcomes. One type of mechanism that remains understudied involves extracellular vesicles (EVs), representing small cell-derived particles capable of carrying molecular signals such as RNAs, miRNAs, proteins, lipids, and chemicals through biological fluids and imparting beneficial, neutral, or negative effects on target cells. In fact, evidence is just now starting to grow that supports the role of EVs in various disease etiologies. This review aims to (1) Provide a landscape of the current understanding of the functional relationship between EVs and environmental chemicals; (2) Summarize current knowledge of EV regulatory processes including production, packaging, and release; and (3) Conduct a database-driven analysis of known chemical-gene interactions to predict and prioritize environmentally relevant chemicals that may impact EV regulatory genes and thus EV regulatory processes. This approach to predicting environmentally relevant chemicals that may alter EVs provides a novel method for evidence-based hypothesis generation for future studies evaluating the link between environmental exposures and EVs.

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Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

Cited by 14 publications

References 52 publications

Autotaxin signaling, purinergic receptors and lung damage

Autotaxin signaling, purinergic receptors and lung damage

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

The impact of environmental contaminants on extracellular vesicles and their key molecular regulators: A literature and database‐driven review

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