Identification of novel cytokine biomarkers of hexanal exposure associated with pulmonary toxicity☆
Graphical abstract
Introduction
Inflammatory responses play key roles in the many pathogenesis of diseases, such as autoimmune disease, chronic diseases, and cancer. Inflammation is increasingly linked to inflammatory diseases and cytokine-targeted therapies (Lin and Karin, 2007). Inflammation is mediated by the cytokines, which are produced by immune cells, and they have various effects on diverse cell types. Cytokines act as mediators in important parts of the immune system, such as host defense, autoimmunity, and immunoregulation (O'Shea et al., 2011, Fan et al., 2016), which reveals powerful novel biomarkers for risk prediction and aids in understanding the mechanism of the inflammatory mediated diseases (Mack, 2007). A number of recent studies have indicated that the cytokine biomarkers contribute to the clues to the mechanism of inflammatory mediated diseases and potential therapeutic targets (Mack, 2007, Doll et al., 2014). In pulmonary inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, there are many known cytokine biomarkers. Previous studies have revealed that matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) are associated with airway and pulmonary inflammation (Lee and Yang, 2013). These cytokine biomarkers are currently used for the investigation of associations between environmental exposure and immune-related environmental health diseases.
In the field of the immunotoxicology, recognition of the association between exposure to environmental factors (EFs) and immune-based diseases has rapidly expanded (Duramad and Holland, 2011, Boverhof et al., 2014). For example, a variety of environmental chemicals, such as polyhalogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons (PAHs), heavy metals, and pesticides, have been shown to be immunotoxic (Luster and Rosenthal, 1993, Kimber and Dearman, 2002). The lung is a principal target organ of entry for environmental chemical stressors in air pollutants (Hasenberg et al., 2013). Indeed, the area of pulmonary immunotoxicology has received more recognition in providing further insights into a molecular immunologically related mechanism under environmental factors (Cohen, 2004).
Our previous studies have reported that increased pro-inflammatory responses are induced by environmental chemical exposures. We have shown that in vitro exposure of human alveolar epithelial cells (A549) to lower-molecular-weight saturated aliphatic aldehydes (LSAAs) induces an inflammatory response, immune response, cytokine activity, and cytokine-cytokine receptor interaction (Lee et al., 2013, Song et al., 2015). Furthermore, we verified that IL-6 and IL-8 levels were elevated due to exposure to LSAA using an in vitro system. IL-6 and IL-8 are well-known cytokines that play the role of an initiator of inflammatory cascades and critical markers of inflammation and pro-tumorigenic signaling (Grivennikov et al., 2010); however, among LSAAs, it is not known whether hexanal exposure affects both the immune system and inflammatory responses related to pulmonary immunotoxicity. Hexanal (hexaldehyde) is known as a major indoor air irritant, as a group of aldehydes (Zheng, 2010, Meininghaus et al., 2001). It is emitted from the wood pellets and drying lumber, which have been increasing in production and use (Svedberg et al., 2004). Hexanal is also found in synthetic rubber and polyurethane tracks, furniture coating compounds, particleboard panels, and newly built house (Hall, 2010, Tarlo et al., 2010). Furthermore, there is a report that the two hours of exposure to hexanal results in eyes and nose irritation, and headache at 10 ppm (40,960 μg/m3) in humans (Ernstgård et al., 2006); however, there are only limited studies on health risk assessment of humoral immunity after hexanal exposure. Therefore, we focused on hexanal, and the aim of this study was to investigate the patterns in the expression of cytokines using multiplex cytokine antibody array technology exposed to hexanal with in vitro and in vivo systems. Further, we investigated whether hexanal exposure causes an airway inflammatory response in relation to environmental pulmonary disease.
Section snippets
Chemicals and reagents
For the in vitro study, hexanal (98%), dimethylsulfoxide (DMSO), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Sigma–Aldrich Co (USA). The cell culture media and supplemented buffer solutions were purchased from GIBCO™ (USA): Roswell Park Memorial Institute (RPMI) 1640, Dulbecco's Phosphate Buffered Saline (PBS), Fetal Bovine Serum (FBS), and antibiotics (penicillin and streptomycin). All of the chemicals used in this study were analytical grade or
Cytotoxicity
To determine the in vitro exposure concentrations, the cytotoxicity of hexanal was assessed by the MTT assay, as in an earlier study described by Yoon Cho et al. (2014). Based on these cytotoxicity data, the 5% inhibitory concentration (IC5), 10% inhibitory concentration (IC10) and 20% inhibitory concentration (IC20) of hexanal were calculated (Fig. S1). A549 cells were exposed to IC5 (0.1 mM), IC10 (0.3 mM) and IC20 (0.8 mM) doses of hexanal for the investigation of the dose response
Discussion
Previous studies have shown that environmental chemicals such as aldehydes induce pulmonary inflammation through the secretion of pro-inflammatory cytokines and the various immune/inflammation-related genes (Song et al., 2015). Research on the relationships between biomarkers of immunotoxicity, such as cytokine biomarkers and environmental chemicals, for environmental and public health is also increasing (Duramad and Holland, 2011). Based on these studies, we have suggested that environmental
Conclusions
In conclusion, this approach provides useful novel cytokine biomarkers for a high throughput hexanal exposure-induced pulmonary toxicity screening. These findings support the potential immunotoxic effects on the human pulmonary system after hexanal exposure and show the close relation to pulmonary inflammatory/immune responses on the respiratory system, and it could be considered a critical cytokine biomarkers for the evaluation of hexanal exposure screening and the potential prediction of
Declaration of interest
The authors declared that there are no conflicts of interest.
Acknowledgements
This work was supported by the Korea Research Foundation grants from Korea Ministry of Environment as “The Ecoinnovation Project [412-111-010]”, and KIST Program to Ryu, J. C. of the Republic of Korea.
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This paper has been recommended for acceptance by David Carpenter.