Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms

Abstract

Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS) with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.

Effects of fuel components and combustion particle physicochemical properties on toxicological responses of lung cells

“…[39] Combusting two different precisely defined fuels (BD and AD) under identical conditions resulted in particles and extracts with significant differences in their physicochemical properties, including differences in size, surface area, extractable chemical content, total and relative PAH content, and oxidizing potential/electrophile content. These differences manifested as variable effects on lung cells using a panel of relevant toxicological endpoint assays.…”

“…Additionally, this study focused on the role of specific cdPM physicochemical properties, on the activation of a set of toxicologically relevant endpoints using human H441 and THP1 cells as models. The following biological outcomes were evaluated: cytochrome P450 (CYP) 1A1 and 1B1 mRNA induction, enzymes that both detoxify and bioactivate polycyclic aromatic hydrocarbons (PAHs) in human airway epithelial cells[35–37]; secretion of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNFα, proteins that regulate host-defenses and inflammation) [35,38,39]; activation of transient receptor potential ankyrin-1 (TRPA1), a protein that triggers irritation sensations and the cough reflex via C-fibers, as well as inflammation and edema[40,41]; and oxidizing potential (oxidative stress induced by cdPM is believed to be a cause of many adverse biological effects). Finally, the role of specific cdPM physicochemical properties and their effects on different biological processes were evaluated using a combination of standardized PAH samples and inhibitors of both TRPA1 and oxidative stress.…”

Oxidative Stress and Inflammation Induced by Environmental and Psychological Stressors: A Biomarker Perspective

“…This sequence does not distinguish between the capacity of ENM to generate ROS in cell-free systems (111) and ROS generation consequent to nano-bio interaction. In a complex system (tissue, organ) a different three-pronged model can be proposed for the inflammatory response to ENM ( Figure 3).…”

“…Typically, OS is induced by ENM in a three-tiered hierarchical sequence ( Figure 2) (106,111). Pre-peer-review manuscript 8 A mild production of ROS induced by ENM (Tier 1) lowers the reduced glutathione (GSH) / oxidized GSH (GSSG) ratio and upregulates genes encoding type II anti-oxidant enzymes, thus re-establishing homeostasis.…”

“…In addition, the reactive surface of ENM may absorb transition metals that catalyze ROSgenerating reactions (Fenton, Fenton-like, Haber-Weiss) and produce cytotoxic and genotoxic hydroxyl radicals (106,111,117). Production of ROS resulting from the interaction of ENM with living systems is mainly indirect, due to damage or alterations caused by ENM to membranes, which trigger an alarm inflammatory reaction.…”