The Role of Toll-like Receptor 4 in Environmental Airway Injury in Mice

Abstract

Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. In this study, we investigated the requirement of toll-like receptor 4 (TLR4) in mice for pulmonary responses to three environmental toxins: aerosolized lipopolysaccharide, particulate matter (residual oil fly ash), and ozone. The physiologic and biologic responses to these toxins were evaluated by the extent of airway responsiveness, neutrophil recruitment to the lower respiratory tract, changes in inflammatory cytokines, and the concentration of protein in the lavage fluid. Genetically engineered, TLR4-deficient mice (C57BL/6(TLR4-/-)) were unresponsive to inhaled lipopolysaccharide, except for minimal increases in some inflammatory cytokines. In contrast, C57BL/6(TLR4-/-) mice did not differ from wild-type mice in their airway response to instilled residual oil fly ash or acute ozone exposure; however, we found that, despite a robust inflammatory response, C57BL/6(TLR4-/-) mice are protected against the development of airway hyperresponsiveness after subchronic ozone exposure. These data demonstrate in the mouse that the requirement of TLR4 for pulmonary inflammation depends on the nature of the toxin and appears specific to toxin and exposure conditions.

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

“…Our study further sheds light on how a low dose of lung-sensitizing Ags such as LPS can facilitate tumor progression. Low levels of environmental LPS in inhaled air has been established to lead to latent chronic inflammation, which is deleterious for many pathologies that turn into a Th2-like immune environment (39)(40)(41). For example, asthma, which is characterized by a Th2-like environment (24), is exacerbated by low-dose LPS compared with high-dose LPS.…”

Impact of Particulate Matter Exposition on the Risk of Ischemic Stroke: Epidemiologic Evidence and Putative Mechanisms

“…40,41 Despite a functioning airway defense such as mucociliary clearance, large fractions of fine and ultrafine PMs are capable of reaching the respiratory zone of the lungs. 40,41 In vitro and in vivo studies showed that PM exposure increases reactive oxygen species (ROS) formation and the number of proinflammatory markers in bronchoalveolar lavage. 40,41 This suggests that local proinflammatory processes and oxidative stress within the lungs are of relevance in the complex cascade that subsequently has deleterious systemic effects.…”

“…via toll-like receptors and scavenger receptors. 41 Alveolar macrophages and dendritic cells recognize pathogenic patterns via toll- CI, confidence interval; IQR, interquartile range, lagx, days before onset or hospital admission; N, study population, 0.95 CI, 95%; OR, odds ratio; PMx, particulate matter with median aerodynamic diameter, RR, relative risk, *, result is statistically significant (P-valueo0.05). Search in Medline (PubMed search engine) 30, July 2013, search terms: all combinations of 'air pollution' , 'particulate matter' , and 'stroke' , 'ischemic stroke' .…”

“…41 Subsequently, ROSreleasing enzymes such as nicotinamide adenine dinucleotide phosphate-oxidase oxidase are activated, and proinflammatory cytokines such as interleukin 6 are released. [41][42][43] Large fractions of PM, e.g. transition metals, oxidize phospholipids (surfactants) in the lungs.…”

“…[41][42][43] Oxidized surfactants in turn are ligands for toll-like receptor and scavenger receptor. [41][42][43] This activation of the local pulmonary innate immune system leads to a powerful burst of ROS and proinflammatory markers within the lung parenchyma. In addition, up to 80% of PM, predominantly the coarse fraction, is able to enter pulmonary parenchyma by transcytosis through macrophages and alveolar epithelium cells.…”