Group II innate lymphoid cells and microvascular dysfunction from pulmonary titanium dioxide nanoparticle exposure

Abstract

BackgroundThe cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano-TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity.MethodsFemale, virgin, Sprague-Dawley rats (8–12 weeks) were exposed to 100 μg of nano-TiO2 via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles.ResultsPulmonary nano-TiO2 exposure was associated with an increase in IL-1ß, 4, 5 and 13 and TNF- α 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66 ± 0.19%) compared to controls (0.19 ± 0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-κB in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8 ± 4.3% and 137 ± 11% of controls respectively) by nano-TiO2 exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27 ± 12%), while endothelium-independent dilation (7 ± 14%) and α-adrenergic sensitivity (8 ± 2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO2 exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid.ConclusionsThese results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12989-018-0280-2) contains supplementary material, which is available to authorized users.

Rethinking Nano‐TiO2 Safety: Overview of Toxic Effects in Humans and Aquatic Animals

“…In mammals, inhalation of nano-TiO 2 (≈21 nm) results in cardiopulmonary impairment and negative effects on microcirculation as a result of oxidative damage and inflammation. [49][50][51][52][53][54] Nano-TiO 2 impairs endothelium-dependent vasodilation in subepicardial arterioles blunting response to acetylcholine and impairing flow-induced dilation. [51] The vasodilatory response of the aorta was less sensitive to nano-TiO 2 .…”

Particle toxicology and health - where are we?

“…Parameters that are characteristic for local responses are well detectable in many professional immune cells, but also in tissue cells which in vivo produce alarm signals to attract immune cells into a potentially threatened site. A good marker for local response is activation of the transcription factor NF-kB, which indicates cell stress that occurs during immune stimulation [45, 148]. The chemokine IL-8 is another example: It is produced very early and can be defined as a relatively unspecific alert signal, which indicates local inflammation that can be extreme enough to induce cytotoxicity [149–152].…”

ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

“…Unfortunately, the repercussions of the rampant use of ENMs remain unclear, along with the mechanisms and solutions to the potential negative consequences. In order to determine how the current exposure paradigm, which achieved a lung burden of 95.10 μg over 6 days, reflects ENM occupational exposure in humans in a manufacturing setting, alveolar surface area was used as previously described [11, 13, 51, 52]. The mouse alveolar surface area is 0.05 m 2 [52].…”