The objective of this study was to investigate mechanisms underlying species specificity in particle-induced lung inflammation.
Rats, mice, and hamsters exposed to air, 1, 7, or 50 mg/m3 of carbon black for 13 weeks were killed at 1 day, 3 months, and 11 months after exposure. Bronchoalveolar lavage was performed and characterized for cell number, cell type, reactive oxygen and nitrogen species, and cytokine levels. Ex vivo mutational analysis of inflammatory cells was evaluated by coincubating with lung epithelial cells. Lung tissue was evaluated for gene expression of various antiinflammatory mediators.
There was a dose- and time-related effect with all the parameters. Rats demonstrated greater propensity for generating a proinflammatory response, whereas mice and hamsters demonstrated an increased antiinflammatory response.
These differences in pro- and antiinflammatory responses may contribute to the apparent species differences in inflammation and tumorigenesis.
"We measured several inflammatory mediators by ELISA in order to identify the drivers of the neutrophil responses following instillation and inhalation exposures to TiO2 and to determine if the mechanisms of response are different based on dose rate. Several studies have demonstrated links between NP exposure, oxidative stress and pro-inflammatory mediator release [51,58,59]. We selected mediators that are well-documented in the nanotoxicology literature as playing a role in RT inflammation, namely: monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) (Figure 4 and Table 4). "
[Show abstract][Hide abstract] ABSTRACT: The increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose-response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant.
F-344 rats were exposed to the same deposited doses of titanium dioxide (TiO2) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure.
Although the initial lung burdens of TiO2 were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO2 instillation compared to saline controls and to TiO2 inhalation, whereas TiO2 inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO2 inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends, although the responses for single exposures were more robust.
High dose rate NP delivery elicits significantly greater inflammation compared to low dose rate delivery. Although high dose rate methods can be used for quantitative ranking of NP hazards, these data caution against their use for quantitative risk assessment.
"Selecting the appropriate metric by which to normalize the dose received in cellular exposures to mineral particles in vitro is a critical yet controversial issue . Historically, mass has been the most commonly utilized metric in comparative studies of particulates [14,17,29-33]; however without additional information on the physicochemical properties of the samples under investigation there is a lot of uncertainty with this approach that makes interpretation of comparative toxicity data difficult. To address the issue of alternative dose metrics, we have, for the first time, conducted extensive physicochemical characterization of the Libby amphibole samples, in addition to the more well-studied standard reference amosite samples, to ensure accurate interpretation of the acquired cellular response data. "
[Show abstract][Hide abstract] ABSTRACT: An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples.
Primary human airway epithelial cells (HAEC) were exposed two different LA samples as well as standard amphibole reference samples. Analysis of the samples included a complete particle size distribution analysis, calculation of surface area by electron microscopy and by gas adsorption and quantification of surface-conjugated iron and hydroxyl radical production by the fibers. Interleukin-8 mRNA levels were quantified by qRT-PCR to measure relative pro-inflammatory response induced in HAEC in response to amphibole fiber exposure. The relative contribution of key physicochemical determinants on the observed pro-inflammatory response were also evaluated.
The RTI reference sample contained the longest fibers and demonstrated the greatest potency at increasing IL-8 transcript levels when evaluated on an equal mass basis. The two LA samples and the UICC reference sample consisted of similar particle numbers per milligram as well as similar particle size distributions and induced comparable levels of IL-8 mRNA. A strong correlation was observed between the elongated particle (aspect ratio >=3:1) dose metrics of length and external surface area. Expression of the IL-8 data with respect to either of these metrics eliminated the differential response between the RTI amosite sample and the other samples that was observed when HAEC were exposed on an equal mass basis.
On an equal mass basis, LA is as potent as the UICC amosite reference sample at inducing a pro-inflammatory response in HAEC but is less potent than the RTI amosite sample. The results of this study show that the particle length and particle surface area are highly correlated metrics that contribute significantly to the toxicological potential of these amphibole samples with respect to the inflammogenic response induced in airway epithelial cells.
"Pulmonary inflammation is a common response to the inhalation of particles and is closely associated with chronic pathological outcomes [17-19]. For this reason, measuring cell differentiation of BAL cells (i.e., the numbers of total cells, macrophages, PMNs cells and lymphocytes) and cytotoxicity parameters (i.e., LDH activities and albumin concentrations) was undertaken to identify the chronic inflammation caused by nano-sized carbon black. "
[Show abstract][Hide abstract] ABSTRACT: This study was conducted to determine whether nano-sized carbon black exposure results in greater damage in high fat diet-induced overweight rats than normal weight ones and to identify the possible causes of any differences.
Two groups of Sprague-Dawley rats allocated by body weight (normal and overweight) were exposed to aerosolized nano-sized carbon black for 6 hours a day, 5 days per week over a 4-week period. Differential cell counts, lactate dehydrogenase (LDH) activities and albumin concentrations were measured in bronchoalveolar lavage (BAL) fluid, and histopathological findings in the lungs were evaluated. Tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 were measured in BAL fluid and supernatants of lipopolysaccharide(LPS)-stimulated lymphocyte culture.
Rats exposed to high concentrations of nano-sized carbon black showed significantly increased (p<0.05) polymorphonuclear leukocyte number and LDH activity in the BAL fluid from both overweight and normal rats. Mild histopathological changes were observed in normal rats irrespective of carbon black concentrations. However, severe histological scores were found in overweight rats (1.75±0.46, 2.25±0.46, and 2.88±0.35 after low, medium, and high concentration exposures). Proinflammatory cytokine levels of TNF-α and IL-6 were significantly higher in the supernatant of LPS-stimulated lymphocytes of overweight rats, whereas there was no significant difference in the BAL fluid between normal and overweight rats.
Inflammation and damage to lungs exposed to nano-sized carbon black was more severe in high fat diet-induced overweight rats compared to normal rats.
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