Instillation of crystalline silica into the lungs of mice is a common experimental model of pulmonary fibrosis. Typically, a suspension of silica in saline is injected into the trachea via intubation or surgical tracheostomy. These techniques require a high degree of technical skill, have a lengthy training period, and can suffer from a high failure rate. In oropharyngeal aspiration, a droplet of liquid is placed in the animal's mouth while simultaneously holding its tongue (to block the swallow reflex) and pinching its nose shut, forcing it to breathe through its mouth, aspirating the liquid. To determine whether oropharyngeal aspiration (OA) could replace intratracheal instillation (IT) in a model of silica-induced fibrosis, a comparison was performed. Crystalline silica was introduced into the lungs of male C57BL/6 mice by the IT or OA procedure, and the resulting inflammation and fibrosis was assessed after 3 weeks. IT and OA instillation of silica both resulted in neutrophilic inflammation and fibrotic changes, including interstitial fibrosis and dense fibrotic foci. Mice treated via IT demonstrated a few large lesions proximal to conducting airways with little involvement of the distal parenchyma and large interanimal variability. In contrast, OA resulted in a diffuse pathology with numerous fibrotic foci distributed throughout the lung parenchyma, which is more representative of human fibrotic lung disease. OA- but not IT-treated mice exhibited significantly increased lung collagen content. Furthermore, the interanimal variability within the OA group was significantly less than in the IT group. Oropharyngeal aspiration should be considered as an alternative to intratracheal instillation of silica and other particulates in studies of respiratory toxicity and lung disease.
"The limited quantity of PM10 available prevented exposure by dry aerosol. We chose to use intranasal exposure over intratracheal instillation to avoid a biased deposition of the particles in the large airways  and to ensure that the particles were able to reach the alveoli we used an optimised protocol with a delivery volume of 50 µL and mild sedation . The 100 µg dose was chosen based on the dose-response data from our previous study  as a dose that produces a robust and measurable inflammatory response. "
[Show abstract][Hide abstract] ABSTRACT: There are many communities around the world that are exposed to high levels of particulate matter <10 µm (PM10) of geogenic (earth derived) origin. Mineral dusts in the occupational setting are associated with poor lung health, however very little is known about the impact of heterogeneous community derived particles. We have preliminary evidence to suggest that the concentration of iron (Fe) may be associated with the lung inflammatory response to geogenic PM10. We aimed to determine which physico-chemical characteristics of community sampled geogenic PM10 are associated with adverse lung responses.
We collected geogenic PM10 from four towns in the arid regions of Western Australia. Adult female BALB/c mice were exposed to 100 µg of particles and assessed for inflammatory and lung function responses 6 hours, 24 hours and 7 days post-exposure. We assessed the physico-chemical characteristics of the particles and correlated these with lung outcomes in the mice using principal components analysis and multivariate linear regression.
Geogenic particles induced an acute inflammatory response that peaked 6 hours post-exposure and a deficit in lung mechanics 7 days post-exposure. This deficit in lung mechanics was positively associated with the concentration of Fe and particle size variability and inversely associated with the concentration of Si.
The lung response to geogenic PM10 is complex and highly dependent on the physico-chemical characteristics of the particles. In particular, the concentration of Fe in the particles may be a key indicator of the potential population health consequences for inhaling geogenic PM10.
PLoS ONE 02/2014; 9(2):e90609. DOI:10.1371/journal.pone.0090609 · 3.23 Impact Factor
"WT and T-bet-/- mice (n = 49, Taconic Farms, Inc.) were exposed to NiNPs or MWCNTs at 4 mg/kg or 0.1% Pluronic (Sigma Aldrich, St. Louis, MO) surfactant solution in phosphate-buffered saline by oropharyngeal aspiration under an isoflurane anesthetic, as previously described . On day 1 or day 21 after initial NiNP exposure, mice were euthanized via intraperitoneal injection of Fatal Plus (Vortech Pharmaceuticals, Dearborn, MI). "
[Show abstract][Hide abstract] ABSTRACT: Nickel nanoparticles (NiNPs) are increasingly used in a variety of industrial applications, including the manufacturing of multi-walled carbon nanotubes (MWCNTs). While occupational nickel exposure is a known cause of pulmonary alveolitis, fibrosis, and cancer, the health risks of NiNPs are not well understood, especially in susceptible individuals such as asthmatics. The T-box transcription factor Tbx21 (T-bet) maintains Th1 cell development and loss of T-bet is associated with a shift towards Th2 type allergic airway inflammation that characterizes asthma. The purpose of this study was to determine the role of T-bet in susceptibility to lung remodeling by NiNPs or MWCNTs.
Wild-type (WT) and T-bet-/- mice were exposed to NiNPs or MWCNTs (4 mg/kg) by oropharyngeal aspiration (OPA). Necropsy was performed at 1 and 21 days. Bronchoalveolar lavage fluid (BALF) was collected for differential counting of inflammatory cells and for measurement of cytokines by ELISA. The left lung was collected for histopathology. The right lung was analyzed for cytokine or mucin (MUC5AC and MUC5B) mRNAs.
Morphometry of alcian-blue/periodic acid Schiff (AB/PAS)-stained lung tissue showed that NiNPs, significantly increased mucous cell metaplasia in T-bet-/- mice at 21 days (p < 0.001) compared to WT mice, and increased MUC5AC and MUC5B mRNAs (p < 0.05). MWCNTs also increased mucous cell metaplasia in T-bet-/- mice, but to a lesser extent than NiNPs. Chronic alveolitis was also increased by NiNPs, but not MWCNTs, in T-bet-/- mice compared to WT mice at 21 days (P < 0.001). NiNPs also increased IL-13 and eosinophils (p < 0.001) in BALF from T-bet-/- mice after 1 day. Interestingly, the chemokine CCL2 in the BALF of T-bet-/- mice was increased at 1 and 21 days (p < 0.001 and p < 0.05, respectively) by NiNPs, and to a lesser extent by MWCNTs at 1 day. Treatment of T-bet-/- mice with a monoclonal anti-CCL2 antibody enhanced NiNP-induced mucous cell metaplasia and MUC5AC mRNA levels (p < 0.05), yet marginally reduced NiNP-induced alveolitis.
These findings identify T-bet as a potentially important susceptibility factor for NiNP exposure and to a lesser extent for MWCNT exposure, and suggests that individuals with asthma are at greater risk.
"The instillation technique has been well validated [32-36] and the dose employed is similar to that of other studies using repeated instillations [37,38], and below those commonly used for single instillation exposures. While we cannot rule out that a proportion of the particulate administered deposits in the upper airways, studies have shown that the aspiration instillation technique to provide excellent delivery and dispersity of particulate throughout the alveoli [39,40]. The MPPD particle deposition model  estimates that the average 24-h instilled dose used here (assuming all DEP reaches the alveoli) is approximately 40-fold higher than the comparable alveolar deposition from a 24-h inhalation of 100 μg/m3 in man (adjusted for mice). "
[Show abstract][Hide abstract] ABSTRACT: Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE-/-) mice.
ApoE-/- mice were fed a 'Western diet' (8 weeks) to induce 'complex' atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 muL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery.
Brachiocephalic atherosclerotic plaques were larger in ApoE-/- mice treated with DEP (59+/-10%) than in controls (32+/-7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4+/-0.2 vs 1.8+/-0.2; P = 0.048) and buried fibrous layers (1.2+/-0.2 vs 0.4+/-0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation.
Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.
Stephanie A Matthes, Thomas J LaRouere, Jeffrey C Horowitz, Eric S White
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