Dataset Information

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

ABSTRACT: Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05??g/g body weight) 20 and 110?nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110?nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

SUBMITTER: Botelho DJ

PROVIDER: S-EPMC5033060 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

Botelho Danielle J DJ Leo Bey Fen BF Massa Christopher B CB Sarkar Srijata S Tetley Terry D TD Chung Kian Fan KF Chen Shu S Ryan Mary P MP Porter Alexandra E AE Zhang Junfeng J Schwander Stephan K SK Gow Andrew J AJ

Nanotoxicology 20150707 1

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 ...[more]

PMID: 26152688

Similar Datasets

Project description:Metalloid contamination, such as arsenic poisoning, poses a significant environmental problem, reducing plant productivity and putting human health at risk. Phytohormones are known to regulate arsenic stress; however, the function of strigolactones (SLs) in arsenic stress tolerance in rice is rarely investigated. Here, we investigated shoot responses of wild-type (WT) and SL-deficient d10 and d17 rice mutants under arsenate stress to elucidate SLs' roles in rice adaptation to arsenic. Under arsenate stress, the d10 and d17 mutants displayed severe growth abnormalities, including phenotypic aberrations, chlorosis and biomass loss, relative to WT. Arsenate stress activated the SL-biosynthetic pathway by enhancing the expression of SL-biosynthetic genes D10 and D17 in WT shoots. No differences in arsenic levels between WT and SL-biosynthetic mutants were found from Inductively Coupled Plasma-Mass Spectrometry analysis, demonstrating that the greater growth defects of mutant plants did not result from accumulated arsenic in shoots. The d10 and d17 plants had higher levels of reactive oxygen species, water loss, electrolyte leakage and membrane damage but lower activities of superoxide dismutase, ascorbate peroxidase, glutathione peroxidase and glutathione S-transferase than did the WT, implying that arsenate caused substantial oxidative stress in the SL mutants. Furthermore, WT plants had higher glutathione (GSH) contents and transcript levels of OsGSH1, OsGSH2, OsPCS1 and OsABCC1 in their shoots, indicating an upregulation of GSH-assisted arsenic sequestration into vacuoles. We conclude that arsenate stress activated SL biosynthesis, which led to enhanced arsenate tolerance through the stimulation of cellular antioxidant defense systems and vacuolar sequestration of arsenic, suggesting a novel role for SLs in rice adaptation to arsenic stress. Our findings have significant implications in the development of arsenic-resistant rice varieties for safe and sustainable rice production in arsenic-polluted soils.

Project description:BackgroundLow-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Uncertainty about the therapeutic dose range (TDR) required for general and paediatric populations challenge the implementation of the World Health Organisation's recommendation to add 0.25 mg/kg to current standard antimalarial treatment in such settings. Modelling work shows that for low-dose primaquine to have an impact, high efficacy and extensive population coverage are needed. In practice, age-based dose regimens, often used in MDA, could lead to safety concerns and a different effectiveness profile. We aimed to define TDRs for primaquine and to assess dosing accuracy of age-based dose regimens.MethodsOptimised regional age-based dosing regimens for low-dose primaquine were developed in steps. First, we identified potential TDR options based on suggested published efficacy and safety thresholds (i.e. 0.1-0.4, 0.125-0.375, 0.15-0.35 mg/kg). We then used our previously defined weight-for-age growth references and age-based dose optimisation tool to model predicted regimen accuracies for Africa, Asia and Latin America based on low-dose primaquine tablets (3.75 mg and 7.5 mg) currently under development by Sanofi while employing the identified dose range options and pre-specified regimen characteristics.ResultsDose regimens employing TDRs of 0.1-0.4 and 0.125-0.375 mg/kg had the highest average predicted dose accuracies in all regions with the widest dose range of 0.1-0.4 mg/kg resulting in ≥99% dose accuracy in all three regions. The narrower 0.15-0.35 mg/kg range was on average predicted to correctly dose 91.4% of the population in Africa, 93.2% in Asia and 92.6% in Latin America. This range would prescribe ≥20% of 3-year-olds doses below 0.15 mg/kg and ≥20% of 11-year-olds doses above 0.35 mg/kg. Widening the TDR from 0.15-0.35 to 0.1-0.4 mg/kg increased the dose accuracy by ≥20% in Africa, ≥15% in Asia and ≥10% in Latin America.ConclusionOptimised age-based dose regimens derived from wider TDRs are predicted to attain the dose accuracies required for effective MDA in malaria transmission reduction and elimination settings. We highlight the need for a clearly defined TDR and for safety and efficacy trials to focus on doses compatible with age-based dosing often employed in such settings.

Dataset Information

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

Publications

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets