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The

Nano-Safety Research Group

Specialists in the assessment of nanomaterial toxicity to human health and the environment

NC3Rs: Activation and Resolution of Neutrophil Responses

 

Developing alternative models to evaluate the impact of nanomaterials on neutrophils during the stimulation and resolution of inflammation

Staff: Helinor Johnston, Rachel Verdon, Vicki Stone, Ted Henry                 nc3rs models 

Funding: NC3Rs

Activation of the immune system (inflammation) is essential to protect the body from harm caused by infection (e.g. bacteria), chemicals or pollution. Immune cells (white blood cells) are responsible for recognising these harmful stimuli and if possible, destroying them. Different types of immune cells vary with regards to their appearance, what stimuli they recognise, and how quickly they respond (hours vs days). Neutrophils (a type of immune cell) are part of the first line of defence; they travel in blood and patrol organs. Following recognition of a harmful stimulus neutrophils accumulate in the affected organ (e.g. lungs, liver) causing inflammation. This inflammation can last for a few hours or persist for weeks to years. In order to stop an inflammatory response neutrophils die. Failure of neutrophil responses to resolve (recover) can cause illness,as during inflammation neutrophils release molecules which destroy harmful stimuli but unfortunately may also damage the body. Toxicology studies investigate if substances cause harmful effects in humans, including inflammation.

There is evidence that some nanomaterials (NMs) can cause inflammation which may lead to adverse health effects. Laboratory experiments commonly use animals (rodents) to assess neutrophil accumulation in organs over time as an indicator of how toxic NMs are. Many studies therefore focus on neutrophil accumulation as a marker of toxicity. More studies are needed to assess whether this inflammation resolves. If inflammation resolves then NMs can be regarded as being of low toxicity. As NM use increases there is more demand for rodent studies to assess their potential toxicity. However, rodent studies are expensive, time consuming and there are ethical concerns about the use of rodents for scientific research and regulatory testing. The availability of good alternatives to rodent models for NM toxicity testing will reduce or replace rodent use. In vitro experiments study the response of neutrophils in the laboratory, without requiring rodents. Cells can be isolated from human blood (termed primary cells). Primary cells have a short lifetime and require humans to provide blood samples. Instead, neutrophil cell lines, which live longer, can be purchased, however they may not respond in the same way as primary cells. For the immune system to function properly communication between different cell types in the body is required. Zebrafish (ZF) allow inflammatory responses to be evaluated in an intact non-rodent and so can be employed to reduce rodent use. Zebrafish are available with fluorescent immune cells, and can be used to investigate inflammatory responses as neutrophil accumulation can be visualized and quantified over time.

Our project will identify approaches to investigate the ability of NMs to stimulate neutrophil responses in the laboratory and will identify if cells and ZF are good alternatives to rodents. We will compare our results to findings previously obtained from rodent studies to identify whether cells and ZF provide a good prediction of the rodent response. If they behave similarly then the scientific community may use these alternatives to decrease the numbers of rodents used to assess NM safety. Importantly, these alternatives are not restricted to testing NM safety and could be used to test the toxicity of a wider range of pollutants, chemicals (e.g. drugs) and microbes.

Partners:

  • Prof Adriano Rossi (University of Edinburgh)
  • Prof Charles Tyler (University of Exeter)
  • Prof Lang Tran (Institute of Occupational Medicine)

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