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Keywords:

  • airborne pollutants;
  • asthma exacerbation;
  • interleukin-33

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

High levels of ambient environmental particulate matter (PM10 i.e. < 10 μm median aerodynamic diameter) have been linked to acute exacerbations of asthma. We examined the effects of delivering a single dose of Sydney PM10 by intranasal instillation to BALB/c mice that had been sensitized to ovalbumin and challenged repeatedly with a low (≈3 mg/m3) mass concentration of aerosolized ovalbumin for 4 weeks. Responses were compared to animals administered carbon black as a negative control, or a moderate (≈30 mg/m3) concentration of ovalbumin to simulate an allergen-induced acute exacerbation of airway inflammation. Delivery of PM10 to mice, in which experimental mild chronic asthma had previously been established, elicited characteristic features of enhanced allergic inflammation of the airways, including eosinophil and neutrophil recruitment, similar to that in the allergen-induced exacerbation. In parallel, there was increased expression of mRNA for interleukin (IL)-33 in airway tissues and an increased concentration of IL-33 in bronchoalveolar lavage fluid. Administration of a monoclonal neutralizing anti-mouse IL-33 antibody prior to delivery of particulates significantly suppressed the inflammatory response induced by Sydney PM10, as well as the levels of associated proinflammatory cytokines in lavage fluid. We conclude that IL-33 plays a key role in driving airway inflammation in this novel experimental model of an acute exacerbation of chronic allergic asthma induced by exposure to PM10.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

Asthma is characterized by chronic allergic inflammation of the airways, with superimposed episodes of acute inflammation [1]. These acute exacerbations are the most clinically significant feature of asthma and are the main contributor to direct health-care costs associated with the disease [2]. Exacerbations are typified by increased distal airway inflammation, with exaggeration of symptoms such as cough, chest tightness and dyspnoea [3, 4]. As many as 80% of acute exacerbations of asthma are triggered by respiratory viral infections, most commonly human rhinovirus [5, 6]. Allergens and other triggers may also be important. Notably, there is accumulating epidemiological evidence that high levels of atmospheric pollutants, including particulates and oxides of nitrogen, can trigger acute exacerbations of asthma [7-10]. However, little is understood about the mechanisms involved.

Airborne particulate matter (PM) may be solid or liquid material, which can be generated as a result of natural phenomena such as dust storms, bush and forest fires or volcanic eruptions, as well as by human activity. Environmental PM with the potential to cause respiratory effects is categorized on the basis of size as PM10, PM2·5, PM1 or PM0·1; i.e. all particles less than a median aerodynamic diameter of 10, 2·5, 1 or 0·1 μm, respectively [11]. A major source of ‘man-made’ particulate matter is the combustion of fossil fuels, typically associated with vehicular emissions and industrial activity. Thus, a number of experimental studies have examined the effects of diesel exhaust particulates (DEP) on cells of the respiratory tract and on acute allergic inflammation of the airways [12-17].

However, although DEP represent an important component of urban air pollution, exposure to DEP does not accurately represent the widely varying nature of particulate pollutants in urban environments. Ambient urban PM has a bimodal size distribution, with peaks at approximately 1 μm and 5 μm median aerodynamic diameter [18, 19]. Whereas DEP contribute primarily to PM2·5 [20], at least half of the airborne particulate mass is in the PM2·5–10 range. These so-called coarse particles have a higher metal content [19] and may have a greater potential to cause injury to cells of the respiratory system [21]. Thus, experimental assessment of the relationship between particulate air pollution and exacerbations of asthma needs to focus on ambient particulate matter in an animal model of pre-existing mild chronic asthma. However, to date no such studies have been performed.

We have previously described a model of mild chronic allergic asthma in mice [22]. In this well-characterized animal model, we have demonstrated chronic asthmatic inflammation of the airways and changes of structural remodelling in mice that were systemically sensitized to ovalbumin (OVA) and received long-term inhalational challenge with a controlled low mass concentration of aerosolized OVA. Importantly, lesions are confined to the conducting airways and there is minimal parenchymal inflammation, unlike conventional short-term models of allergic airway inflammation. We have shown that this model of chronic asthma can be used to assess the effects of potential triggers of an acute exacerbation. Thus, following exposure to a single moderate-level challenge with aerosolized OVA, acute inflammatory changes simulating an allergen-induced asthmatic exacerbation are elicited, with rapid and enhanced accumulation of eosinophils and neutrophils around intrapulmonary airways [23]. In the present study, we show that ambient particulate matter (PM10) collected from the geographical centre of the Sydney region provokes enhanced allergic airway inflammation in mice in which experimental chronic asthma had previously been established. Furthermore, we provide evidence that interleukin (IL)-33 plays a key role in the development of a PM10-induced acute exacerbation of airway inflammation.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

Animals

Specific pathogen-free female BALB/c mice aged 7–8 weeks were obtained from the Biological Resources Centre, University of New South Wales. Animals were held in individually ventilated cages, exposed to a 12-h light/dark cycle and were provided with autoclaved water and food ad libitum. All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the University of New South Wales (reference number: 12/108B).

Particulate matter

Ambient particulate matter (PM10) was collected on Teflon sampling filters by the Air Quality Monitoring Unit, Office of Environment and Heritage, New South Wales Government, Sydney, Australia. Particulates were released from filters and dispersed in solution by ultrasonication in endotoxin-free 0·9% saline for 30 min. To quantify the mass of released particles, filters were dried for a minimum of 48 h and weighed on a precision balance before and after ultrasonication. PM10 were resuspended in saline at a concentration of 1 mg/ml.

These particulates have been shown previously to be associated with a variety of trace metals, notably including Mg, Al, Fe, Zn and Cu; as well as with alkanes (C10–30, with major peaks in the range C12–14) and various aromatic hydrocarbons. Suspensions of PM10 contained < 3 ng/ml bacterial endotoxin as assessed by a Limulus lysate assay [24].

Sensitization and challenge of mice

The protocol for sensitization and inhalational challenge has been described previously in detail [23]. Briefly, animals were systemically sensitized by intraperitoneal injection of 50 μg of alum-precipitated chicken egg ovalbumin (OVA) (grade V, ≥ 98% pure; Sigma, Sydney, Australia) 21 and 7 days prior to the commencement of inhalational challenge. Mice were placed in a whole-body inhalation chamber (Unifab Corporation, Kalamazoo, MI, USA) and challenged with a low mass concentration of aerosolized ovalbumin (3 mg/m3) for 30 min/day, 3 days/week on alternate weekdays for 4 weeks, to establish a background of chronic asthmatic inflammation (Fig. 1). Aerosol concentration was assessed throughout all inhalational challenges, using a DustTrak 8520 instrument (TSI, St Paul, MN, USA).

figure

Figure 1. Model of particulate-induced exacerbation of asthma: timeline for sensitization, inhalational challenges with ovalbumin and intranasal challenge with particulates.

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At the end of the 4-week period, animals received 50 μg of Sydney PM10 intranasally in 50 μl of saline, or an equivalent amount of carbon black (Langridge Colours, Yarraville, Victoria, Australia) as negative control particulates. Additional groups of mice received a single 30-min challenge with a moderate level of aerosolized OVA (30 mg/m3) to simulate an allergen-induced acute exacerbation, as a positive control. Further controls included animals that received only chronic challenge with a low mass concentration of OVA aerosol for 4 weeks, as well as naive mice that received either Sydney PM10 or carbon black. Each experimental group comprised six animals.

Assessment of inflammatory response

At 4 h after the final airway challenge, mice were killed by exsanguination following an overdose of sodium pentobarbital. This time-point was selected on the basis of our earlier studies using this model, which established that in animals which had previously been chronically challenged, cytokine expression and cellular recruitment occurred more rapidly than in conventional short-term models [23, 25]. Bronchoalveolar lavage (BAL) was performed with 2 × 1 ml of phosphate-buffered saline (PBS) for total and differential cell counts and measurement of concentrations of proinflammatory cytokines. Intrapulmonary accumulation of eosinophils was assessed using a colorimetric assay of eosinophil peroxidase activity in lung tissue, adapted from previously described methods [26], which we have demonstrated to yield results equivalent to direct counts of eosinophils. Intrapulmonary neutrophil accumulation was assessed by immunostaining in frozen lung sections, using rat anti-Gr-1 (RB6-8C5; BD Bioscience, Sydney, Australia). Cells were enumerated in a minimum of 10 microscopic fields of lung tissue in one to two sections per animal. All counting/grading was performed by a single observer blinded to the identity of the samples and slides were examined in a random order.

Cytokine expression in airway tissue

Proximal airway tissue was isolated by blunt dissection as described previously [27]. RNA was extracted using TriReagent. Samples were treated with DNase (Turbo DNase; Ambion, Scoresby, Australia) and reverse-transcribed into cDNA using Superscript III (Invitrogen, Carlsbad, CA, USA). Quantitative real-time PCR was used to assess expression of IL-4 and IL-33, with detection of amplified products using SYBR green (BioLine, Tauton, MA, USA). Reactions were performed using a LightCyler 480 (Roche Diagnostics, Sydney, Australia) and expression was normalized to hypoxanthine phosphoribosyltransferase (HPRT).

Protein immunoassays

The concentrations of IL-33, tumour necrosis factor (TNF)-α and CXCL1 in BAL fluid were assessed using enzyme-linked immunoassays (R&D Systems, Braeside, Australia) according to the manufacturer's instructions.

Neutralization of IL-33

To assess the role of IL-33 in the development of a particulate-induced acute exacerbation, mice received an intraperitoneal injection of 100 μg of either a blocking monoclonal antibody to IL-33 (clone 1F11; MBL, Nagano, Japan) [28] or a control monoclonal antibody to β-galactosidase (βGL-113) [29], 30 min prior to the final moderate-level challenge.

Statistical analysis

Data are presented as arithmetic means ± standard error of the mean. Results were analysed by one-way analysis of variance (anova) followed by a Holm–Sidak multiple comparison test. The software package GraphPad Prism version 6·02 (GraphPad Software, San Diego, CA, USA) was used for all data analysis and preparation of graphs.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

Ambient particulates promote asthmatic airway inflammation

In preliminary experiments, naive animals that received intranasal Sydney PM10 or carbon black did not exhibit evidence of airway inflammation at 4 h, in terms of either the total number of cells in BAL fluid or the percentage of neutrophils in BAL (total cell counts for naive animals administered saline = 15·6 ± 1·9 × 104, carbon black = 18·8 ± 3·5 × 104, PM10 = 17·1 ± 2·1 × 104; percentage of neutrophils for naive animals administered saline = 0·0 ± 0·0, carbon black = 0·0 ± 0·0, PM10 = 0·1 ± 0·1). Animals that received intranasal Sydney PM10 at the end of the 4-week period of chronic challenge had a significant increase in the total number of cells in BAL fluid compared to the carbon black negative control group, in which cell numbers were comparable to the naive and chronic challenge control groups (Fig. 2a) (analysis by one-way anova including all groups and post-hoc testing for differences compared to the relevant control group). The increase was similar to that observed in the group of mice in which moderate-level challenge with aerosolized OVA was used to simulate an allergen-induced acute exacerbation; this group served as a positive control. The percentage of neutrophils in BAL was also increased significantly in the PM group compared to the carbon black negative control group (Fig. 2b), and again this was comparable to the increase observed in the allergen-induced acute exacerbation group, relative to the chronic challenge group. The percentage of lymphocytes in BAL was similarly increased and that of macrophages was correspondingly decreased in the PM group, analogous to the allergen-induced acute exacerbation group (Fig. 2c,d).

figure

Figure 2. Airway inflammation in the model of a particulate-induced exacerbation of asthma. (a) Numbers of cells in bronchoalveolar lavage (BAL) fluid. (b) Percentage of neutrophils in BAL fluid. (c) Percentage of lymphocytes in BAL fluid. (d) Percentage of macrophages in BAL fluid. (e) Numbers of neutrophils in lung tissue, assessed by immunostaining. (f) Relative numbers of eosinophils in lung tissue, assessed by colorimetric assay for erythropoietin (EPO) in lung tissue. Data are mean ± standard error of the mean (n = 6 samples per group). In this and subsequent figures, the acute group refers to the allergen-induced acute exacerbation group, which served as a positive control. Significant differences between the chronic and acute groups shown as **(P < 0·01) and ***(P < 0·001); between the carbon black and particulate matter (PM10)-treated groups shown as #(P < 0·05) and ###(P < 0·001).

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In lung tissue, there was a parallel increase in numbers of intrapulmonary neutrophils, as revealed by immunohistochemical staining (Fig. 2e). Again, the increase was significant compared to the carbon black negative control group, which remained as low as the naive and chronic challenge control groups, and was equivalent to that observed in the allergen-induced acute exacerbation group. Importantly, there was also an increase in intrapulmonary eosinophils in the animals that received intranasal Sydney PM10, as demonstrated by the assay for eosinophil peroxidase activity (Fig. 2f). Once more, these changes were equivalent to those seen in the allergen-induced acute exacerbation group.

Ambient particulates increase expression of IL-4 and IL-33 in airways

Following the 4-week period of chronic challenge, intranasal administration of particulate matter significantly increased the expression of mRNA for both IL-4 and IL-33 in airway wall tissue, to an extent comparable to that observed in animals in which an acute exacerbation of airway inflammation was induced by moderate-level exposure to aerosolized ovalbumin (Fig. 3a,b). This was paralleled by a significant increase in the concentration of IL-33 in BAL fluid (Fig. 3c), which again was similar to that seen in the allergen-induced acute exacerbation group. No such increases were seen in relevant control groups.

figure

Figure 3. Cytokine expression in the model of a particulate-induced exacerbation of asthma. (a) Relative expression of mRNA for interleukin (IL)-4 in airway wall tissue. (b) Relative expression of mRNA for IL-33 in airway wall tissue. (c) Concentration of IL-33 in bronchoalveolar lavage (BAL) fluid. Data are mean ± standard error of the mean (n = 6 samples per group). Significant differences between the chronic and acute groups shown as *(P < 0·05) and ***(P < 0·001); between the carbon black and particulate matter (PM10)-treated groups shown as #(P < 0·05) and ###(P < 0·001).

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Inhibition of IL-33 suppresses particulate matter-induced airway inflammation

Compared to treatment with the control antibody, treatment of animals with anti-IL-33 prior to induction of an acute exacerbation with PM10 inhibited recruitment of inflammatory cells to the airways (Fig. 4a). Although the decrease in cell numbers in BAL fluid was not statistically significant, there was a significant reduction in the percentage of neutrophils in BAL fluid in animals pretreated with anti-IL-33, compared to the control antibody-treated group that received PM10 (Fig. 4b). This was paralleled by a significant reduction in the numbers of intrapulmonary neutrophils (Fig. 4c). There was also significant inhibition of the recruitment of eosinophils into the lung tissue associated with exposure to particulates, demonstrated using the assay for eosinophil peroxidase activity (Fig. 4d).

figure

Figure 4. Effect of anti-interleukin (IL)-33 on airway inflammation in the model of a particulate-induced exacerbation of asthma. (a) Numbers of cells in bronchoalveolar lavage (BAL) fluid. (b) Percentage of neutrophils in BAL fluid. (c) Numbers of neutrophils in lung tissue, assessed by immunostaining. (d) Relative numbers of eosinophils in lung tissue, assessed by colorimetric assay for erythropoietin (EPO) in lung tissue. (e) Tumour necrosis factor (TNF)-α concentration in BAL fluid (f) CXCL1 concentration in BAL fluid. Data are mean ± standard error of the mean (n = 6 samples per group). Significant differences between the chronic and acute groups shown as ***(P < 0·001); between the carbon black and particulate matter (PM10) groups treated with control antibody shown as ##(P < 0·01) and ###(P < 0·001); and between the PM10 group treated with control antibody and the PM10 group treated with anti-IL-33 as (P < 0·05), ∧∧(P < 0·01) and ∧∧∧(P < 0·001).

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Treatment with the anti-IL-33 neutralizing antibody also significantly diminished levels of TNF-α and CXCL1 proteins in BAL fluid (Fig. 4e,f) compared to animals which received the control antibody prior to challenge with particulate matter.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

In this report, we provide the first experimental evidence that ambient particulate matter can trigger an acute exacerbation of airway inflammation in mice with experimental mild chronic asthma. Exposure to ambient particulates induced changes in the airways similar to those of an allergen-induced exacerbation of airway inflammation, including up-regulation of expression of IL-4 as well as recruitment of both eosinophils and neutrophils, consistent with an augmented T helper type 2 (Th2)-biased immunological response. This was paralleled by increased levels of proinflammatory cytokines in BAL fluid. Importantly, these particulates did not induce airway inflammation when administered to naive animals. The data thus highlight the ability of ambient particulates, a non-allergic trigger, to elicit an antigen-independent allergic response in the setting of pre-existing mild asthmatic inflammation.

While epidemiological data published to date have been somewhat controversial, our findings are consistent with those studies that have suggested an association between exposure to high levels of ambient particulates and aggravation of asthma, potentially requiring increased medication use and/or hospital admission [7, 9, 10, 30]. In this context, it is noteworthy that our studies used ambient particulate matter collected by air sampling in the geographical centre of the Sydney region, including all particulates with median aerodynamic diameter less that 10 μm (PM10). Most recently published experimental studies of the effects of airborne particulate pollutants on allergic inflammation and asthma have focused on PM2·5, which include the majority of particulates derived from vehicular emissions [16, 17, 31, 32]. While these clearly pose a significant risk to human health, the larger so-called coarse particulates of median aerodynamic diameter 2·5–10 μm have, to some extent, been overlooked. However, PM10 particulates are potentially more hazardous [21], possibly because they have a higher content of metal oxides [19], which may be related to the much higher fraction of particulates of geological origin.

The relevance of our findings is strengthened by the fidelity of the animal model of asthma employed in this study. Most animal models of asthma typically involve systemic sensitization to a protein, followed by short-term, high-level inhalational exposure to the aerosolized protein. Although these models trigger the development of allergic airway inflammation, they fail to replicate the background features of chronic inflammation classically seen in human disease [33]. The model which has been developed in our laboratory is one of long-term, low-level inhalational challenge which mimics many of the features of mild chronic human asthma, including airway-specific acute-on-chronic inflammation and airway wall remodelling [22]. Importantly, in our model the animals do not develop inflammation of the lung parenchyma, a feature present in many of the short-term models but absent in human disease. Thus, our findings are more likely to reflect the cellular and molecular events associated with particulate-induced exacerbations in asthmatic patients.

Our results may help to explain the mechanisms by which particulate matter is able to promote an acute exacerbation of airway inflammation in chronic asthma. Typical airborne particulates are comprised of a relatively inert carbonaceous core, onto which a variety of polyaromatic hydrocarbons, quinones, metals and volatile organic compounds may be adsorbed [34, 35]. Many of these compounds are capable of inducing oxidative stress, and in the context of developing a model of the induction phase of childhood asthma we have shown previously that the ambient particulates used in this study elicit an oxidative stress response in airway epithelial cells [24]. In turn, this may lead to the production of proinflammatory cytokines, potentially important among which is IL-33, a member of the IL-1 cytokine superfamily [36, 37]. IL-33 is expressed by airway epithelial cells and by resident macrophages, and can drive production of Th2-associated cytokines such as IL-4, IL-5 and IL-13, as well as of chemokines relevant to allergic inflammation [38-42], which are likely to be important in the inflammation associated with an exacerbation of chronic allergic asthma. Because it can be generated in response to both allergic and non-allergic stimuli [43], IL-33 may be an important mechanism of cross-talk between innate host defences and the adaptive immune response. Such cross-talk is increasingly being recognized as important in the pathogenesis of respiratory inflammation, including in acute exacerbations of asthma [44, 45].

Using our model of moderate-level allergen challenge on a background of low-level chronic challenge with OVA, we have demonstrated recently that IL-33 plays a key role in an experimental acute exacerbation of asthma, with suppression of airway inflammation following treatment with a neutralizing antibody [46]. Therefore, we hypothesized that this cytokine may similarly play an important role in the novel experimental model described in this study. This concept was supported by evidence of increased expression of IL-33 in the airways and BAL fluid following challenge with Sydney PM10. We found that prior administration of a neutralizing antibody against IL-33 largely suppressed the particulate matter-induced exacerbation of airway inflammation. Specifically, there was a significant reduction in neutrophil recruitment and in BAL fluid levels of proinflammatory cytokines such as TNF-α and CXCL1. Of importance in this context is that whereas previous reports have suggested that the endotoxin content of ambient particulates may account for their capacity to induce an inflammatory response, at least on the basis of in-vitro studies using macrophages [34, 47], the preparations of particulates that we used had a low endotoxin content [24]. Thus, each animal would have received a dose of < 0·2 ng intranasally, which would have been insufficient to explain the resultant airway inflammation. Moreover, administration of particulates to naive animals did not directly induce inflammation.

Our study has limitations. For technical reasons, we were unable to assess whether the exacerbation of airway inflammation induced by PM10 was associated with airway hyper-responsivess, as demonstrated previously in an allergen-induced model of an asthmatic exacerbation [23]. We were also unable to generate a complete profile of the changes in concentrations of proinflammatory and Th2 cytokines in BAL fluid, as we had obtained in previous work [23, 25].

Nevertheless, our data emphasize the importance of IL-33 in the development of a PM10-induced exacerbation of airway inflammation, analogous to our previous findings in an experimental allergen-induced exacerbation, suggesting that it may therefore be a relevant therapeutic target. However, as yet the relative contributions of airway epithelial cells and macrophages to the increased levels of this cytokine remain undefined. Furthermore, additional studies will also be required to define the cellular mechanisms by which IL-33 exerts its effects. An intriguing possibility is that IL-33 may promote a Th2 cytokine response by IL-5/IL-13-producing innate lymphoid cells (ILCs), which appear to have a crucial role in Th2 allergic responses, including in the setting of established allergic inflammatory disease of the airways [48, 49]. While both IL-25 and IL-33 can stimulate Th2 cytokine production by ILCs, IL-33 is particularly effective in inducing IL-13-producing cells [50].

In conclusion, we have demonstrated that in a setting of experimental chronic asthma in mice, exposure to ambient particulate matter induces airway inflammation similar to an allergen-induced exacerbation of disease. This is mediated at least in part by IL-33, which may thus illustrate the role of cross-talk between innate host defences and the adaptive immune response in particulate-induced acute exacerbations of chronic asthma.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

We thank John Kirkwood, Barbara Veluppillai and Gunaratnam Gunashanhar of the Office of Environment and Heritage, New South Wales Government, Sydney, for providing the air sampling filters. This work was supported by grants from the National Health and Medical Research Council of Australia (ID#630501) and the Rebecca Cooper Medical Research Foundation.

Author contributions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

R. K. K. and C. H. conceived and designed the experiments. A. M. S. and C. H. performed the experiments. R. K. K., A. M. S. and C. H. analysed the data and wrote the paper.

Disclosure

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References

All authors declare they have no actual or potential conflicts of interest.

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  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Disclosure
  10. References
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