Rodger Duffin

The University of Edinburgh | UoE · Queen's Medical Research Institute

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxi...

BACKGROUND BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithro...

Although inflammation is a normal and beneficial response, it is also a key event in the pathology of many chronic diseases, including pulmonary and systemic particle-induced disease. In addition, inflammation is now considered as the key response in standard settings for inhaled particles and a critical endpoint in OECD-based sub-acute/ chronic an...

Graphene oxide nanomaterials have been developed for wide-ranging applications, but has potential safety concerns for human health. Controlled inhalation exposures in human volunteers have been a vital means to determine the effects and mechanisms of ultrafine particles in air pollution, however, few studies have used this approach to explore the e...

Background: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same d...

Cyclin-dependent kinase (CDK) inhibitor drugs (CDKi), such as R-roscovitine and AT7519, induce neutrophil apoptosis in vitro and enhance the resolution of inflammation in a number of in vivo models. This class of compounds are potential novel therapeutic agents that could promote the resolution of acute and chronic inflammatory conditions where neu...

Programmed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tis...

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with incre...

Length and aspect ratio represent important toxicity determinants of fibrous nanomaterials. We have previously shown that anatase TiO2 nanofibers (TiO2 NF) cause a dose-dependent decrease of cell viability as well as the loss of epithelial barrier integrity in polarized airway cell monolayers. Herein we have investigated the impact of fiber shorten...

Grinding and drilling of chrysotile asbestos-containing brake pads during the 20th century led to release of chrysotile, resulting in varying levels of workplace exposures of mechanics. Despite exposures, excess risk of mesothelioma remains in doubt. Objectives: The toxicity of particulates is primarily derived through a combination of physicochemi...

The global use of “asbestos” in various commercial products has led to a wide range and pervasive legacy of disease. One such use of chrysotile asbestos was brake pads and was utilized commonly in automobiles and heavy vehicles. The result of incorporation of chrysotile into brake pads is associated with the exposure of mechanics fitting and servic...

Fibres such as asbestos have long been known to cause a litany of occupational disease and are tightly regulated. Exposure limits are based on fibre number rather than mass, reflecting the critical role dimension plays in toxicity and, in particular, the generation of mesothelioma. The definition of a fibre has, at its heart, minimum and maximum di...

Acute lung injury is a neutrophil-dominant, life-threatening disease without effective therapies and better understanding of the pathophysiological mechanisms involved is an urgent need. Here we show that interleukin (IL)-22 is produced from innate lymphoid cells (ILC) and is responsible for suppression of experimental lung neutrophilic inflammatio...

Background: Eosinophils play a central role in the propagation of allergic diseases including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia but the question of whether alterations in apoptotic cell clearance by phagocytes directly contributes to resolution of allergic airway inflammation remains unexplored....

Engineered nanomaterials are central to a range of novel technologies that may have applications for the early detection and treatment of cardiovascular disease. Nanoparticles targeted to components of atheromatous plaque, permit rapid, noninvasive assessment of plaque burden and composition in patients with vascular disease. Early diagnosis and id...

Background Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) ha...

Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the...

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a...

Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent...

Exposure to high aspect ratio nanomaterials, such as multi-walled carbon nanotubes (MWCNTs) may be associated with increased risk of atherosclerosis, pulmonary disease, and cancer. In the present study, we investigated the cardiovascular and pulmonary health effects of 10 weeks of repeated oral or pulmonary exposures to MWCNTs (4 or 40 μg each week...

In biological fluids nanoparticles bind a range of molecules, particularly proteins, on their surface. The resulting protein corona influences biological activity and fate of nanoparticle in vivo. Corona composition is often determined by the biological milieu encountered at the entry portal into the body, and, can therefore, depend on the route of...

A prostaglandin barrier to inflammation Blood-borne bacterial infections and severe trauma can send the immune system into overdrive, causing it to pump out inflammatory mediators, sometimes at lethal doses. Duffin et al. now report on a role for prostaglandins in keeping systemic inflammation in check. Systemic inflammation correlates with decreas...

Background Accelerated thrombus formation induced by exposure to combustion-derived air pollution has been linked to alterations in endogenous fibrinolysis and platelet activation in response to pulmonary and systemic inflammation. We hypothesised that mechanisms independent of inflammation contribute to accelerated thrombus formation following exp...

Inhaled combustion-derived nanoparticles are associated with cardiovascular disease, however, the pathways linking the pulmonary and cardiovascular effects remain to be established. • Here we use complimentary human and animal studies to investigate whether gold nanoparticles can translocate from the lung into the blood and accumulate at sites of v...

Rationale: Eosinophils are key effector cells in allergic diseases, including allergic rhinitis, eczema, and asthma. Their tissue presence is regulated by both recruitment and increased longevity at inflamed sites. Objectives: To investigate the ability of the flavone wogonin to induce eosinophil apoptosis in vitro and attenuate eosinophil-domin...

The issue of reproducibility of results in toxicology has long been a concern and, perhaps, at the back of many of our minds but not necessarily at the forefront of our thinking – ‘the elephant in the room’. Are the results we have published literallyourresults or are they reproducible and truly part of a credible theory? In the excellent editorial...

Background / Purpose: The mechanisms by which inhaled combustion derived nano particles, such as those in diesel exhaust, cause their prominent cardiovascular effects remains to be fully established. Here we explore the mechanisms involved in both the acute and chronic vascular effects of diesel exhaust particulate (DEP). Main conclusion: Dies...

We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR+CD14++CD16+cells) and inducible PMLC (iPMLC, HLA-DR+CD14++CD16- cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We...

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 'co...

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation...

Fig. S1. AT7519 overrides the survival effects of lipoteichoic acid (LTA) and peptidoglycan (PepG). Fig. S2. AT7519 induces caspase-dependent apoptosis and down-regulates the key survival protein Mcl-1 in mouse bone marrow-derived neutrophils. Fig. S3. Mcl-1 down-regulation by either AT7519 or siRNA drives death by caspase-dependent apoptosis in...

Hazard identification for risk assessment of nanoparticles (NPs) is mainly composed of in vitro cell-based assays and in vivo animal experimentation. The rapidly increasing number and functionalizations of NPs makes in vivo toxicity tests undesirable on both ethical and financial grounds, creating an urgent need for development of in vitro cell-bas...

GCs are highly effective in treating a wide range of inflammatory diseases but are limited in their ability to control neutrophilic lung inflammation in conditions such as COPD. Neutrophil apoptosis, a central feature of inflammation resolution, is delayed in response to microenvironmental cues, such as hypoxia and inflammatory cytokines, present a...

Nanoparticles (NPs) are tiny particles with a diameter of less than 100 nm. Traffic exhaust is a major source of combustion-derived NPs (CDNPs), which represent a significant component in urban air pollution. Epidemiological, panel and controlled human chamber studies clearly demonstrate that exposure to CDNPs is associated with multiple adverse ca...

Abstract Nano materials are commonly functionalized to boost their physicochemical properties. However, there is little known about the impact of these modifications on cellular systems. Herein, we synthesized 8 types of polymeric nanoparticles bearing different functional groups, and investigated their effects on interactions with cellular membran...

Air pollution by diesel exhaust particles is associated with elevated mortality and increased hospital admissions in individuals with respiratory diseases such as asthma and chronic obstructive pulmonary disease. During active inflammation monocytes are recruited to the airways and can replace resident alveolar macrophages. We therefore investigate...

Timelapse video: Monocytes rapidly phagocytose DEP. Purified monocytes were obtained and cultured at 2.5×106/ml as described in the methods. Cells were incubated with 50 µg/ml DEP and timelapse microscopy performed every 30 seconds for 60 minutes as described in the methods. Data shown are representative images of n = 2, performed on different dono...

Still images: Monocytes rapidly phagocytose DEP. Methods are described as in Figure S1. Figure S2 are still images of monocytes and DEP at time t = 0 minutes (A) and t = 60 minutes (B) of timelapse microscopy. Data shown are representative images of n = 2, performed on different donors. (TIFF)

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. H...

In all branches of toxicology, the biologically effective dose (BED) is thefraction of the total dose of a toxin that actually drives any toxic effect. Knowledge of the BED has a number of applications including in building structure–activity relationships, the selection of metrics, the design of safe particles, and the determination of when a nano...

Background: Carbon nanotubes (CNT) are fibre-like nanomaterials whose structural similarity to asbestos has raised concerns that they may also pose a mesothelioma hazard. The objective of this study was to examine the inflammatory potential of three CNT samples of differing length on the lungs and pleural cavity following introduction into the air...

Rationale: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of...

Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have a prominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-a...

The widespread and increasing use of carbon nanotubes in scientific and engineering research and their incorporation into manufactured goods has urged an assessment of the risks and hazards associated with exposure to them. The field of nanotoxicology studies the toxicology of nanoparticles such as carbon nanotubes and has become a major growth are...

The widespread and increasing use of carbon nanotubes in scientific and engineering research and their incorporation into manufactured goods has urged an assessment of the risks and hazards associated with exposure to them. The field of nanotoxicology studies the toxicology of nanoparticles such as carbon nanotubes and has become a major growth are...

1. Carbon nanotube structure, synthesis and applications C. Singh and W. Song; 2. The aerodynamic behaviour and pulmonary deposition of carbon nanotubes A. Buckley, R. Smith and R Maynard; 3. Utilising the concept of the biologically effective dose to define the particle and fibre hazards of carbon nanotubes K. Donaldson, R. Duffin, F. Murphy and C...

Cerium oxide (CeO(2)) nanoparticles improve the burning efficiency of fuel, however, little is known about health impacts of altered emissions from the vehicles. Atherosclerosis-prone apolipoprotein E knockout (ApoE(-/-)) mice were exposed by inhalation to diluted exhaust (1.7 mg/m(3), 20, 60 or 180 min, 5 day/week, for 4 weeks), from an engine usi...

Inhalation of diesel exhaust impairs vascular function in man, by a mechanism that has yet to be fully established. We hypothesised that pulmonary exposure to diesel exhaust particles (DEP) would cause endothelial dysfunction in rats as a consequence of pulmonary and systemic inflammation. Wistar rats were exposed to DEP (0.5 mg) or saline vehicle...

Engineered nanomaterials are central to a range of novel technologies that may have applications for the early detection and treatment of cardiovascular disease. However, possible adverse affects on the cardiovascular system cannot be excluded, given the central role of lipid particles and oxidative stress (a paradigmatic pathogenetic mechanism of...

The co-ordinated recruitment of monocyte subpopulations, neutrophils and regulatory T-cells (Tregs) during the early stages of human acute lung inflammation remains poorly understood. We therefore performed a detailed characterisation of these lineages in the blood and lungs in a model of human acute lung inflammation. Healthy volunteers inhaled li...

The toxicology of nanoparticles (NPs) is an area of intense investigation that would be greatly aided by improved understanding of the relationship between NP structure and inflammogenicity. To evaluate how their physicochemical parameters influence toxicity, we assembled a panel of 15 metal/metal oxide NPs and attempted to relate various physicoch...

Introduction and Objectives Terminally-differentiated neutrophils are short-lived but key effector cells of the innate immune response and play a prominent role in the pathogenesis and propagation of many inflammatory diseases including interstitial lung disease. BAL neutrophilia has been correlated with poor outcome in idiopathic pulmonary fibrosi...

Abstract We hypothesise that inflammatory response and morphological characteristics of lung parenchyma differ after exposure to short or long multi-walled carbon nanotubes (MWCNT). Mice were subjected to a single dose of vehicle, short or long MWCNT by pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) obtained at 24 h was analysed for inf...

Abstract The use of fibre-shaped nanomaterials in commercial applications has met with concern that they could cause health effects similar to those seen with pathogenic fibres such as certain forms of asbestos. Of the attributes which form the fibre pathogenicity paradigm, fibre length is thought to be a critical factor in determining fibre toxici...

Background: Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be...

The effects of hydrodynamic size of ZnONP on the eosinophilia (n = 4). This file contains the number of eosinophils in the BAL after instillation of well-dispersed or highly agglomerated ZnONP.

Representative lung lesion 4 wks after instillation of Zn(II) at 92.5 μg per rat. (A) The lungs showed fibrosis, contraction, atelectasis, and (B) goblet cell hyperplasia.

Expression of eotaxin and IL-13 in the BAL from mice 24 h after aspiration of ZnONP or NiONP at 15 cm2 per mouse. (A), eotaxin; (B), IL-13. Values are mean ± S.D. n = 4 for each treatment group. Significance versus vehicle control (VEH): * p < 0.05, ** p < 0.01, # p < 0.001. NS, not significant.

Pulmonary toxicity of ZnONP at 24 h after aspiration into lungs of C57BL/6 (A - C) or BALB/c (D - F) mice. (A, D), number of total cells; (B, E), number of PMN; (C, F), number of eosinophils. Values are mean ± S.D. n = 4 for each treatment group. Significance versus vehicle control (VEH): * p < 0.05, ** p < 0.01, # p < 0.001.

Cytotoxicity of THP-1 cells after exposure to NP for 24 h, measured as percentage compared to complete lysis (Triton X-100). THP-1 cells were differentiated by treatment with PMA (10 ng/ml) for 48 h and LDH levels were measured 24 h after NP treatment. Values are mean ± S.D. n = 4 for each treatment group. Significance versus vehicle control (VEH):...

Detailed materials and methods. All detailed materials and methods were described.

Immunohistochemistry for eotaxin in the lung tissues 24 h after instillation of ZnONP at 150 cm2/rat. (A), vehicle control; (B and C), ZnONP treatment; (D) serially sectioned H&E staining of (C). (B) is imaged under higher magnification at 400× in (C). Note that eotaxin was strongly positive in the bronchial epithelial cells (arrow) and inflammator...

PAS staining for goblet cells in the lung tissues 1 wk after instillation of ZnONP at 150 cm2 per rat. Goblet cells were found even in terminal bronchioles (arrow) but were not present in the transitional region between bronchiolar and alveolar tissue.

Large production volumes of zinc oxide nanoparticles (ZnONP) might be anticipated to pose risks, of accidental inhalation in occupational and even in consumer settings. Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action. Two doses of ZnONP (50 and 150 cm2/rat) were intratracheally instil...

Lung exposure to metal oxide nanoparticles (NP) comprising soluble metal haptens may produce Type 1 helper T cells (Th1) and Type 17 helper T cells (Th17) associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NP (NiO, Co3O4, Cr2O3, and CuO) were instilled into...

Exposure to road traffic and air pollution may be a trigger of acute myocardial infarction, but the individual pollutants responsible for this effect have not been established. We assess the role of combustion-derived-nanoparticles in mediating the adverse cardiovascular effects of air pollution. To determine the in vivo effects of inhalation of di...

Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. We used mu...

Exposure to air pollution containing diesel exhaust particulate (DEP) is linked to adverse cardiovascular events. This study tested the hypothesis that DEP not only causes direct endothelial cell injury, but also induces indirect endothelial cell activation via the release of soluble proinflammatory cytokines from macrophages. Human umbilical vein...

The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response...

Background: The rate at which radioactive albumin particles clear from the bloodstream is used to measure reticuloendothelial capacity. Traditionally, iodine radioisotopes have been used. Non-active albumin particles mixed with the technetium-99 m labelled particles of the readily available radiopharmaceutical 99 mTc Albumin Nanocolloid (ANC) would...

Dissociating anti-inflammatory efficacy from the metabolic side effects of glucocorticoids is an attractive therapeutic goal. 5α-Tetrahydro-corticosterone (5αTHB), produced from corticosterone by 5α-reductases, activates glucocorticoid receptors. This study compares the effects of 5αTHB on inflammation and metabolism in vitro and in vivo. Suppressi...

There is evidence that nanoparticles (NP) can enter the bloodstream following deposition in the lungs, where they may interact with platelets. Polystyrene latex nanoparticles (PLNP) of the same size but with different surface charge—unmodified (umPLNP), aminated (aPLNP), and carboxylated (cPLNP)—were used as model NP to study interactions with huma...

Abstract Nickel, zinc, and copper oxide nanoparticles (NiONP, ZnONP, and CuONP) and their aqueous extracts (AEs) were applied to A549 lung epithelial cells to determine the cytotoxicity, IL-8 production, and activation of transcription factors. Nanoparticles (NPs) and their AEs were also instilled into rat lungs to evaluate acute and chronic inflam...

High aspect ratio, or fiber-shaped, nanoparticles (HARNs) represent a growth area in nanotechnology as their useful properties become more apparent. Carbon nanotubes, the best known and studied of the HARNs are handled on an increasingly large scale, with subsequent potential for human inhalation exposure. Their resemblance to asbestos fibers preci...

Metal oxide nanoparticles (NPs) have been widely used in industry, cosmetics, and biomedicine. We examined hazards of several well-characterized high production volume NPs because of increasing concern about occupational exposure via inhalation. A panel of well-characterized NPs [cerium oxide (CeO₂NP), titanium dioxide (TiO₂NP), carbon black (CBNP)...

Introduction and objectives Idiopathic pulmonary fibrosis (IPF) remains one of the few respiratory conditions for which there are no effective therapies. The role of monocytes and macrophages in IPF has been disputed as anti-inflammatory therapies produce questionable benefit. Corticosteroids, however, actually induce an alternatively activated, pr...

Introduction Acute lung injury (ALI) has a mortality rate of over 30%, with no proven pharmacological treatment. Inhalation of lipopolysaccharide (LPS) in healthy volunteers induces transient inflammation resembling that found in patients with ALI. Inhaled LPS causes neutrophilia that is detectable in bronchoalveolar lavage fluid (BALF) and blood,...

Air pollution has been linked to the development of atherosclerosis and cardiovascular disease. Diesel exhaust particulate (DEP) accounts for a substantial proportion of urban air pollution but its effects on atherogenesis are unknown. We hypothesised that DEP will exacerbate plaque formation in a murine model of atherosclerosis. Apolipoprotein E k...

Induction of effective inflammation in the lung in response to environmental and microbial stimuli is dependent on cooperative signaling between leukocytes and lung tissue cells. We explored how these inflammatory networks are modulated by diesel exhaust particles (DEP) using cocultures of human monocytes with epithelial cells. Cocultures, or monoc...

The inflammatory process is a complex series of tightly controlled cellular and biochemical events initiated by the immune system, which has evolved to eliminate or contain infectious agents and to repair damaged tissue. Apoptosis is essential for the clearance of potentially injurious inflammatory cells, such as neutrophils, eosinophils, and basop...

Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly...