Polydatin protects the respiratory system from PM2.5 exposure

NASA Astrophysics Data System (ADS)

Yan, Xiao-Dan; Wang, Qi-Ming; Tie, Cai; Jin, Hong-Tao; Han, Yan-Xing; Zhang, Jin-Lan; Yu, Xiao-Ming; Hou, Qi; Zhang, Piao-Piao; Wang, Ai-Ping; Zhang, Pei-Cheng; Gao, Zhonggao; Jiang, Jian-Dong

2017-01-01

Atmospheric particle is one of the risk factors for respiratory disease; however, their injury mechanisms are poorly understood, and prevention methods are highly desirable. We constructed artificial PM2.5 (aPM2.5) particles according to the size and composition of actual PM2.5 collected in Beijing. Using these artificial particles, we created an inhalation-injury animal model. These aPM2.5 particles simulate the physical and chemical characteristics of the actual PM2.5, and inhalation of the aPM2.5 in rat results in a time-dependent change in lung suggesting a declined lung function, injury from oxidative stress and inflammation in lung. Thus, this aPM2.5-caused injury animal model may mimic that of the pulmonary injury in human exposed to airborne particles. In addition, polydatin (PD), a resveratrol glucoside that is rich in grapes and red wine, was found to significantly decrease the oxidative potential (OP) of aPM2.5 in vitro. Treating the model rats with PD prevented the lung function decline caused by aPM2.5, and reduced the level of oxidative damage in aPM2.5-exposed rats. Moreover, PD inhibited aPM2.5-induced inflammation response, as evidenced by downregulation of white blood cells in bronchoalveolar lavage fluid (BALF), inflammation-related lipids and proinflammation cytokines in lung. These results provide a practical means for self-protection against particulate air pollution.

Effect of aerosol particles generated by ultrasonic humidifiers on the lung in mouse.

PubMed

Umezawa, Masakazu; Sekita, Keisuke; Suzuki, Ken-Ichiro; Kubo-Irie, Miyoko; Niki, Rikio; Ihara, Tomomi; Sugamata, Masao; Takeda, Ken

2013-12-21

Ultrasonic humidifiers silently generate water droplets as a cool fog and produce most of the dissolved minerals in the fog in the form of an aerosolized "white dust." However, the health effect of these airborne particles is largely unknown. This study aimed to characterize the aerosol particles generated by ultrasonic humidifiers and to investigate their effect on the lung tissue of mice. An ultrasonic humidifier was operated with tap water, high-silica water, ultrapure water, or other water types. In a chamber (0.765 m3, ventilation ratio 11.5 m3/hr), male ICR mice (10-week-old) were exposed by inhalation to an aerosol-containing vapor generated by the humidifier. After exposure for 7 or 14 days, lung tissues and bronchoalveolar lavage fluid (BALF) were collected from each mouse and examined by microarray, quantitative reverse transcription-polymerase chain reaction, and light and electron microscopy. Particles generated from the humidifier operated with tap water had a mass concentration of 0.46 ± 0.03 mg/m3, number concentration of (5.0 ± 1.1) × 10(4)/cm3, and peak size distribution of 183 nm. The particles were phagocytosed by alveolar macrophages in the lung of mice. Inhalation of particles caused dysregulation of genes related to mitosis, cell adhesion molecules, MHC molecules and endocytosis, but did not induce any signs of inflammation or tissue injury in the lung. These results indicate that aerosol particles released from ultrasonic humidifiers operated with tap water initiated a cellular response but did not cause severe acute inflammation in pulmonary tissue. Additionally, high mineral content tap water is not recommended and de-mineralized water should be recommended in order to exclude any adverse effects.

Respiratory deposition of inhaled micron particles in subjects with mild asthma

EPA Science Inventory

Rational: Particulate matter (PM) in the ambient air can cause adverse health effects to some people including an aggravation of asthma. Although compromised lung conditions in disease are likely to be the primary cause of the effects, enhanced respiratory dose of particles may a...

PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

EPA Science Inventory

Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

Silica nanoparticles and biological dispersants: genotoxic effects on A549 lung epithelial cells

NASA Astrophysics Data System (ADS)

Brown, David M.; Varet, Julia; Johnston, Helinor; Chrystie, Alison; Stone, Vicki

2015-10-01

Silica nanoparticle exposure could be intentional (e.g. medical application or food) or accidental (e.g. occupational inhalation). On entering the body, particles become coated with specific proteins depending on the route of entry. The ability of silica particles of different size and charge (non-functionalized 50 and 200 nm and aminated 50 and 200 nm) to cause genotoxic effects in A549 lung epithelial cells was investigated. Using the modified comet assay and the micronucleus assay, we examined the effect of suspending the particles in different dispersion media [RPMI or Hanks' balanced salt solution (HBSS), supplemented with bovine serum albumin (BSA), lung lining fluid (LLF) or serum] to determine if this influenced the particle's activity. Particle characterisation suggested that the particles were reasonably well dispersed in the different media, with the exception of aminated 50 nm particles which showed evidence of agglomeration. Plain 50, 200 nm and aminated 50 nm particles caused significant genotoxic effects in the presence of formamidopyrimidine-DNA glycosylase when dispersed in HBSS or LLF. These effects were reduced when the particles were dispersed in BSA and serum. There was no significant micronucleus formation produced by any of the particles when suspended in any of the dispersants. The data suggest that silica particles can produce a significant genotoxic effect according to the comet assay in A549 cells, possibly driven by an oxidative stress-dependent mechanism which may be modified depending on the choice of dispersant employed.

Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust.

PubMed Central

Rudell, B; Ledin, M C; Hammarström, U; Stjernberg, N; Lundbäck, B; Sandström, T

1996-01-01

OBJECTIVES: Diesel exhaust is a common air pollutant made up of several gases, hydrocarbons, and particles. An experimental study was carried out which was designed to evaluate if a particle trap on the tail pipe of an idling diesel engine would reduce effects on symptoms and lung function caused by the diesel exhaust, compared with exposure to unfiltered exhaust. METHODS: Twelve healthy non-smoking volunteers (aged 20-37) were investigated in an exposure chamber for one hour during light work on a bicycle ergometer at 75 W. Each subject underwent three separate double blind exposures in a randomised sequence: to air and to diesel exhaust with the particle trap at the tail pipe and to unfiltered diesel exhaust. Symptoms were recorded according to the Borg scale before, every 10 minutes during, and 30 minutes after the exposure. Lung function was measured with a computerised whole body plethysmograph. RESULTS: The ceramic wall flow particle trap reduced the number of particles by 46%, whereas other compounds were relatively constant. It was shown that the most prominent symptoms during exposure to diesel exhaust were irritation of the eyes and nose and an unpleasant smell increasing during exposure. Both airway resistance (R(aw)) and specific airway resistance (SR(aw)) increased significantly during the exposures to diesel exhaust. Despite the 46% reduction in particle numbers by the trap effects on symptoms and lung function were not significantly attenuated. CONCLUSION: Exposure to diesel exhaust caused symptoms and bronchoconstriction which were not significantly reduced by a particle trap. PMID:8943829

Translocation and potential neurological effects of fine and ultrafine particles a critical update

PubMed Central

Peters, Annette; Veronesi, Bellina; Calderón-Garcidueñas, Lilian; Gehr, Peter; Chen, Lung Chi; Geiser, Marianne; Reed, William; Rothen-Rutishauser, Barbara; Schürch, Samuel; Schulz, Holger

2006-01-01

Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop. The purpose of this critical update is to summarize the evidence presented for the mechanisms involved in the translocation of particles from the lung to other organs and to highlight the potential of particles to cause neurodegenerative effects. Fine and ultrafine particles, after deposition on the surfactant film at the air-liquid interface, are displaced by surface forces exerted on them by surfactant film and may then interact with primary target cells upon this displacement. Ultrafine and fine particles can then penetrate through the different tissue compartments of the lungs and eventually reach the capillaries and circulating cells or constituents, e.g. erythrocytes. These particles are then translocated by the circulation to other organs including the liver, the spleen, the kidneys, the heart and the brain, where they may be deposited. It remains to be shown by which mechanisms ultrafine particles penetrate through pulmonary tissue and enter capillaries. In addition to translocation of ultrafine particles through the tissue, fine and coarse particles may be phagocytized by macrophages and dendritic cells which may carry the particles to lymph nodes in the lung or to those closely associated with the lungs. There is the potential for neurodegenerative consequence of particle entry to the brain. Histological evidence of neurodegeneration has been reported in both canine and human brains exposed to high ambient PM levels, suggesting the potential for neurotoxic consequences of PM-CNS entry. PM mediated damage may be caused by the oxidative stress pathway. Thus, oxidative stress due to nutrition, age, genetics among others may increase the susceptibility for neurodegenerative diseases. The relationship between PM exposure and CNS degeneration can also be detected under controlled experimental conditions. Transgenic mice (Apo E -/-), known to have high base line levels of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicated unequivocally that the brain is a critical target for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and susceptibility to neurodegeneration. Together, these data present evidence for potential translocation of ambient particles on organs distant from the lung and the neurodegenerative consequences of exposure to air pollutants. PMID:16961926

Translocation and potential neurological effects of fine and ultrafine particles a critical update.

PubMed

Peters, Annette; Veronesi, Bellina; Calderón-Garcidueñas, Lilian; Gehr, Peter; Chen, Lung Chi; Geiser, Marianne; Reed, William; Rothen-Rutishauser, Barbara; Schürch, Samuel; Schulz, Holger

2006-09-08

Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop. The purpose of this critical update is to summarize the evidence presented for the mechanisms involved in the translocation of particles from the lung to other organs and to highlight the potential of particles to cause neurodegenerative effects. Fine and ultrafine particles, after deposition on the surfactant film at the air-liquid interface, are displaced by surface forces exerted on them by surfactant film and may then interact with primary target cells upon this displacement. Ultrafine and fine particles can then penetrate through the different tissue compartments of the lungs and eventually reach the capillaries and circulating cells or constituents, e.g. erythrocytes. These particles are then translocated by the circulation to other organs including the liver, the spleen, the kidneys, the heart and the brain, where they may be deposited. It remains to be shown by which mechanisms ultrafine particles penetrate through pulmonary tissue and enter capillaries. In addition to translocation of ultrafine particles through the tissue, fine and coarse particles may be phagocytized by macrophages and dendritic cells which may carry the particles to lymph nodes in the lung or to those closely associated with the lungs. There is the potential for neurodegenerative consequence of particle entry to the brain. Histological evidence of neurodegeneration has been reported in both canine and human brains exposed to high ambient PM levels, suggesting the potential for neurotoxic consequences of PM-CNS entry. PM mediated damage may be caused by the oxidative stress pathway. Thus, oxidative stress due to nutrition, age, genetics among others may increase the susceptibility for neurodegenerative diseases. The relationship between PM exposure and CNS degeneration can also be detected under controlled experimental conditions. Transgenic mice (Apo E -/-), known to have high base line levels of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicated unequivocally that the brain is a critical target for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and susceptibility to neurodegeneration. Together, these data present evidence for potential translocation of ambient particles on organs distant from the lung and the neurodegenerative consequences of exposure to air pollutants.

[Are inhaled dust particles harmful for our lungs?].

PubMed

Brändli, O

1996-12-14

Particles with diameters ranging from less than 0.02 to more than 100 microns and in concentration up to 120 micrograms/m3 daily average TSP (total suspended particles) are measurable in the air of Swiss cities and responsible for the decrease of visibility on the Swiss Plateau and south of the Alps. The particle size shows a typical distribution: the coarse particles (> 2.5 microns mass median diameter) are mostly of natural origin (plants, pollen, earth particles) and are deposited in the upper airways. The fine particles (PM2.5 < 2.5 microns) are predominantly deposited into the alveolar space. These fine and ultrafine particles (< 0.02 microns) are produced by the burning of fossil fuels or by photochemical reactions. By bypassing the mucociliary and cellular defense mechanisms, fine particles can invade the lung parenchyma and cause an inflammatory response. The additional chemical layering of a carbon core by nitrates, sulfates and other organic materials and metals such as iron cause greater local oxidative and/or carcinogenic damage than in the vaporized state. In comparing worldwide epidemiological studies, there seems to be a cohesive and consistent relationship between increases of particle concentration and the increase of mortality (mostly among patients over 65 with concomitant lung and heart diseases and among smokers) and morbidity (bronchitis, pneumonia, COPD, and, less convincingly, asthma). An increase in daily average PM10 (particles < 10 microns) is correlated with an increase in mortality not related to accidents and suicides of 1.0% for the same and/or the following days. In Switzerland, mean annual concentrations of 14-53 micrograms/m3 TSP or 10-33 micrograms/m3 PM10, well below the national standard (annual mean TSP 70 micrograms/m3) have been measured in rural and urban areas. Even at these concentrations an increase in respiratory symptoms and a decrease in lung function, without evidence for a "safe" threshold, have been observed in the Swiss study of air pollution and lung diseases in adults (SAPALDIA). Although the noxious effects of the particles cannot be clearly separated from the effect of other pollutants (e.g. NOx, SO2, ozone) in complex pollutant mixtures, the emission standards and national standards for ambient air should be revised, in particular by adding a standard for fine particles (e.g. PM10 or PM2.5).

Co-immunization with virus-like particle and DNA vaccines induces protection against respiratory syncytial virus infection and bronchiolitis

PubMed Central

Hwang, Hye Suk; Kwon, Young-Man; Lee, Jong Seok; Yoo, Si-Eun; Lee, Yu-Na; Ko, Eun-Ju; Kim, Min-Chul; Cho, Min-Kyoung; Lee, Young-Tae; Jung, Yu-Jin; Lee, Ji-Yun; Li, Jian Dong; Kang, Sang-Moo

2014-01-01

This study demonstrates that immunization with non-replicating virus-like particle (FFG VLP) containing RSV F and G glycoproteins together with RSV F DNA induced T helper type 1 antibody responses to RSV F similar to live RSV infection. Upon RSV challenge 21 weeks after immunization, FFG VLP vaccination induced protection against RSV infection as shown by clearance of lung viral loads, and the absence of eosinophil infiltrates, and did not cause lung pathology. In contrast, formalin-inactivated RSV (FI-RSV) vaccination showed significant pulmonary eosinophilia, severe mucus production, and extensive histopathology resulting in a hallmark of pulmonary pathology. Substantial lung pathology was also observed in mice with RSV re-infections. High levels of systemic and local inflammatory cytokine-secreting cells were induced in mice with FI-RSV but not with FFG VLP immunization after RSV challenge. Therefore, the results provide evidence that recombinant RSV FFG VLP vaccine can confer long-term protection against RSV without causing lung pathology. PMID:25110201

Health and Environmental Effects of Particulate Matter (PM)

EPA Pesticide Factsheets

Particles less than 10 micrometers in diameter pose the greatest problems, because they can get deep into your lungs, and some may even get into your bloodstream. Fine particles (PM2.5) are the main cause of reduced visibility (haze).

Release of copper-amended particles from micronized copper-pressure-treated wood during mechanical abrasion.

PubMed

Civardi, Chiara; Schlagenhauf, Lukas; Kaiser, Jean-Pierre; Hirsch, Cordula; Mucchino, Claudio; Wichser, Adrian; Wick, Peter; Schwarze, Francis W M R

2016-11-28

We investigated the particles released due to abrasion of wood surfaces pressure-treated with micronized copper azole (MCA) wood preservative and we gathered preliminary data on its in vitro cytotoxicity for lung cells. The data were compared with particles released after abrasion of untreated, water (0% MCA)-pressure-treated, chromated copper (CC)-pressure-treated wood, and varnished wood. Size, morphology, and composition of the released particles were analyzed. Our results indicate that the abrasion of MCA-pressure-treated wood does not cause an additional release of nanoparticles from the unreacted copper (Cu) carbonate nanoparticles from of the MCA formulation. However, a small amount of released Cu was detected in the nanosized fraction of wood dust, which could penetrate the deep lungs. The acute cytotoxicity studies were performed on a human lung epithelial cell line and human macrophages derived from a monocytic cell line. These cell types are likely to encounter the released wood particles after inhalation. Our findings indicate that under the experimental conditions chosen, MCA does not pose a specific additional nano-risk, i.e. there is no additional release of nanoparticles and no specific nano-toxicity for lung epithelial cells and macrophages.

Method to characterize inorganic particulates in lung tissue biopsies using field emission scanning electron microscopy

USGS Publications Warehouse

Lowers, Heather; Breit, George N.; Strand, Matthew; Pillers, Renee M.; Meeker, Gregory P.; Todorov, Todor I.; Plumlee, Geoffrey S.; Wolf, Ruth E.; Robinson, Maura; Parr, Jane; Miller, Robert J.; Groshong, Steve; Green, Francis; Rose, Cecile

2018-01-01

Humans accumulate large numbers of inorganic particles in their lungs over a lifetime. Whether this causes or contributes to debilitating disease over a normal lifespan depends on the type and concentration of the particles. We developed and tested a protocol for in situ characterization of the types and distribution of inorganic particles in biopsied lung tissue from three human groups using field emission scanning electron microscopy (FE-SEM) combined with energy dispersive spectroscopy (EDS). Many distinct particle types were recognized among the 13 000 particles analyzed. Silica, feldspars, clays, titanium dioxides, iron oxides and phosphates were the most common constituents in all samples. Particles were classified into three general groups: endogenous, which form naturally in the body; exogenic particles, natural earth materials; and anthropogenic particles, attributed to industrial sources. These in situ results were compared with those using conventional sodium hypochlorite tissue digestion and particle filtration. With the exception of clays and phosphates, the relative abundances of most common particle types were similar in both approaches. Nonetheless, the digestion/filtration method was determined to alter the texture and relative abundances of some particle types. SEM/EDS analysis of digestion filters could be automated in contrast to the more time intensive in situ analyses.

Potential health hazards from thermal degradation events - Particulate vs. gas phase effects

NASA Technical Reports Server (NTRS)

Oberdorster, Gunter; Ferin, Juraj; Finkelstein, Jacob; Baggs, Raymond; Stavert, D. M.; Lehnert, Bruce E.

1992-01-01

The effect of instillation of ultrafine TiO2 particles (10-nm anatase-TiO2 and 12-nm rutile-TiO2 (administered in doses from 60 to 1000 microg/rat and 500 microg/rat, respectively) on the respiratory tract of exposed rats was compared to the effects of larger (250 nm anatase-TiO2 and 220-nm rutile-TiO2 particles (given in doses 500 or 1000 microg/rat and 500 microg/rat, respectively). These effects were also compared to the effects of inhalation of 20-nm and 250-nm anatase-TiO2 particles and inhalation with surrogate gas phase components (HF and HCl). It was found that ultrafine TiO2 particles induced greater inflammatory reaction in the lung, had greater adverse effect on alveolar macrophage-mediated clearance function, and had a greater potential to induce mediators which can adversely affect other lung cells than did larger-sized particles. Inhalation of surrogate gas phase components caused injury only to the upper respiratory tract, in contrast to the ultrafine particles, which affected the deep lung.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sigaud, Samuel; Goldsmith, Carroll-Ann W.; Zhou Hongwei

Epidemiological studies reveal increased incidence of lung infection when air pollution particle levels are increased. We postulate that one risk factor for bacterial pneumonia, prior viral infection, can prime the lung for greater deleterious effects of particles via the interferon-gamma (IFN-{gamma}) characteristic of successful host anti-viral responses. To test this postulate, we developed a mouse model in which mice were treated with {gamma}-interferon aerosol, followed by exposure to concentrated ambient particles (CAPs) collected from urban air. The mice were then infected with Streptococcus pneumoniae and the effect of these treatments on the lung's innate immune response was evaluated. The combinationmore » of IFN-{gamma} priming and CAPs exposure enhanced lung inflammation, manifest as increased polymorphonuclear granulocyte (PMN) recruitment to the lung, and elevated expression of pro-inflammatory cytokine mRNAs. Combined priming and CAPs exposure resulted in impaired pulmonary bacterial clearance, as well as increased oxidant production and diminished bacterial uptake by alveolar macrophages (AMs) and PMNs. The data suggest that priming and CAPs exposure lead to an inflamed alveolar milieu where oxidant stress causes loss of antibacterial functions in AMs and recruited PMNs. The model reported here will allow further analysis of priming and CAPs exposure on lung sensitivity to infection.« less

Analysis of the Murine Immune Response to Pulmonary Delivery of Precisely Fabricated Nano- and Microscale Particles

PubMed Central

Roberts, Reid A.; Shen, Tammy; Allen, Irving C.; Hasan, Warefta; DeSimone, Joseph M.; Ting, Jenny P. Y.

2013-01-01

Nanomedicine has the potential to transform clinical care in the 21st century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs. PMID:23593509

Particle-related exposure, dose and lung cancer risk of primary school children in two European countries.

PubMed

Pacitto, A; Stabile, L; Viana, M; Scungio, M; Reche, C; Querol, X; Alastuey, A; Rivas, I; Álvarez-Pedrerol, M; Sunyer, J; van Drooge, B L; Grimalt, J O; Sozzi, R; Vigo, P; Buonanno, G

2018-03-01

Schools represent a critical microenvironment in terms of air quality due to the proximity to outdoor particle sources and the frequent lack of proper ventilation and filtering systems. Moreover, the population exposed in schools (i.e. children) represents a susceptible population due to their age. Air quality-based studies involving students' exposure at schools are still scarce and often limited to mass-based particle metrics and may thus underestimate the possible effect of sub-micron particles and particle toxicity. To this purpose, the present paper aims to evaluate the exposure to different airborne particle metrics (including both sub- and super-micron particles) and attached carcinogenic compounds. Measurements in terms of particle number, lung-deposited surface area, and PM fraction concentrations were measured inside and outside schools in Barcelona (Spain) and Cassino (Italy). Simultaneously, PM samples were collected and chemically analysed to obtain mass fractions of carcinogenic compounds. School time airborne particle doses received by students in classrooms were evaluated as well as their excess lung cancer risk due to a five-year primary school period. Median surface area dose received by students during school time in Barcelona and Cassino resulted equal to 110mm 2 and 303mm 2 , respectively. The risk related to the five-year primary school period was estimated as about 2.9×10 -5 and 1.4×10 -4 for students of Barcelona and Cassino, respectively. The risk in Barcelona is slightly higher with respect to the maximum tolerable value (10 -5 , according to the U.S. Environmental Protection Agency), mainly due to toxic compounds on particles generated from anthropogenic emissions (mainly industry). On the other hand, the excess lung cancer risk in Cassino is cause of concern, being one order of magnitude higher than the above-mentioned threshold value due to the presence of biomass burning heating systems and winter thermal inversion that cause larger doses and great amount of toxic compounds on particles. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats.

PubMed

Antonini, James M; Stone, Sam; Roberts, Jenny R; Chen, Bean; Schwegler-Berry, Diane; Afshari, Aliakbar A; Frazer, David G

2007-09-15

Many welders have experienced bronchitis, metal fume fever, lung function changes, and an increase in the incidence of lung infection. Questions remain regarding the possible mechanisms associated with the potential pulmonary effects of welding fume exposure. The objective was to assess the early effects of stainless steel (SS) welding fume inhalation on lung injury, inflammation, and defense responses. Male Sprague-Dawley rats were exposed to gas metal arc-SS welding fume at a concentration of 15 or 40 mg/m(3) x 3 h/day for 1, 3, or 10 days. The control group was exposed to filtered air. To assess lung defense responses, some animals were intratracheally inoculated with 5x10(4) Listeria monocytogenes 1 day after the last exposure. Welding particles were collected during exposure, and elemental composition and particle size were determined. At 1, 4, 6, 11, 14, and 30 days after the final exposure, parameters of lung injury (lactate dehydrogenase and albumin) and inflammation (PMN influx) were measured in the bronchoalveolar lavage fluid. In addition, particle-induced effects on pulmonary clearance of bacteria and macrophage function were assessed. SS particles were composed of Fe, Cr, Mn, and Ni. Particle size distribution analysis indicated the mass median aerodynamic diameter of the generated fume to be 0.255 microm. Parameters of lung injury were significantly elevated at all time points post-exposure compared to controls except for 30 days. Interestingly, no significant difference in lung PMNs was observed between the SS and control groups at 1, 4, and 6 days post-exposure. After 6 days post-exposure, a dramatic increase in lung PMNs was observed in the SS group compared to air controls. Lung bacteria clearance and macrophage function were reduced and immune and inflammatory cytokines were altered in the SS group. In summary, short-term exposure of rats to SS welding fume caused significant lung damage and suppressed lung defense responses to bacterial infection, but had a delayed effect on pulmonary inflammation. Additional chronic inhalation studies are needed to further examine the lung effects associated with SS welding fume exposure.

Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antonini, James M.; Stone, Sam; Roberts, Jenny R.

Many welders have experienced bronchitis, metal fume fever, lung function changes, and an increase in the incidence of lung infection. Questions remain regarding the possible mechanisms associated with the potential pulmonary effects of welding fume exposure. The objective was to assess the early effects of stainless steel (SS) welding fume inhalation on lung injury, inflammation, and defense responses. Male Sprague-Dawley rats were exposed to gas metal arc-SS welding fume at a concentration of 15 or 40 mg/m{sup 3} x 3 h/day for 1, 3, or 10 days. The control group was exposed to filtered air. To assess lung defense responses,more » some animals were intratracheally inoculated with 5 x 10{sup 4}Listeria monocytogenes 1 day after the last exposure. Welding particles were collected during exposure, and elemental composition and particle size were determined. At 1, 4, 6, 11, 14, and 30 days after the final exposure, parameters of lung injury (lactate dehydrogenase and albumin) and inflammation (PMN influx) were measured in the bronchoalveolar lavage fluid. In addition, particle-induced effects on pulmonary clearance of bacteria and macrophage function were assessed. SS particles were composed of Fe, Cr, Mn, and Ni. Particle size distribution analysis indicated the mass median aerodynamic diameter of the generated fume to be 0.255 {mu}m. Parameters of lung injury were significantly elevated at all time points post-exposure compared to controls except for 30 days. Interestingly, no significant difference in lung PMNs was observed between the SS and control groups at 1, 4, and 6 days post-exposure. After 6 days post-exposure, a dramatic increase in lung PMNs was observed in the SS group compared to air controls. Lung bacteria clearance and macrophage function were reduced and immune and inflammatory cytokines were altered in the SS group. In summary, short-term exposure of rats to SS welding fume caused significant lung damage and suppressed lung defense responses to bacterial infection, but had a delayed effect on pulmonary inflammation. Additional chronic inhalation studies are needed to further examine the lung effects associated with SS welding fume exposure.« less

Comparison of stochastic lung deposition fractions with experimental data.

PubMed

Majid, Hussain; Hofmann, Werner; Winkler-Heil, Renate

2012-04-01

Deposition fractions of inhaled particles predicted by different computational models vary with respect to physical and biological factors and mathematical modeling techniques. These models must be validated by comparison with available experimental data. Experimental data supplied by different deposition studies with surrogate airway models or lung casts were used in this study to evaluate the stochastic deposition model Inhalation, Deposition and Exhalation of Aerosols in the Lung at the airway generation level. Furthermore, different analytical equations derived for the three major deposition mechanisms, diffusion, impaction, and sedimentation, were applied to different cast or airway models to quantify their effect on calculated particle deposition fractions. The experimental results for ultrafine particles (0.00175 and 0.01) were found to be in close agreement with the stochastic model predictions; however, for coarse particles (3 and 8 μm), experimental deposition fractions became higher with increasing flow rate. An overall fair agreement among the calculated deposition fractions for the different cast geometries was found. However, alternative deposition equations resulted in up to 300% variation in predicted deposition fractions, although all equations predicted the same trends as functions of particle diameter and breathing conditions. From this comparative study, it can be concluded that structural differences in lung morphologies among different individuals are responsible for the apparent variability in particle deposition in each generation. The use of different deposition equations yields varying deposition results caused primarily by (i) different lung morphometries employed in their derivation and the choice of the central bifurcation zone geometry, (ii) the assumption of specific flow profiles, and (iii) different methods used in the derivation of these equations.

A new mechanism for DNA alterations induced by alpha particles such as those emitted by radon and radon progeny.

PubMed Central

Lehnert, B E; Goodwin, E H

1997-01-01

The mechanism(s) by which alpha (alpha) particles like those emitted from inhaled radon and radon progeny cause their carcinogenic effects in the lung remains unclear. Although direct nuclear traversals by alpha-particles may be involved in mediating these outcomes, increasing evidence indicates that a particles can cause alterations in DNA in the absence of direct hits to cell nuclei. Using the occurrence of excessive sister chromatid exchanges (SCE) as an index of DNA damage in human lung fibroblasts, we investigated the hypothesis that alpha-particles may induce DNA damage through the generation of extracellular factors. We have found that a relatively low dose of alpha-particles can result in the generation of extracellular factors, which, upon transfer to unexposed normal human cells, can cause excessive SCE to an extent equivalent to that observed when the cells are directly irradiated with the same irradiation dose. A short-lived, SCE-inducing factor(s) is generated in alpha-irradiated culture medium containing serum in the absence of cells. A more persistent SCE-inducing factor(s), which can survive freeze-thaw and is heat labile is produced by fibroblasts after exposure to the alpha-particles. These results indicate that the initiating target for alpha-particle-induced genetic changes can be larger than a cell's nucleus or even a whole cell. How transmissible factors like those observed here in vitro may extend to the in vivo condition in the context of a-particle-induced carcinogenesis in the respiratory tract remains to be determined. PMID:9400706

Increase in relative deposition of fine particles in the rat lung periphery in the absence of gravity.

PubMed

Darquenne, Chantal; Borja, Maria G; Oakes, Jessica M; Breen, Ellen C; Olfert, I Mark; Scadeng, Miriam; Prisk, G Kim

2014-10-15

While it is well recognized that pulmonary deposition of inhaled particles is lowered in microgravity (μG) compared with gravity on the ground (1G), the absence of sedimentation causes fine particles to penetrate deeper in the lung in μG. Using quantitative magnetic resonance imaging (MRI), we determined the effect of gravity on peripheral deposition (DEPperipheral) of fine particles. Aerosolized 0.95-μm-diameter ferric oxide particles were delivered to spontaneously breathing rats placed in plethysmographic chambers both in μG aboard the NASA Microgravity Research Aircraft and at 1G. Following exposure, lungs were perfusion fixed, fluid filled, and imaged in a 3T MR scanner. The MR signal decay rate, R2*, was measured in each voxel of the left lung from which particle deposition (DEP) was determined based on a calibration curve. Regional deposition was assessed by comparing DEP between the outer (DEPperipheral) and inner (DEPcentral) areas on each slice, and expressed as the central-to-peripheral ratio. Total lung deposition tended to be lower in μG compared with 1G (1.01 ± 0.52 vs. 1.43 ± 0.52 μg/ml, P = 0.1). In μG, DEPperipheral was larger than DEPcentral (P < 0.03), while, in 1G, DEPperipheral was not significantly different from DEPcentral. Finally, central-to-peripheral ratio was significantly less in μG than in 1G (P ≤ 0.05). These data show a larger fraction of fine particles depositing peripherally in μG than in 1G, likely beyond the large- and medium-sized airways. Although not measured, the difference in the spatial distribution of deposited particles between μG and 1G could also affect particle retention rates, with an increase in retention for particles deposited more peripherally. Copyright © 2014 the American Physiological Society.

Instillation versus Inhalation of Multiwalled Carbon Nanotubes: Exposure-Related Health Effects, Clearance, and the Role of Particle Characteristics

PubMed Central

2015-01-01

Inhaled multiwalled carbon nanotubes (MWCNTs) may cause adverse pulmonary responses due to their nanoscale, fibrous morphology and/or biopersistance. This study tested multiple factors (dose, time, physicochemical characteristics, and administration method) shown to affect MWCNT toxicity with the hypothesis that these factors will influence significantly different responses upon MWCNT exposure. The study is unique in that (1) multiple administration methods were tested using particles from the same stock; (2) bulk MWCNT formulations had few differences (metal content, surface area/functionalization); and (3) MWCNT retention was quantified using a specialized approach for measuring unlabeled MWCNTs in rodent lungs. Male Sprague–Dawley rats were exposed to original (O), purified (P), and carboxylic acid functionalized (F) MWCNTs via intratracheal instillation and inhalation. Blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected at postexposure days 1 and 21 for quantifying biological responses and MWCNTs in lung tissues by programmed thermal analysis. At day 1, MWCNT instillation produced significant BALF neutrophilia and MWCNT-positive macrophages. Instilled O- and P-MWCNTs produced significant inflammation in lung tissues, which resolved by day 21 despite MWCNT retention. MWCNT inhalation produced no BALF neutrophilia and no significant histopathology past day 1. However, on days 1 and 21 postinhalation of nebulized MWCNTs, significantly increased numbers of MWCNT-positive macrophages were observed in BALF. Results suggest (1) MWCNTs produce transient inflammation if any despite persistence in the lungs; (2) instilled O-MWCNTs cause more inflammation than P- or F-MWCNTs; and (3) MWCNT suspension media produce strikingly different effects on physicochemical particle characteristics and pulmonary responses. PMID:25144856

Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yanamala, Naveena, E-mail: wqu1@cdc.gov; Hatfield, Meghan K., E-mail: wla4@cdc.gov; Farcas, Mariana T., E-mail: woe7@cdc.gov

2013-10-15

The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-basedmore » D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure.« less

Iron homeostatis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study

EPA Science Inventory

ABSTRACT: BACKGROUND: Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosi...

Size-dependent proinflammatory effects of ultrafine polystyrene particles: a role for surface area and oxidative stress in the enhanced activity of ultrafines.

PubMed

Brown, D M; Wilson, M R; MacNee, W; Stone, V; Donaldson, K

2001-09-15

Studies into the effects of ultrafine particles in the lung have shown adverse effects considered to be due in part to the particle size. Air pollution particles (PM(10)) are associated with exacerbations of respiratory disease and deaths from cardiovascular causes in epidemiological studies and the ultrafine fraction of PM(10) has been hypothesized to play an important role. The aim of the present study was to investigate proinflammatory responses to various sizes of polystyrene particles as a simple model of particles of varying size including ultrafine. In the animal model, we demonstrated that there was a significantly greater neutrophil influx into the rat lung after instillation of 64-nm polystyrene particles compared with 202- and 535-nm particles and this was mirrored in other parameters of lung inflammation, such as increased protein and lactate dehydrogenase in bronchoalveolar lavage. When surface area instilled was plotted against inflammation, these two variables were directly proportional and the line passed through zero. This suggests that surface area drives inflammation in the short term and that ultrafine particles cause a greater inflammatory response because of the greater surface area they possess. In vitro, we measured the changes in intracellular calcium concentration in mono mac 6 cells in view of the potential role of calcium as a signaling molecule. Calcium changes after particle exposure may be important in leading to proinflammatory gene expression such as chemokines. We demonstrated that only ultrafine polystyrene particles induced a significant increase in cytosolic calcium ion concentration. Experiments using dichlorofluorescin diacetate demonstrated greater oxidant activity of the ultrafine particles, which may explain their activity in these assays. There were significant increases in IL-8 gene expression in A549 epithelial cells after treatment with the ultrafine particles but not particles of other sizes. These findings suggest that ultrafine particles composed of low-toxicity material such as polystyrene have proinflammatory activity as a consequence of their large surface area. This supports a role for such particles in the adverse health effects of PM(10). Copyright 2001 Academic Press.

Siderite (FeCO₃) and magnetite (Fe₃O₄) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content.

PubMed

Pauluhn, Jürgen; Wiemann, Martin

2011-11-01

The two poorly soluble iron containing solid aerosols of siderite (FeCO₃) and magnetite (Fe₃O₄) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100 mg/m³. The particle size distributions were essentially identical (MMAD ≈1.4 μm). The iron-based concentrations were 12 or 38 and 22 or 66 mg Fe/m³ for FeCO₃ and Fe₃O₄, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a postexposure period of 3 months. The objective of study was to identify the most germane exposure metrics, that are the concentration of elemental iron (mg Fe/m³), total particle mass (mg PM/m³) or particle volume (μl PM/m³) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of iron. Despite its lower iron content, the exposure to FeCO₃ caused a more pronounced and sustained inflammation as compared to Fe₃O₄. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO₃ at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO₃ and Fe₃O₄ particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.

Pollution characteristics, sources and lung cancer risk of atmospheric polycyclic aromatic hydrocarbons in a new urban district of Nanjing, China.

PubMed

Wang, Tao; Xia, Zhonghuan; Wu, Minmin; Zhang, Qianqian; Sun, Shiqi; Yin, Jing; Zhou, Yanchi; Yang, Hao

2017-05-01

This paper focused on the pollution characteristics, sources and lung cancer risk of atmospheric polycyclic aromatic hydrocarbons (PAHs) in a new urban district of Nanjing, China. Gaseous and aerosol PM 2.5 (particulate matter with aerodynamic diameter smaller than 2.5μm) samples were collected in spring of 2015. Sixteen PAHs were extracted and analyzed after sampling. Firstly, arithmetic mean concentrations of PAHs and BaP eq (benzo[a]pyrene equivalent) were calculated. The mean concentrations of PAHs were 29.26±14.13, 18.14±5.37 and 48.47±16.03ng/m 3 in gas phase, particle phase and both phases, respectively. The mean concentrations of BaP eq were 0.87±0.51, 2.71±2.17 and 4.06±2.31ng/m 3 in gas phase, particle phase and both phases, respectively. Secondly, diagnostic ratios and principal component analysis were adopted to identify the sources of PAHs and the outcomes were the same: traffic exhaust was the predominant source followed by fuel combustion and industrial process. Finally, incremental lung cancer risk (ILCR) induced by whole year inhalation exposure to PAHs for population groups of different age and gender were estimated based on a Monte Carlo simulation. ILCR values caused by particle phase PAHs were greater than those caused by gas phase PAHs. ILCR values for adults were greater than those for other age groups. ILCR values caused by total (gas+particle) PAHs for diverse groups were all greater than the significant level (l0 -6 ), indicating high potential lung cancer risk. Sensitivity analysis results showed that cancer slope factor for BaP inhalation exposure and BaP eq concentration had greater impact than body weight and inhalation rate on the ILCR. Copyright © 2016. Published by Elsevier B.V.

Pulmonary effects induced by ultrafine PTFE particles.

PubMed

Johnston, C J; Finkelstein, J N; Mercer, P; Corson, N; Gelein, R; Oberdörster, G

2000-11-01

PTFE (polytetrafluoroethylene) fumes consisting of large numbers of ultrafine (uf) particles and low concentrations of gas-phase compounds can cause severe acute lung injury. Our studies were designed to test three hypotheses: (i) uf PTFE fume particles are causally involved in the induction of acute lung injury, (ii) uf PTFE elicit greater pulmonary effects than larger sized PTFE accumulation mode particles, and (iii) preexposure to the uf PTFE fume particles will induce tolerance. We used uf Teflon (PTFE) fumes (count median particle size approximately 16 nm) generated by heating PTFE in a tube furnace to 486 degrees C to evaluate principles of ultrafine particle toxicity. Teflon fumes at ultrafine particle concentrations of 50 microg/m(3) were extremely toxic to rats when inhaled for only 15 min. We found that when generated in argon, the ultrafine Teflon particles alone are not toxic at these exposure conditions; neither were Teflon fume gas-phase constituents when generated in air. Only the combination of both phases when generated in air caused high toxicity, suggesting either the existence of radicals on the surface or a carrier mechanism of the ultrafine particles for adsorbed gas compounds. Aging of the fresh Teflon fumes for 3.5 min led to a predicted coagulation to >100 nm particles which no longer caused toxicity in exposed animals. This result is consistent with a greater toxicity of ultrafine particles compared to accumulation mode particles, although changes in particle surface chemistry during the aging process may have contributed to the diminished toxicity. Furthermore, the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-min exposures on 3 days prior to a 15-min exposure. Messages encoding antioxidants and chemokines were increased substantially in nonadapted animals, yet were unaltered in adapted animals. This study shows the importance of preexposure history for the susceptibility to acute ultrafine particle effects. Copyright 2000 Academic Press.

Effects of Fuel Components and Combustion Particle Physicochemical Properties on Toxicological Responses of Lung Cells

PubMed Central

Jaramillo, Isabel C.; Sturrock, Anne; Ghiassi, Hossein; Woller, Diana J.; Deering-Rice, Cassandra E.; Lighty, JoAnn S.; Paine, Robert; Reilly, Christopher; Kelly, Kerry E.

2017-01-01

The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1). Particles were generated from controlled combustion of two simple biofuel/diesel surrogates (methyl decanoate and dodecane/BD, and butanol and dodecane/AD) and compared to a widely studied reference diesel particle (NIST SRM2975/RD). BD, AD, and RD particles exhibited differences in size, surface area, extractable chemical mass, and the content of individual polycyclic aromatic hydrocarbons (PAHs). Some of these differences were directly associated with different effects on biological responses. BD particles had the greatest surface area, amount of extractable material and oxidizing potential. These particles and extracts induced cytochrome P450 1A1 and 1B1 enzyme mRNA in lung cells. AD particles and extracts had the greatest total PAH content and also caused CYP1A1 and 1B1 mRNA induction. The RD extract contained the highest relative concentration of 2-ring PAHs and stimulated the greatest level of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNFα) cytokine secretion. Finally, AD and RD were more potent activators of TRPA1 than BD, and while neither the TRPA1 antagonist HC-030031 nor the antioxidant N-acetylcysteine (NAC) affected CYP1A1 or 1B1 mRNA induction, both inhibitors reduced IL-8 secretion and mRNA induction. These results highlight that differences in fuel and combustion conditions affect the physicochemical properties of particles, and these differences, in turn, affect commonly studied biological/toxicological responses. PMID:29227181

Numerical investigation of diesel exhaust particle transport and deposition in the CT-scan based lung airway

NASA Astrophysics Data System (ADS)

Islam, Mohammad S.; Saha, Suvash C.; Sauret, Emilie; Gu, Y. T.; Molla, Md Mamun

2017-06-01

Diesel exhaust particulates matter (DEPM) is a compound mixture of gasses and fine particles that contain more than 40 toxic air pollutants including benzene, formaldehyde, and nitrogen oxides. Exposure of DEPM to human lung airway during respiratory inhalation causes severe health hazards like diverse pulmonary diseases. This paper studies the DEPM transport and deposition in upper three generations of the realistic lung airways. A 3-D digital airway bifurcation model is constructed from the computerized tomography (CT) scan data of a healthy adult man. The Euler-Lagrange approach is used to solve the continuum and disperse phases of the calculation. Local averaged Navier-Stokes equations are solved to calculate the transport of the continuum phase. Lagrangian based Discrete Phase Model (DPM) is used to investigate the particle transport and deposition in the current anatomical model. The effects of size specific monodispersed particles on deposition are extensively investigated during different breathing pattern. The numerical results illustrate that particle diameter and breathing pattern have a substantial impact on particles transport and deposition in the tracheobronchial airways. The present realistic bifurcation model also depicts a new deposition hot spot which could advance the understanding of the therapeutic drug delivery system to the specific position of the respiratory airways.

Aerosol characterization and pulmonary responses in rats after short-term inhalation of fumes generated during resistance spot welding of galvanized steel.

PubMed

Antonini, James M; Afshari, Aliakbar; Meighan, Terence G; McKinney, Walter; Jackson, Mark; Schwegler-Berry, Diane; Burns, Dru A; LeBouf, Ryan F; Chen, Bean T; Shoeb, Mohammad; Zeidler-Erdely, Patti C

2017-01-01

Resistance spot welding is a common process to join metals in the automotive industry. Adhesives are often used as sealers to seams of metals that are joined. Anti-spatter compounds sometimes are sprayed onto metals to be welded to improve the weldability. Spot welding produces complex aerosols composed of metal and volatile compounds (VOCs) which can cause lung disease in workers. Male Sprague-Dawley rats (n = 12/treatment group) were exposed by inhalation to 25 mg/m 3 of aerosol for 4 h/day × 8 days during spot welding of galvanized zinc (Zn)-coated steel in the presence or absence of a glue or anti-spatter spray. Controls were exposed to filtered air. Particle size distribution and chemical composition of the generated aerosol were determined. At 1 and 7 days after exposure, bronchoalveolar lavage (BAL) was performed to assess lung toxicity. The generated particles mostly were in the submicron size range with a significant number of nanometer-sized particles formed. The primary metals present in the fumes were Fe (72.5%) and Zn (26.3%). The addition of the anti-spatter spray and glue did affect particle size distribution when spot welding galvanized steel, whereas they had no effect on metal composition. Multiple VOCs (e.g., methyl methacrylate, acetaldehyde, ethanol, acetone, benzene, xylene) were identified when spot welding using either the glue or the anti-spatter spray that were not present when welding alone. Markers of lung injury (BAL lactate dehydrogenase) and inflammation (total BAL cells/neutrophils and cytokines/chemokines) were significantly elevated compared to controls 1 day after exposure to the spot welding fumes. The elevated pulmonary response was transient as lung toxicity mostly returned to control values by 7 days. The VOCs or the concentrations that they were generated during the animal exposures had no measurable effect on the pulmonary responses. Inhalation of galvanized spot welding fumes caused acute lung toxicity most likely due to the short-term exposure of particles that contain Zn.

Component-specific, cigarette particle deposition modeling in the human respiratory tract

PubMed Central

Price, Owen T.; Yurteri, Caner U.; Dickens, Colin; McAughey, John

2014-01-01

Inhalation of cigarette smoke particles (CSP) leads to adverse health effects in smokers. Determination of the localized dose to the lung of the inhaled smoke aids in determining vulnerable sites, and identifying components of the smoke that may be responsible for the adverse effects; thus providing a roadmap for harm reduction of cigarette smoking. A particle deposition model specific to CSP was developed for the oral cavity and the lung by accounting for cigarette particle size growth by hygroscopicity, phase change and coagulation. In addition, since the cigarette puff enters the respiratory tract as a dense cloud, the cloud effect on particle drag and deposition was accounted for in the deposition model. Models of particle losses in the oral cavities were developed during puff drawing and subsequent mouth-hold. Cigarette particles were found to grow by hygroscopicity and coagulation, but to shrink as a result of nicotine evaporation. The particle size reached a plateau beyond which any disturbances in the environmental conditions caused the various mechanisms to balance each other out and the particle size remain stable. Predicted particle deposition considering the cloud effects was greater than when treated as a collection of non-interacting particles (i.e. no cloud effects). Accounting for cloud movement provided the necessary physical mechanism to explain the greater than expected, experimentally observed and particle deposition. The deposition model for CSP can provide the necessary input to determine the fate of inhaled CSP in the lung. The knowledge of deposition will be helpful for health assessment and identification and reduction of harmful components of CSP. PMID:24354791

Histological changes in lung tissues related with sub-chronic exposure to ambient urban levels of PM2.5 in Córdoba, Argentina

NASA Astrophysics Data System (ADS)

Tavera Busso, Iván; Vera, Anahí; Mateos, Ana Carolina; Amarillo, Ana Carolina; Carreras, Hebe

2017-10-01

Concentration of fine particulate matter (PM2.5) is one of the most important environmental parameters to estimate health impacts attributable to air pollution. Despite the fact there are many studies regarding PM2.5 effects on human health, most of them were performed under conditions that do not simulate the natural particles interaction with the organism. In the present paper, we studied the effects of mammals' sub-chronic exposure to PM2.5 on the lower respiratory tract, addressing realistic exposure conditions to normal urban air. Thus, we exposed Wistar rats under controlled settings to the same normal urban air, with and without particles. Next, we analyzed chemical composition of PM2.5 and lungs samples, performed a histologic examination and run the comet assay to assess genotoxic effects. We found a strong agreement between lung tissues and PM2.5 elemental composition suggesting that metals found in lungs came from the particles inhaled. Histological analysis showed a mild to moderate infiltration, with a reduction of alveoli lumen and increment of alveolar macrophages and periodic acid-Schiff (PAS) (+) cells in treated animals. We also observed an increase in the number of nuclei with comets, mostly comets type 3, with a high DNA fragmentation as well. These results provide strong evidence that sub-chronic exposure to low particle levels, even below the 24 h WHO standard, can cause injuries in lungs tissues and DNA damage, as well.

Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

PubMed Central

Yanamala, Naveena; Hatfield, Meghan K.; Farcas, Mariana T.; Schwegler-Berry, Diane; Hummer, Jon A.; Shurin, Michael R.; Birch, M. Eileen; Gutkin, Dmitriy W.; Kisin, Elena; Kagan, Valerian E.; Bugarski, Aleksandar D.; Shvedova, Anna A.

2015-01-01

The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. PMID:23886933

Diesel exhaust particle promotes tumor lung metastasis via the induction of BLT1-mediated neutrophilic lung inflammation.

PubMed

Li, Wenjing; Liu, Ting; Xiong, Yingluo; Lv, Jiaoyan; Cui, Xinyi; He, Rui

2018-06-05

BLT1, the primary functional receptor of Leukotriene B4 (LTB4), is involved in tissue inflammation by mediating leukocyte recruitment, and recently LTB4-dependent inflammation was reported to promote lung tumor growth. Exposure to diesel exhaust particle (DEP), the major component of particulate matter 2.5 (PM 2.5 ), can elicit lung inflammation, which may increase the risk of lung cancer. However, it remains unknown about the critical factors mediating DEP-induced lung inflammation and the subsequent effect on tumor metastasis. In this study, we found that DEP exposure led to acute lung inflammation, characterized by abundant infiltration of neutrophils and elevated lung levels in LTB4, as well as several pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α, CXCL1/2. Furthermore, DEP exposure promoted lung metastasis of 3LL and 4T1 cells. BLT1 blockade by its specific antagonist U75302 significantly inhibited neutrophilic lung inflammation following DEP exposure. Importantly, BLT1 blockade before the onset of inflammation significantly reduced DEP-enhanced lung metastasis, which was associated with greatly decreased infiltrating neutrophils in lungs. Interestingly, BLT1 blockade after the occurrence of lung metastases had no effect on the magnitude of lung metastasis, suggesting that inhibition of BLT1-mediated lung inflammation was insufficient to suppress established metastatic tumor. Administration of BLT2 inhibitor LY255283 fails to inhibit DEP-induced lung inflammation and tumor metastasis. Collectively, our results demonstrate that DEP exposure causes BLT1-mediated lung neutrophilic inflammation, which is critical for tumor lung metastasis, and suggest that interruption of the LTB4-BLT1 axis could be useful for preventing PM 2.5 -induced inflammation and subsequent susceptible to lung metastasis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor.

PubMed

Ignjatović, Nenad L; Penov-Gaši, Katarina M; Wu, Victoria M; Ajduković, Jovana J; Kojić, Vesna V; Vasiljević-Radović, Dana; Kuzmanović, Maja; Uskoković, Vuk; Uskoković, Dragan P

2016-12-01

In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. 1 H NMR and 13 C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d 50 =168nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46±2%), while simultaneously preserving high viability (83±3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells. Copyright © 2016 Elsevier B.V. All rights reserved.

Aluminium Pneumoconiosis I. In Vitro Comparison of Stamped Aluminium Powders Containing Different Lubricating Agents and a Granular Aluminium Powder

PubMed Central

Corrin, B.

1963-01-01

The discrepancy in previous reports of the action of aluminium on the lung may be explained by differences between stamped and granular aluminium powders. A stamped powder of the variety causing pulmonary fibrosis showed a brisk reaction with water, but a granular powder was unreactive. This difference is primarily due to the granular particles being covered by inert aluminium oxide, the formation of which is partially prevented in the stamping process by stearine and mineral oil. The reactivity of the flake-like stamped particles is also dependent on their large surface area per unit volume. The appearance of aluminium pneumoconiosis in Britain is explained by the introduction of mineral oil into the stamping industry for, in contrast to stearine, mineral oil permits the powder to react with water. The lung damage is believed to be caused by a soluble form of aluminium. PMID:14072616

A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung

PubMed Central

Thomson, M. L.; Pavia, D.; McNicol, M. W.

1973-01-01

Thomson, M. L., Pavia, D., and McNicol, M. W. (1973).Thorax, 28, 742-747. A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung. The effect of guaiphenesin (administered as Robitussin1) on mucociliary clearance has been assessed in 15 subjects from the rate of removal from the lung of previously inhaled radioactive tracer particles. The guaiphenesin was compared with a positive control preparation consisting of the guaiphenesin vehicle only in two double-blind crossover trials. The first trial examined eight aged `healthy' volunteer subjects and the second trial examined seven chronic bronchitic patients. Sequential gamma counts were made from the whole lung by scintillation counters for 6 hours after inhalation and the chest was also scanned rectilinearly. In the first 5 hours after inhalation the mean rate of removal of particles and therefore of secretions was faster after guaiphenesin than after the control preparation. This difference was not statistically significant in the healthy volunteers but achieved significance (P <0·05) in the chronic bronchitic patients. Lung scans after inhaling the tracer aerosol indicated that on average the initial penetration of the particles into the lung was similar in the guaiphenesin and control runs. The faster clearance after guaiphenesin was unlikely to be due to bulk movements of mucus caused by coughing since the mean frequency of coughing during the experiment was somewhat less after the drug. PMID:4595814

Screening strategy to avoid toxicological hazards of inhaled nanoparticles for drug delivery: The use of a-quartz and nano zinc oxide particles as benchmark

NASA Astrophysics Data System (ADS)

Beyerle, Andrea; Schulz, Holger; Kissel, Thomas; Stoeger, Tobias

2009-02-01

Nanotechnology is a broad, revolutionary field with promising advantages for new medicine. In this context the rapid development and improvement of so called nanocarriers is of high pharmaceutical interest and some devices are already on the market. In our project we aim to develop well characterized nanoscaled drug delivery systems for an inhalative application. To this end, we focus on the most adverse side-effects within the lung, the cytotoxic and the proinflammatory responses to these nanoparticles (NPs). Before performing any animal experiments, we start with an in vitro screening for analyzing the cytotoxic and proinflammatory effects of the investigated particles on two murine lung target cell lines, the alveolar epithelial like typ II cell line (LA4) and the alveolar macrophage cell line (MH-S). Three different endpoints were estimated, (i) cellular metabolic activity, determined by the WST-1 assay, (ii) membrane integrity, by detection of LDH release and hemolytic activity, and (iii) secretion of inflammatory mediators. To analyze the relative particle toxicity we choose two reference particles as benchmarks, (i) fine a-quartz, and (ii) ultrafine ZnO particles. The investigation of dose-response and kinetics of proinflammatory and toxic effects caused to the named cell lines provide an insight to a close evaluation of our cell based screening strategy. oc-quartz is well known for its inflammatory and toxic potential caused by inhalation, and nanosized ZnO particles - used in a broad field of nanotechnology like electronics, but also cosmetics and pharmaceuticals - is to a high degree cytotoxic and proinflammatory in vitro. Preliminary experiments indicated not only particle and cell specific inflammatory responses, but also different susceptibilities of the cell types being exposed to our benchmark particles regarding their size and surface activities. Exposure to the μm-sized a-quartz particles affected the viability of epithelia cells less than that of macrophages, pointing to the impact of particle uptake by phagocytosis. In contrast, the nanosized ZnO particles caused much stronger decrease in cell viability and higher levels of LDH in the macrophage cell line compared to epithelial cells, even though the hemolytic activity was much higher for the a-quartz particles than for the nanosized ZnO. For the proinflammatory effects, we observed a clear dose-dependent release of acute phase cytokines (TNF-α, IL-6, G-CSF> CXCL10>CCL2) for both alveolar cell lines after Min-U-Sil exposure. After ZnO treatment the cytokine responses were negligible compare to control cells. In conclusion, our data attach value to the use of different cell types to detect different pathways of toxicity generated by different particle properties. Therefore, we will establish both lung target cell lines for an in vitro screening to analyze proinflammatory and cytotoxicity effects of nanocarriers. The implementation of the two reference particles facilitate the validated classification of the cytotoxic responses caused by the NPs investigated.

Effects of fuel components and combustion particle physicochemical properties on toxicological responses of lung cells.

PubMed

Jaramillo, Isabel C; Sturrock, Anne; Ghiassi, Hossein; Woller, Diana J; Deering-Rice, Cassandra E; Lighty, JoAnn S; Paine, Robert; Reilly, Christopher; Kelly, Kerry E

2018-03-21

The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1). Particles were generated from controlled combustion of two simple biofuel/diesel surrogates (methyl decanoate and dodecane/biofuel-blended diesel (BD), and butanol and dodecane/alcohol-blended diesel (AD)) and compared to a widely studied reference diesel (RD) particle (NIST SRM2975/RD). BD, AD, and RD particles exhibited differences in size, surface area, extractable chemical mass, and the content of individual polycyclic aromatic hydrocarbons (PAHs). Some of these differences were directly associated with different effects on biological responses. BD particles had the greatest surface area, amount of extractable material, and oxidizing potential. These particles and extracts induced cytochrome P450 1A1 and 1B1 enzyme mRNA in lung cells. AD particles and extracts had the greatest total PAH content and also caused CYP1A1 and 1B1 mRNA induction. The RD extract contained the highest relative concentration of 2-ring PAHs and stimulated the greatest level of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNFα) cytokine secretion. Finally, AD and RD were more potent activators of TRPA1 than BD, and while neither the TRPA1 antagonist HC-030031 nor the antioxidant N-acetylcysteine (NAC) affected CYP1A1 or 1B1 mRNA induction, both inhibitors reduced IL-8 secretion and mRNA induction. These results highlight that differences in fuel and combustion conditions affect the physicochemical properties of particles, and these differences, in turn, affect commonly studied biological/toxicological responses.

Development of pulmonary alveolar proteinosis following exposure to dust after the Great East Japan Earthquake.

PubMed

Hisata, Shu; Moriyama, Hiroshi; Tazawa, Ryushi; Ohkouchi, Shinya; Ichinose, Masakazu; Ebina, Masahito

2013-12-01

We report a unique case of pulmonary alveolar proteinosis that developed 3 weeks after the Great East Japan Earthquake and the subsequent tsunami. The patient had inhaled dust repeatedly while visiting her devastated neighborhood without wearing a protective mask. Five weeks after the earthquake, lung samples taken from the patient showed foreign particle deposition; however, her serum was negative for GM-CSF autoantibody. The patient's clinical symptoms resolved following whole lung lavage. We conclude that inhalation of fine dust particles after natural disasters may cause the onset of pulmonary alveolar proteinosis. Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Aerosol impacts on climate and environment over East Asia

NASA Astrophysics Data System (ADS)

Nakata, M.; Sano, I.; Mukai, S.

2014-12-01

It is well known that the aerosol distribution in East Asia is complex due to both the increasing emissions of the anthropogenic aerosols associated with economic growth and the behavior of natural dusts. Therefore, detailed observations of atmospheric particles in East Asian are important. It is concerned about the change of concentration of aerosols causes various effects on the climate by directly and indirectly modifying the optical properties and lifetimes of cloud. In addition to radiation budget change, aerosol has a significant potential to change cloud and precipitation. These circulation fields change influence on emission of natural aerosols such as dust aerosols and sea salt aerosols. Also, air pollution in megacities in East Asia has become a serious problem. Especially problematic are fine particles called PM2.5, whose diameter is 2.5 mm or less. Particulate matter (PM) pollution as indicated by high PM2.5 readings will cause a spike in the mortality rate of patients suffering from heart and lung diseases. Because fine particles are much smaller than inhalable coarse particles, the can penetrate deeper into the lungs and cause more severe effects on human health. Anthropogenic sources of PM2.5 include automobiles, factories, coal-burning power plants, and heaters in homes. It is well known that the size of dust particles decreases during long-range transport via westerly winds, and the resulting dust storms can contain high concentrations of fine particles. Accordingly, PM2.5 concentrations correspond well to both anthropogenic and dust aerosols. This work intends to investigate impacts of aerosol on regional climate change and environment over East Asia using observations and model simulations.

Acute diesel exhaust particle exposure increases viral titre and inflammation associated with existing influenza infection, but does not exacerbate deficits in lung function

PubMed Central

Larcombe, Alexander N.; Foong, Rachel E.; Boylen, Catherine E.; Zosky, Graeme R.

2012-01-01

Please cite this paper as: Larcombe et al. (2012) Acute diesel exhaust particle exposure increases viral titre and inflammation associated with existing influenza infection, but does not exacerbate deficits in lung function. Influenza and Other Respiratory Viruses DOI:10.1111/irv.12012. Background  Exposure to diesel exhaust particles (DEP) is thought to exacerbate many pre‐existing respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease, however, there is a paucity of data on whether DEP exacerbates illness due to respiratory viral infection. Objectives  To assess the physiological consequences of an acute DEP exposure during the peak of influenza‐induced illness. Methods  We exposed adult female BALB/c mice to 100 μg DEP (or control) 3·75 days after infection with 104·5 plaque forming units of influenza A/Mem71 (or control). Six hours, 24 hours and 7 days after DEP exposure we measured thoracic gas volume and lung function at functional residual capacity. Bronchoalveolar lavage fluid was taken for analyses of cellular inflammation and cytokines, and whole lungs were taken for measurement of viral titre. Results  Influenza infection resulted in significantly increased inflammation, cytokine influx and impairment to lung function. DEP exposure alone resulted in less inflammation and cytokine influx, and no impairment to lung function. Mice infected with influenza and exposed to DEP had higher viral titres and neutrophilia compared with infected mice, yet they did not have more impaired lung mechanics than mice infected with influenza alone. Conclusions  A single dose of DEP is not sufficient to physiologically exacerbate pre‐existing respiratory disease caused by influenza infection in mice. PMID:22994877

Effect of delayed pMDI actuation on the lung deposition of a fixed-dose combination aerosol drug.

PubMed

Farkas, Árpád; Horváth, Alpár; Kerekes, Attila; Nagy, Attila; Kugler, Szilvia; Tamási, Lilla; Tomisa, Gábor

2018-06-07

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2-5 s and inhalation flow rate between 30-150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition. Copyright © 2018. Published by Elsevier B.V.

In Vivo Protective Effects of Nootkatone against Particles-Induced Lung Injury Caused by Diesel Exhaust Is Mediated via the NF-κB Pathway

PubMed Central

Nemmar, Abderrahim; Al-Salam, Suhail; Beegam, Sumaya; Yuvaraju, Priya; Hamadi, Naserddine; Ali, Badreldin H.

2018-01-01

Numerous studies have shown that acute particulate air pollution exposure is linked with pulmonary adverse effects, including alterations of pulmonary function, inflammation, and oxidative stress. Nootkatone, a constituent of grapefruit, has antioxidant and anti-inflammatory effects. However, the effect of nootkatone on lung toxicity has not been reported so far. In this study we evaluated the possible protective effects of nootkatone on diesel exhaust particles (DEP)-induced lung toxicity, and the possible mechanisms underlying these effects. Mice were intratracheally (i.t.) instilled with either DEP (30 µg/mouse) or saline (control). Nootkatone was given to mice by gavage, 1 h before i.t. instillation, with either DEP or saline. Twenty-four hours following DEP exposure, several physiological and biochemical endpoints were assessed. Nootkatone pretreatment significantly prevented the DEP-induced increase in airway resistance in vivo, decreased neutrophil infiltration in bronchoalveolar lavage fluid, and abated macrophage and neutrophil infiltration in the lung interstitium, assessed by histolopathology. Moreover, DEP caused a significant increase in lung concentrations of 8-isoprostane and tumor necrosis factor α, and decreased the reduced glutathione concentration and total nitric oxide activity. These actions were all significantly alleviated by nootkatone pretreatment. Similarly, nootkatone prevented DEP-induced DNA damage and prevented the proteolytic cleavage of caspase-3. Moreover, nootkatone inhibited nuclear factor-kappaB (NF-κB) induced by DEP. We conclude that nootkatone prevented the DEP-induced increase in airway resistance, lung inflammation, oxidative stress, and the subsequent DNA damage and apoptosis through a mechanism involving inhibition of NF-κB activation. Nootkatone could possibly be considered a beneficial protective agent against air pollution-induced respiratory adverse effects. PMID:29495362

Preparation and properties of inhalable nanocomposite particles for treatment of lung cancer.

PubMed

Tomoda, Keishiro; Ohkoshi, Takumi; Hirota, Keiji; Sonavane, Ganeshchandra S; Nakajima, Takehisa; Terada, Hiroshi; Komuro, Masahito; Kitazato, Kenji; Makino, Kimiko

2009-07-01

Nanoparticles have widely been studied in drug delivery research for targeting and controlled release. The aim of this article is application of nanoparticles as an inhalable agent for treatment of lung cancer. To deposit effectively deep the particles in the lungs, the PLGA nanoparticles loaded with the anticancer drug 6-{[2-(dimethylamino)ethyl]amino}-3-hydroxyl-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) were prepared in the form of nanocomposite particles. The nanocomposite particles consist of the complex of drug-loaded nanoparticles and excipients. In this study, the anticancer effects of the nanocomposite particles against the lung cancer cell line A549. Also, the concentration of TAS-103 in blood and lungs were determined after administration of the nanocomposite particles by inhalation to rats. TAS-103-loaded PLGA nanoparticles were prepared with 5% and 10% of loading ratio by spray drying method with trehalose as an excipient. The 5% drug-loaded nanocomposite particles were more suitable for inhalable agent because of the sustained release of TAS-103 and higher FPF value. Cytotoxicity of nanocomposite particles against A549 cells was higher than that of free drug. When the nanocomposite particles were administered in rats by inhalation, drug concentration in lung was much higher than that in plasma. Furthermore, drug concentration in lungs administered by inhalation of nanocomposite particles was much higher than that after intravenous administration of free drug. From these results, the nanocomposite particle systems could be promising for treatment of lung cancer.

[A case of volcanic ash lung: report of a case].

PubMed

Shojima, Junko; Ikushima, Soichiro; Ando, Tsunehiro; Mochida, Akihiko; Yanagawa, Takashi; Takemura, Tamiko; Oritsu, Masaru

2006-03-01

A 57-year-old woman inhaled much volcanic ash without using a mask every day during the eruption of the Miyake Volcano in August 2000. An abnormal shadow was pointed out on her chest radiography by chance, after she sought refuge in Higashimurayama city in September. She had no respiratory symptoms and her chest radiography in an annual health check in July 2000 had showed no abnormality. She was admitted to our hospital and thoracoscopic lung biopsy was performed. We diagnosed it as lung inflammation caused by volcanic ash. The reasons for diagnosis were because the abnormal shadow appeared after the inhalation of volcanic ash, chest computed tomography showed diffuse irregular shadows with air bronchogram, thoracoscopic lung biopsy showed cellular-bronchiolitis around crystals, and the results of mineralogical analysis of the particles in alveolar macrophages detected in the biopsy specimen by scanning electron microscopy (SEM) were very similar to those of volcanic ash. The shadow on her chest radiography disappeared gradually without any treatment, but she avoided further exposure to volcanic ash. It is necessary to consider volcanic ash capable of causing lung inflammation.

Induction of pulmonary fibrosis by cerium oxide nanoparticles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Jane Y., E-mail: jym1@cdc.gov; Mercer, Robert R.; Barger, Mark

2012-08-01

Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO{sub 2}) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO{sub 2}-induced lung responses including sustained pulmonary inflammation and cellular signaling that could lead to pulmonary fibrosis. In this study, we investigated the fibrogenic responses induced by CeO{sub 2} in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO{sub 2} by a single intratracheal instillation. Alveolar macrophagesmore » (AM) were isolated by bronchial alveolar lavage (BAL). AM-mediated cellular responses, osteopontin (OPN) and transform growth factor (TGF)-β1 in the fibrotic process were investigated. The results showed that CeO{sub 2} exposure significantly increased fibrotic cytokine TGF-β1 and OPN production by AM above controls. The collagen degradation enzymes, matrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1 day- and subsequently declined at 28 days after exposure, but remained much higher than the controls. CeO{sub 2} induced elevated phospholipids in BAL fluid and increased hydroxyproline content in lung tissue in a dose- and time-dependent manner. Immunohistochemical analysis showed MMP-2, MMP-9 and MMP-10 expressions in fibrotic regions. Morphological analysis noted increased collagen fibers in the lungs exposed to a single dose of 3.5 mg/kg CeO{sub 2} and euthanized at 28 days post-exposure. Collectively, our studies show that CeO{sub 2} induced fibrotic lung injury in rats, suggesting it may cause potential health effects. -- Highlights: ► Cerium oxide exposure significantly affected the following parameters in the lung. ► Induced fibrotic cytokine OPN and TGF-β1 production and phospholipidosis. ► Caused imbalance of the MMP-9/ TIMP-1 ratio that favors fibrosis. ► Cerium oxide particles were detected in lung tissue and AM. ► Cerium oxide caused lung fibrosis in a dose- and time-dependent manner.« less

Elemental analysis of occupational and environmental lung diseases by electron probe microanalyzer with wavelength dispersive spectrometer.

PubMed

Takada, Toshinori; Moriyama, Hiroshi; Suzuki, Eiichi

2014-01-01

Occupational and environmental lung diseases are a group of pulmonary disorders caused by inhalation of harmful particles, mists, vapors or gases. Mineralogical analysis is not generally required in the diagnosis of most cases of these diseases. Apart from minerals that are encountered rarely or only in specific occupations, small quantities of mineral dusts are present in the healthy lung. As such when mineralogical analysis is required, quantitative or semi-quantitative methods must be employed. An electron probe microanalyzer with wavelength dispersive spectrometer (EPMA-WDS) enables analysis of human lung tissue for deposits of elements by both qualitative and semi-quantitative methods. Since 1993, we have analyzed 162 cases of suspected occupational and environmental lung diseases using an EPMA-WDS. Our institute has been accepting online requests for elemental analysis of lung tissue samples by EPMA-WDS since January 2011. Hard metal lung disease is an occupational interstitial lung disease that primarily affects workers exposed to the dust of tungsten carbide. The characteristic pathological findings of the disease are giant cell interstitial pneumonia (GIP) with centrilobular fibrosis, surrounded by mild alveolitis with giant cells within the alveolar space. EPMA-WDS analysis of biopsied lung tissue from patients with GIP has demonstrated that tungsten and/or cobalt is distributed in the giant cells and centrilobular fibrosing lesion in GIP. Pneumoconiosis, caused by amorphous silica, and acute interstitial pneumonia, associated with the giant tsunami, were also elementally analyzed by EPMA-WDS. The results suggest that commonly found elements, such as silicon, aluminum, and iron, may cause occupational and environmental lung diseases. Copyright © 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Particulate deposition in the human lung under lunar habitat conditions.

PubMed

Darquenne, Chantal; Prisk, G Kim

2013-03-01

Lunar dust may be a toxic challenge to astronauts. While deposition in reduced gravity is less than in normal gravity (1 G), reduced gravitational sedimentation causes particles to penetrate deeper in the lung, potentially causing more harm. The likely design of the lunar habitat has a reduced pressure environment and low-density gas has been shown to reduce upper airway deposition and increase peripheral deposition. Breathing air and a reduced-density gas approximating the density of the proposed lunar habitat atmosphere, five healthy subjects inhaled 1 -microm diameter aerosol boluses at penetration volumes (V(p)) of 200 ml (central airways), 500 ml, and 1000 ml (lung periphery) in microgravity during parabolic flight, and in 1 G. Deposition in the lunar habitat was significantly less than for Earth conditions (and less than in 1 G with the low-density gas) with a relative decrease in deposition of -59.1 +/- 14.0% (-46.9 +/- 11.7%), -50.7 +/- 9.2% (-45.8 +/- 11.2%), and -46.0 +/- 8.3% (-45.3 +/- 11.1%) at V(p) = 200, 500, and 1000 ml, respectively. There was no significant effect of reduced density on deposition in 1 G. While minimally affected by gas density, deposition was significantly less in microgravity than in 1 G for both gases, with a larger portion of particles depositing in the lung periphery under lunar conditions than Earth conditions. Thus, gravity, and not gas properties, mainly affects deposition in the peripheral lung, suggesting that studies of aerosol transport in the lunar habitat need not be performed at the low density proposed for the atmosphere in that environment.

Numerical simulation of DPF filter for selected regimes with deposited soot particles

NASA Astrophysics Data System (ADS)

Lávička, David; Kovařík, Petr

2012-04-01

For the purpose of accumulation of particulate matter from Diesel engine exhaust gas, particle filters are used (referred to as DPF or FAP filters in the automotive industry). However, the cost of these filters is quite high. As the emission limits become stricter, the requirements for PM collection are rising accordingly. Particulate matters are very dangerous for human health and these are not invisible for human eye. They can often cause various diseases of the respiratory tract, even what can cause lung cancer. Performed numerical simulations were used to analyze particle filter behavior under various operating modes. The simulations were especially focused on selected critical states of particle filter, when engine is switched to emergency regime. The aim was to prevent and avoid critical situations due the filter behavior understanding. The numerical simulations were based on experimental analysis of used diesel particle filters.

Prediction of lung cells oncogenic transformation for induced radon progeny alpha particles using sugarscape cellular automata.

PubMed

Baradaran, Samaneh; Maleknasr, Niaz; Setayeshi, Saeed; Akbari, Mohammad Esmaeil

2014-01-01

Alpha particle irradiation from radon progeny is one of the major natural sources of effective dose in the public population. Oncogenic transformation is a biological effectiveness of radon progeny alpha particle hits. The biological effects which has caused by exposure to radon, were the main result of a complex series of physical, chemical, biological and physiological interactions. The cellular and molecular mechanisms for radon-induced carcinogenesis have not been clear yet. Various biological models, including cultured cells and animals, have been found useful for studying the carcinogenesis effects of radon progeny alpha particles. In this paper, sugars cape cellular automata have been presented for computational study of complex biological effect of radon progeny alpha particles in lung bronchial airways. The model has included mechanism of DNA damage, which has been induced alpha particles hits, and then formation of transformation in the lung cells. Biomarkers were an objective measure or evaluation of normal or abnormal biological processes. In the model, the metabolism rate of infected cell has been induced alpha particles traversals, as a biomarker, has been followed to reach oncogenic transformation. The model results have successfully validated in comparison with "in vitro oncogenic transformation data" for C3H 10T1/2 cells. This model has provided an opportunity to study the cellular and molecular changes, at the various stages in radiation carcinogenesis, involving human cells. It has become well known that simulation could be used to investigate complex biomedical systems, in situations where traditional methodologies were difficult or too costly to employ.

Occupational lung diseases.

PubMed

Furlow, Bryant

2011-01-01

Chest radiography and high-resolution computed tomography are indispensable tools in the detection, classification and characterization of occupational lung diseases that are caused by inhaling mineral particles such as asbestos, silicon-containing rock dust and other tissue-damaging antigens, nanomaterials and toxins. Radiographic evidence of occupational lung disease is interpreted with a patient's clinical signs and symptoms and a detailed occupational history in mind because of high variability in radiographic findings. This Directed Reading reviews the history, epidemiology, functional anatomy, pathobiology and medical diagnostic imaging of occupational lung diseases associated with inhalation of fine particulates in the workplace. This article is a Directed Reading. Your access to Directed Reading quizzes for continuing education credit is determined by your CE preference. For access to other quizzes, go to www.asrt.org/store.

Recurrent secondary spontaneous pneumothorax in silicosis: a case report.

PubMed

Amanda, Gina; Taufik, Feni Fitriani

2016-01-01

Silicosis is an occupational lung disease which is caused by inhalation and accumulation of crystalline silica particles in the lung. It commonly occurs in workers involved in quarrying, mining, sandblasting, tunneling, foundry work, and ceramics. Pneumothorax is one of the complications of silicosis with pleural involvement. The occurrence of pneumothorax in a patient with silicosis is a rare event, but it may be fatal. The rate of pneumothorax recurrence in silicosis is usually low. We report a case of recurrent secondary spontaneous pneumothorax in silicosis.

Emodin mitigates diesel exhaust particles-induced increase in airway resistance, inflammation and oxidative stress in mice.

PubMed

Nemmar, Abderrahim; Al-Salam, Suhail; Yuvaraju, Priya; Beegam, Sumaya; Ali, Badreldin H

2015-08-15

Clinical and experimental studies have reported that short-term exposure to particulate air pollution is associated with inflammation, oxidative stress and impairment of lung function. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has a strong antioxidant and anti-inflammatory actions. Therefore, in the present study, we evaluated the possible ameliorative effect of emodin on diesel exhaust particles (DEP)-induced impairment of lung function, inflammation and oxidative stress in mice. Mice were intratracheally instilled with DEP (20 μg/mouse) or saline (control). Emodin was administered intraperitoneally 1h before and 7h after pulmonary exposure to DEP. Twenty-four hours following DEP exposure, we evaluated airway resistance measured by forced oscillation technique, lung inflammation and oxidative stress. Emodin treatment abated the DEP-induced increase in airway resistance, and prevented the influx of neutrophils in bronchoalveolar lavage fluid. Similarly, lung histopathology confirmed the protective effect of emodin on DEP-induced lung inflammation. DEP induced a significant increase of proinflammatory cytokines in the lung including tumor necrosis factor α, interleukin 6 and interleukin 1β. The latter effect was significantly ameliorated by emodin. DEP caused a significant increase in lung lipid peroxidation, reactive oxygen species and a significant decrease of reduced glutathione concentration. These effects were significantly mitigated by emodin. We conclude that emodin significantly mitigated DEP-induced increase of airway resistance, lung inflammation and oxidative stress. Pending further pharmacological and toxicological studies, emodin may be considered a potentially useful pulmonary protective agent against particulate air pollution-induced lung toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, R.K.; Griffith, W.C. Jr.; Cuddihy, R.G.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2more » h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.« less

Effects of rock wool on the lungs evaluated by magnetometry and biopersistence test

PubMed Central

Kudo, Yuichiro; Kotani, Makoto; Tomita, Masayuki; Aizawa, Yoshiharu

2009-01-01

Background Asbestos has been reported to cause pulmonary fibrosis, and its use has been banned all over the world. The related industries are facing an urgent need to develop a safer fibrous substance. Rock wool (RW), a kind of asbestos substitute, is widely used in the construction industry. In order to evaluate the safety of RW, we performed a nose-only inhalation exposure study in rats. After one-month observation period, the potential of RW fibers to cause pulmonary toxicity was evaluated based on lung magnetometry findings, pulmonary biopersistence, and pneumopathology. Methods Using the nose-only inhalation exposure system, 6 male Fischer 344 rats (6 to 10 weeks old) were exposed to RW fibers at a target fiber concentration of 100 fibers/cm3 (length [L] > 20 μm) for 6 hours daily, for 5 consecutive days. As a magnetometric indicator, 3 mg of triiron tetraoxide suspended in 0.2 mL of physiological saline was intratracheally administered after RW exposure to these rats and 6 unexposed rats (controls). During one second magnetization in 50 mT external magnetic field, all magnetic particles were aligned, and immediately afterwards the strength of their remanent magnetic field in the rat lungs was measured in both groups. Magnetization and measurement of the decay (relaxation) of this remanent magnetic field was performed over 40 minutes on 1, 3, 14, and 28 days after RW exposure, and reflected cytoskeleton dependent intracellular transport within macrophages in the lung. Similarly, 24 and 12 male Fisher 344-rats were used for biopersistence test and pathologic evaluation, respectively. Results In the lung magnetometric evaluation, biopersistence test and pathological evaluation, the arithmetic mean value of the total fiber concentration was 650.2, 344.7 and 390.7 fibers/cm3, respectively, and 156.6, 93.1 and 95.0 fibers/cm3 for fibers with L > 20 μm, respectively. The lung magnetometric evaluation revealed that impaired relaxation indicating cytoskeletal toxicity did not occur in the RW exposure group. In addition, clearance of the magnetic tracer particles was not significantly affected by the RW exposure. No effects on lung pathology were noted after RW exposure. Conclusion These findings indicate that RW exposure is unlikely to cause pulmonary toxicity within four weeks period. Lung magnetometry studies involving long-term exposure and observation will be necessary to ensure the safety of RW. PMID:19323845

Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Hui; Berlo, Damien van; Shi Tingming

2008-02-15

Chronic inhalation of high concentrations of respirable quartz particles has been implicated in various lung diseases including lung fibrosis and cancer. Generation of reactive oxygen species (ROS) and oxidative stress is considered a major mechanism of quartz toxicity. Curcumin, a yellow pigment from Curcuma longa, has been considered as nutraceutical because of its strong anti-inflammatory, antitumour and antioxidant properties. The aim of our present study was to investigate whether curcumin can protect lung epithelial cells from the cytotoxic, genotoxic and inflammatory effects associated with quartz (DQ12) exposure. Electron paramagnetic resonance (EPR) measurements using the spin-trap DMPO demonstrated that curcumin reducesmore » hydrogen peroxide-dependent hydroxyl-radical formation by quartz. Curcumin was also found to reduce quartz-induced cytotoxicity and cyclooxygenase 2 (COX-2) mRNA expression in RLE-6TN rat lung epithelial cells (RLE). Curcumin also inhibited the release of macrophage inflammatory protein-2 (MIP-2) from RLE cells as observed upon treatment with interleukin-1 beta (IL-1{beta}) and tumour necrosis factor-alpha (TNF{alpha}). However, curcumin failed to protect the RLE cells from oxidative DNA damage induced by quartz, as shown by formamidopyrimidine glycosylase (FPG)-modified comet assay and by immunocytochemistry for 8-hydroxydeoxyguanosine. In contrast, curcumin was found to be a strong inducer of oxidative DNA damage itself at non-cytotoxic and anti-inflammatory concentrations. In line with this, curcumin also enhanced the mRNA expression of the oxidative stress response gene heme oxygenase-1 (ho-1). Curcumin also caused oxidative DNA damage in NR8383 rat alveolar macrophages and A549 human lung epithelial cells. Taken together, these observations indicate that one should be cautious in considering the potential use of curcumin in the prevention or treatment of lung diseases associated with quartz exposure.« less

Lungs deposition and pharmacokinetic study of submicron budesonide particles in Wistar rats intended for immediate effect in asthma.

PubMed

Rauf, Abdul; Bhatnagar, Aseem; Sisodia, S S; Khar, Roop K; Ahmad, Farhan J

2017-01-01

The purpose of the present investigation was to study the aerosolization, lungs deposition and pharmacokinetic study of inhalable submicron particles of budesonide in male Wistar rats. Submicron particles were prepared by antisolvent nanoprecipitation method and freeze-dried to obtain free flowing powder. The freeze-drying process yielded dry powder with desirable aerodynamic properties for inhalation therapy. An in-house model inhaler was designed to deliver medicine to lungs, optimized at dose level of 10 mg for 30 sec of fluidization. The in vitro aerosolization study demonstrates that submicron particles dissolve faster with improved aerosolization effect as compared to micronized budesonide. Both submicron and micron particles were compared for in vivo lungs deposition. The results showed that relatively high quantity of submicron particles reaches deep into the lungs as compared to micron particles. Most pronounced effect observed with submicron particles from pharmacokinetic parameters was the enhancement in peak plasma concentration (C max ) by 28.85 %, and increase in area under concentration curve (AUC 0-8h ) by 30.33 % compared to micron sized particles. The results suggested that developed submicronized formulation of budesonide can be used for pulmonary drug delivery for high deposition to deep lungs tissues.

Loss in lung volume and changes in the immune response demonstrate disease progression in African green monkeys infected by small-particle aerosol and intratracheal exposure to Nipah virus.

PubMed

Cong, Yu; Lentz, Margaret R; Lara, Abigail; Alexander, Isis; Bartos, Christopher; Bohannon, J Kyle; Hammoud, Dima; Huzella, Louis; Jahrling, Peter B; Janosko, Krisztina; Jett, Catherine; Kollins, Erin; Lackemeyer, Matthew; Mollura, Daniel; Ragland, Dan; Rojas, Oscar; Solomon, Jeffrey; Xu, Ziyue; Munster, Vincent; Holbrook, Michael R

2017-04-01

Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that emerged in the late 1990s in Malaysia and has since been identified as the cause of sporadic outbreaks of severe febrile disease in Bangladesh and India. NiV infection is frequently associated with severe respiratory or neurological disease in infected humans with transmission to humans through inhalation, contact or consumption of NiV contaminated foods. In the work presented here, the development of disease was investigated in the African Green Monkey (AGM) model following intratracheal (IT) and, for the first time, small-particle aerosol administration of NiV. This study utilized computed tomography (CT) and magnetic resonance imaging (MRI) to temporally assess disease progression. The host immune response and changes in immune cell populations over the course of disease were also evaluated. This study found that IT and small-particle administration of NiV caused similar disease progression, but that IT inoculation induced significant congestion in the lungs while disease following small-particle aerosol inoculation was largely confined to the lower respiratory tract. Quantitative assessment of changes in lung volume found up to a 45% loss in IT inoculated animals. None of the subjects in this study developed overt neurological disease, a finding that was supported by MRI analysis. The development of neutralizing antibodies was not apparent over the 8-10 day course of disease, but changes in cytokine response in all animals and activated CD8+ T cell numbers suggest the onset of cell-mediated immunity. These studies demonstrate that IT and small-particle aerosol infection with NiV in the AGM model leads to a severe respiratory disease devoid of neurological indications. This work also suggests that extending the disease course or minimizing the impact of the respiratory component is critical to developing a model that has a neurological component and more accurately reflects the human condition.

Loss in lung volume and changes in the immune response demonstrate disease progression in African green monkeys infected by small-particle aerosol and intratracheal exposure to Nipah virus

PubMed Central

Cong, Yu; Lentz, Margaret R.; Lara, Abigail; Alexander, Isis; Bartos, Christopher; Bohannon, J. Kyle; Hammoud, Dima; Huzella, Louis; Jahrling, Peter B.; Janosko, Krisztina; Jett, Catherine; Kollins, Erin; Lackemeyer, Matthew; Mollura, Daniel; Ragland, Dan; Rojas, Oscar; Solomon, Jeffrey; Xu, Ziyue; Munster, Vincent

2017-01-01

Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that emerged in the late 1990s in Malaysia and has since been identified as the cause of sporadic outbreaks of severe febrile disease in Bangladesh and India. NiV infection is frequently associated with severe respiratory or neurological disease in infected humans with transmission to humans through inhalation, contact or consumption of NiV contaminated foods. In the work presented here, the development of disease was investigated in the African Green Monkey (AGM) model following intratracheal (IT) and, for the first time, small-particle aerosol administration of NiV. This study utilized computed tomography (CT) and magnetic resonance imaging (MRI) to temporally assess disease progression. The host immune response and changes in immune cell populations over the course of disease were also evaluated. This study found that IT and small-particle administration of NiV caused similar disease progression, but that IT inoculation induced significant congestion in the lungs while disease following small-particle aerosol inoculation was largely confined to the lower respiratory tract. Quantitative assessment of changes in lung volume found up to a 45% loss in IT inoculated animals. None of the subjects in this study developed overt neurological disease, a finding that was supported by MRI analysis. The development of neutralizing antibodies was not apparent over the 8–10 day course of disease, but changes in cytokine response in all animals and activated CD8+ T cell numbers suggest the onset of cell-mediated immunity. These studies demonstrate that IT and small-particle aerosol infection with NiV in the AGM model leads to a severe respiratory disease devoid of neurological indications. This work also suggests that extending the disease course or minimizing the impact of the respiratory component is critical to developing a model that has a neurological component and more accurately reflects the human condition. PMID:28388650

Targeted aerosolized delivery of ascorbate in the lungs of chlorine-exposed rats.

PubMed

Bracher, Andreas; Doran, Stephen F; Squadrito, Giuseppe L; Postlethwait, Edward M; Bowen, Larry; Matalon, Sadis

2012-12-01

Chlorine (Cl(2))-induced lung injury is a serious public health threat that may result from industrial and household accidents. Post-Cl(2) administration of aerosolized ascorbate in rodents decreased lung injury and mortality. However, the extent to which aerosolized ascorbate augments depleted ascorbate stores in distal lung compartments has not been assessed. We exposed rats to Cl(2) (300 ppm for 30 min) and returned them to room air. Within 15-30 min postexposure, rats breathed aerosolized ascorbate and desferal or vehicle (mean particle size 3.3 μm) through a nose-only exposure system for 60 min and were euthanized. We measured the concentrations of reduced ascorbate in the bronchoalveolar lavage (BAL), plasma, and lung tissues with high-pressure liquid chromatography, protein plasma concentration in the BAL, and the volume of the epithelia lining fluid (ELF). Cl(2)-exposed rats that breathed aerosolized vehicle had lower values of ascorbate in their BAL, ELF, and lung tissues compared to air-breathing rats. Delivery of aerosolized ascorbate increased reduced ascorbate in BAL, ELF, lung tissues, and plasma of both Cl(2) and air-exposed rats without causing lung injury. Based on mean diameter of aerosolized particles and airway sizes we calculated that approximately 5% and 1% of inhaled ascorbate was deposited in distal lung regions of air and Cl(2)-exposed rats, respectively. Significantly higher ascorbate levels were present in the BAL of Cl(2)-exposed rats when aerosol delivery was initiated 1 h post-Cl(2). Aerosol administration is an effective, safe, and noninvasive method for the delivery of low molecular weight antioxidants to the lungs of Cl(2)-exposed individuals for the purpose of decreasing morbidity and mortality. Delivery is most effective when initiated 1 h postexposure when the effects of Cl(2) on minute ventilation subside.

VARIATION OF LUNG DEPOSITION OF MICRON SIZE PARTICLES WITH LUNG VOLUME AND BREATHING PATTERN

EPA Science Inventory

Lung volume and breathing pattern are the source of inter-and intra-subject variability of lung deposition of inhaled particles. Controlling these factors may help optimize delivery of aerosol medicine to the target site within the lung. In the present study we measured total lu...

Pneumoconiotic effects of welding-fume particles from mild and stainless steel deposited in the lung of the rat.

PubMed

Hicks, R; Lam, H F; Al-Shamma, K J; Hewitt, P J

1984-03-01

Rats were exposed to single periods of inhalation of fumes generated by arc welding. Two processes were compared: either manual metal arc (MMA) using flux-coated mild steel (MS) electrodes or metal inert-gas (MIG) welding with stainless steel (SS). Widespread but small deposits of fume particles were cleared effectively from alveoli and airways. Peribronchial and subpleural aggregates of particle-laden macrophages remained. More massive and persistent lung-burdens were established by intratracheal administration of suspensions of fume-particles (10 mg and 50 mg, single doses). Initial pneumonitis was attributed to irritant gases or soluble toxic components of particles. MIG-SS particle deposits were more persistent and lesions more severe, inhibition of phagocytosis or clearance and damage to epithelial cells being associated with possible toxic effects in macrophages. Both types of particle caused alveolar epithelial thickening, with proliferation of granular pneumocytes and exudation of lamellar material. Foam cells appeared in alveoli. Long-term effects (80-300 days) involved formation of nodular aggregates of particle-laden macrophages. Giant cells were formed. Nodules containing MIG-SS material were irregular and surrounded by collapsed and thickened epithelium. Soluble chromium or nickel constituents are cited as probable active agents producing effects resembling those of cytotoxic non-fibrogenic dusts, e.g., soluble silicas . MMA-MS particles produced low-grade fibrotic ( collagenised ) changes.

Indium Lung Disease

PubMed Central

Nakano, Makiko; Omae, Kazuyuki; Takeuchi, Koichiro; Chonan, Tatsuya; Xiao, Yong-long; Harley, Russell A.; Roggli, Victor L.; Hebisawa, Akira; Tallaksen, Robert J.; Trapnell, Bruce C.; Day, Gregory A.; Saito, Rena; Stanton, Marcia L.; Suarthana, Eva; Kreiss, Kathleen

2012-01-01

Background: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. Methods: To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. Results: Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. Conclusions: Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies. PMID:22207675

Use of Submicron Vaterite Particles Serves as an Effective Delivery Vehicle to the Respiratory Portion of the Lung

PubMed Central

Gusliakova, Olga; Atochina-Vasserman, Elena N.; Sindeeva, Olga; Sindeev, Sergey; Pinyaev, Sergey; Pyataev, Nikolay; Revin, Viktor; Sukhorukov, Gleb B.; Gorin, Dmitry; Gow, Andrew J.

2018-01-01

Nano- and microencapsulation has proven to be a useful technique for the construction of drug delivery vehicles for use in vascular medicine. However, the possibility of using these techniques within the lung as an inhalation delivery mechanism has not been previously considered. A critical element of particle delivery to the lung is the degree of penetrance that can be achieved with respect to the airway tree. In this study we examined the effectiveness of near infrared (NIR) dye (Cy7) labeled calcium carbonate (vaterite) particles of 3.15, 1.35, and 0.65 μm diameter in reaching the respiratory portion of the lung. First of all, it was shown that, interaction vaterite particles and the components of the pulmonary surfactant occurs a very strong retardation of the recrystallization and dissolution of the particles, which can subsequently be used to create systems with a prolonging release of bioactive substances after the particles penetrate the distal sections of the lungs. Submicro- and microparticles, coated with Cy7 labeled albumin as a model compound, were delivered to mouse lungs via tracheostomy with subsequent imaging performed 24, 48, and 72 h after delivery by in vivo fluorescence. 20 min post administration particles of all three sizes were visible in the lung, with the deepest penetrance observed with 0.65 μm particles. In vivo biodistribution was confirmed by fluorescence tomography imaging of excised organs post 72 h. Laser scanning confocal microscopy shows 0.65 μm particles reaching the alveolar space. The delivery of fluorophore to the blood was assessed using Cy7 labeled 0.65 μm particles. Cy7 labeled 0.65 μm particles efficiently delivered fluorescent material to the blood with a peak 3 h after particle administration. The pharmacokinetics of NIR fluorescence dye will be shown. These studies establish that by using 0.65 μm particles loaded with Cy7 we can efficiently access the respiratory portion of the lung, which represents a potentially efficient delivery mechanism for both the lung and the vasculature.

Use of Submicron Vaterite Particles Serves as an Effective Delivery Vehicle to the Respiratory Portion of the Lung.

PubMed

Gusliakova, Olga; Atochina-Vasserman, Elena N; Sindeeva, Olga; Sindeev, Sergey; Pinyaev, Sergey; Pyataev, Nikolay; Revin, Viktor; Sukhorukov, Gleb B; Gorin, Dmitry; Gow, Andrew J

2018-01-01

Nano- and microencapsulation has proven to be a useful technique for the construction of drug delivery vehicles for use in vascular medicine. However, the possibility of using these techniques within the lung as an inhalation delivery mechanism has not been previously considered. A critical element of particle delivery to the lung is the degree of penetrance that can be achieved with respect to the airway tree. In this study we examined the effectiveness of near infrared (NIR) dye (Cy7) labeled calcium carbonate (vaterite) particles of 3.15, 1.35, and 0.65 μm diameter in reaching the respiratory portion of the lung. First of all, it was shown that, interaction vaterite particles and the components of the pulmonary surfactant occurs a very strong retardation of the recrystallization and dissolution of the particles, which can subsequently be used to create systems with a prolonging release of bioactive substances after the particles penetrate the distal sections of the lungs. Submicro- and microparticles, coated with Cy7 labeled albumin as a model compound, were delivered to mouse lungs via tracheostomy with subsequent imaging performed 24, 48, and 72 h after delivery by in vivo fluorescence. 20 min post administration particles of all three sizes were visible in the lung, with the deepest penetrance observed with 0.65 μm particles. In vivo biodistribution was confirmed by fluorescence tomography imaging of excised organs post 72 h. Laser scanning confocal microscopy shows 0.65 μm particles reaching the alveolar space. The delivery of fluorophore to the blood was assessed using Cy7 labeled 0.65 μm particles. Cy7 labeled 0.65 μm particles efficiently delivered fluorescent material to the blood with a peak 3 h after particle administration. The pharmacokinetics of NIR fluorescence dye will be shown. These studies establish that by using 0.65 μm particles loaded with Cy7 we can efficiently access the respiratory portion of the lung, which represents a potentially efficient delivery mechanism for both the lung and the vasculature.

Silica particles cause NADPH oxidase–independent ROS generation and transient phagolysosomal leakage

PubMed Central

Joshi, Gaurav N.; Goetjen, Alexandra M.; Knecht, David A.

2015-01-01

Chronic inhalation of silica particles causes lung fibrosis and silicosis. Silica taken up by alveolar macrophages causes phagolysosomal membrane damage and leakage of lysosomal material into the cytoplasm to initiate apoptosis. We investigated the role of reactive oxygen species (ROS) in this membrane damage by studying the spatiotemporal generation of ROS. In macrophages, ROS generated by NADPH oxidase 2 (NOX2) was detected in phagolysosomes containing either silica particles or nontoxic latex particles. ROS was only detected in the cytoplasm of cells treated with silica and appeared in parallel with an increase in phagosomal ROS, as well as several hours later associated with mitochondrial production of ROS late in apoptosis. Pharmacological inhibition of NOX activity did not prevent silica-induced phagolysosomal leakage but delayed it. In Cos7 cells, which do not express NOX2, ROS was detected in silica-containing phagolysosomes that leaked. ROS was not detected in phagolysosomes containing latex particles. Leakage of silica-containing phagolysosomes in both cell types was transient, and after resealing of the membrane, endolysosomal fusion continued. These results demonstrate that silica particles can generate phagosomal ROS independent of NOX activity, and we propose that this silica-generated ROS can cause phagolysosomal leakage to initiate apoptosis. PMID:26202463

Incidence of lung cancer among subway drivers in Stockholm.

PubMed

Gustavsson, Per; Bigert, Carolina; Pollán, Marina

2008-07-01

Very high levels of airborne particles have been detected in the subway system in Stockholm. Subway particles are more toxic to DNA in cultured human lung cells than particles from ambient air. This cohort comprised all men in Stockholm County who were gainfully employed in 1970. They were followed for cancer incidence until 1989. Lung cancer cases were identified from the national cancer register. Subway drivers were identified from the census in 1970. The reference cohort comprised all transport and communication workers in Stockholm. There were nine cases of lung cancer among the subway drivers, giving a SIR of 0.82 (95% confidence interval 0.38-1.56). The lung cancer incidence was not increased among the subway drivers. The study gives some evidence against the hypothesis that subway particles would be more potent in inducing lung cancer than particles in ambient air. (c) 2008 Wiley-Liss, Inc.

Dissociation of Hexavalent Chromium from Sanded Paint Particles into a Simulated Lung Fluid

DTIC Science & Technology

2006-06-01

was simulated with a porcine based mucin . Sanded particles were collected based on particle size into the impactor’s six petri dishes, which...was used to imitate particle deposition onto a layer of lung fluid. The lung fluid was simulated with a porcine based mucin . Sanded particles were...documented as those directly related to corrosion control such as maintenance, repair, treatment , washing, painting, depainting, and sealing. These

Biasing left-right particle distribution via sideways bending of the upper body

NASA Astrophysics Data System (ADS)

Bernate, Jorge A.; Lin, Eleanor; Fahrig, Rebecca; Milla, Carlos; Iaccarino, Gianluca; Shaqfeh, Eric S. G.

2014-11-01

The ability to target therapeutic aerosols to specific regions of the lungs would result in more effective treatment of localized pulmonary diseases and may also prove beneficial in systemic delivery via the airways. Previous computational and experimental studies have shown that large particles disproportionately enter the left lung. The observed uneven distribution occurs because the trachea bends to the right just before the first bifurcation, causing particles with sufficient inertia to enter the left main bronchus. Via CT imaging, we have shown that it is possible to modify the normal configuration of the trachea by bending sideways. Bending to the right and left results in configurations in which the trachea monotonically and smoothly bends to the first bifurcation. In the left-bent configuration, inertial particles will tend to accumulate towards the right side of the trachea and enter the right main bronchus, and conversely for the right-bent configuration. In this talk, we will present our results of Large-Eddy simulations and particle tracking showing regional deposition and ventilation as a function of the Reynolds and Stokes numbers for realistic models of the upright and bent configurations of an adult human subject.

Whole DNA methylome profiling in mice exposed to secondhand smoke.

PubMed

Tommasi, Stella; Zheng, Albert; Yoon, Jae-In; Li, Arthur Xuejun; Wu, Xiwei; Besaratinia, Ahmad

2012-11-01

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease.

Deposition of ultrafine (nano) particles in the human lung.

PubMed

Asgharian, Bahman; Price, Owen T

2007-10-01

Increased production of industrial devices constructed with nanostructured materials raises the possibility of environmental and occupational human exposure with consequent adverse health effects. Ultrafine (nano) particles are suspected of having increased toxicity due to their size characteristics that serve as carrier transports. For this reason, it is critical to refine and improve existing deposition models in the nano-size range. A mathematical model of nanoparticle transport by airflow convection, axial diffusion, and convective mixing (dispersion) was developed in realistic stochastically generated asymmetric human lung geometries. The cross-sectional averaged convective-diffusion equation was solved analytically to find closed-form solutions for particle concentration and losses per lung airway. Airway losses were combined to find lobar, regional, and total lung deposition. Axial transport by diffusion and dispersion was found to have an effect on particle deposition. The primary impact was in the pulmonary region of the lung for particles larger than 10 nm in diameter. Particles below 10 nm in diameter were effectively removed from the inhaled air in the tracheobronchial region with little or no penetration into the pulmonary region. Significant variation in deposition was observed when different asymmetric lung geometries were used. Lobar deposition was found to be highest in the left lower lobe. Good agreement was found between predicted depositions of ultrafine (nano) particles with measurements in the literature. The approach used in the proposed model is recommended for more realistic assessment of regional deposition of diffusion-dominated particles in the lung, as it provides a means to more accurately relate exposure and dose to lung injury and other biological responses.

A modeling study of the effect of gravity on airflow distribution and particle deposition in the lung.

PubMed

Asgharian, Bahman; Price, Owen; Oberdörster, Gunter

2006-06-01

Inhalation of particles generated as a result of thermal degradation from fire or smoke, as may occur on spacecraft, is of major health concern to space-faring countries. Knowledge of lung airflow and particle transport under different gravity environments is required to addresses this concern by providing information on particle deposition. Gravity affects deposition of particles in the lung in two ways. First, the airflow distribution among airways is changed in different gravity environments. Second, particle losses by sedimentation are enhanced with increasing gravity. In this study, a model of airflow distribution in the lung that accounts for the influence of gravity was used for a mathematical description of particle deposition in the human lung to calculate lobar, regional, and local deposition of particles in different gravity environments. The lung geometry used in the mathematical model contained five lobes that allowed the assessment of lobar ventilation distribution and variation of particle deposition. At zero gravity, it was predicted that all lobes of the lung expanded and contracted uniformly, independent of body position. Increased gravity in the upright position increased the expansion of the upper lobes and decreased expansion of the lower lobes. Despite a slight increase in predicted deposition of ultrafine particles in the upper lobes with decreasing gravity, deposition of ultrafine particles was generally predicted to be unaffected by gravity. Increased gravity increased predicted deposition of fine and coarse particles in the tracheobronchial region, but that led to a reduction or even elimination of deposition in the alveolar region for coarse particles. The results from this study show that existing mathematical models of particle deposition at 1 G can be extended to different gravity environments by simply correcting for a gravity constant. Controlled studies in astronauts on future space missions are needed to validate these predictions.

Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.

PubMed

Kim, Ha Ryong; Lee, Kyuhong; Park, Chang We; Song, Jeong Ah; Shin, Da Young; Park, Yong Joo; Chung, Kyu Hyuck

2016-03-01

Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form of aerosol particles would induce an airway barrier injury via ROS, release fibrotic inflammatory cytokines, and trigger a wound-healing response, leading to pulmonary fibrosis. A simultaneous state of tissue destruction and inflammation caused by PHMG-phosphate had whipped up a "perfect storm" in the respiratory tract.

Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

PubMed

Asgharian, B; Price, O T; Oldham, M; Chen, Lung-Chi; Saunders, E L; Gordon, T; Mikheev, V B; Minard, K R; Teeguarden, J G

2014-12-01

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Unsafe Air

ERIC Educational Resources Information Center

Journal of College Science Teaching, 2005

2005-01-01

A team of researchers who just finished analyzing 20 years of data from locales around Los Angeles said that particulate matter less than 2.5 micrometers in diameter poses the greatest risk of causing early death as it can penetrate deep into the lungs and sometimes even enter the bloodstream. Such particles are often found in smoke, vehicle…

Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation.

PubMed

Lu, Senlin; Duffin, Rodger; Poland, Craig; Daly, Paul; Murphy, Fiona; Drost, Ellen; Macnee, William; Stone, Vicki; Donaldson, Ken

2009-02-01

There has been concern regarding risks from inhalation exposure to nanoparticles (NPs). The large number of particles requiring testing means that alternative approaches to animal testing are needed. We set out to determine whether short-term in vitro assays that assess intrinsic oxidative stress potential and membrane-damaging potency of a panel of metal oxide NPs can be used to predict their inflammogenic potency. For a panel of metal oxide NPs, we investigated intrinsic free radical generation, oxidative activity in an extracellular environment, cytotoxicity to lung epithelial cells, hemolysis, and inflammation potency in rat lungs. All exposures were carried out at equal surface area doses. Only nickel oxide (NiO) and alumina 2 caused significant lung inflammation when instilled into rat lungs at equal surface area, suggesting that these two had extra surface reactivity. We observed significant free radical generation with 4 of 13 metal oxides, only one of which was inflammogenic. Only 3 of 13 were significantly hemolytic, two of which were inflammogenic. Potency in generating free radicals in vitro did not predict inflammation, whereas alumina 2 had no free radical activity but was inflammogenic. The hemolysis assay was correct in predicting the proinflammatory potential of 12 of 13 of the particles examined. Using a battery of simple in vitro tests, it is possible to predict the inflammogenicity of metal oxide NPs, although some false-positive results are likely. More research using a larger panel is needed to confirm the efficacy and generality of this approach for metal oxide NPs.

Development of a Guinea Pig Lung Deposition Model

DTIC Science & Technology

2016-01-01

Development of a Guinea Pig Lung Deposition Model Distribution Statement A. Approved for public release; distribution is unlimited. January...4 Figure 2. Particle deposition in the lung of the guinea pig via endotracheal breathing...Particle deposition in the lungs of guinea pigs via nasal breathing. ......................................... 12 v PREFACE The research work

Importance of indoor dust biological ultrafine particles in the pathogenesis of chronic inflammatory lung diseases

PubMed Central

Kim, Yoon-Keun; Kang, Tae Soo; Kim, You-Young

2017-01-01

The role of infectious agents in the etiology of inflammatory diseases once believed to be non-infectious is increasingly being recognized. Many bacterial components in the indoor dust can evoke inflammatory lung diseases. Bacteria secrete nanometer-sized vesicles into the extracellular milieu, so-called extracellular vesicles (EV). which are pathophysiologically related to inflammatory diseases. Microbiota compositions in the indoor dust revealed the presence of both Gram-negative and Gram-positive bacteria. Escherichia coli is a model organism of Gram-negative Enterobacteriaceae. The repeated inhalation of E. coli-derived EVs caused neutrophilic inflammation and emphysema in a dose-dependent manner. The emphysema induced by E. coli-derived EVs was partially eliminated by the absence of Interferon-gamma or interleukin-17, suggesting that Th1 and/or Th17 cell responses are important in the emphysema development. Meanwhile, the repeated inhalation of Staphylococcus aureus-derived EVs did not induce emphysema, although they induced neutrophilic inflammation in the lung. In terms of microbial EV compositions in the indoor dust, genera Pseudomonas, Acinetobacter, Enterobacter, and Staphylococcus were dominant. As for the clinical significance of sensitization to EVs in the indoor dust, EV sensitization was closely associated with asthma, chronic obstructive pulmonary disorder (COPD), and lung cancer. These data indicate that biological ultrafine particles in the indoor dust, which are mainly composed of microbial EVs, are important in the pathogenesis of chronic lung diseases associated with neutrophilic inflammation. Taken together, microbial EVs in the indoor dust are an important diagnostic and therapeutic target for the control of chronic lung diseases, such as asthma, COPD, and lung cancer. PMID:29161804

Importance of indoor dust biological ultrafine particles in the pathogenesis of chronic inflammatory lung diseases.

PubMed

Yang, Jinho; Kim, Yoon-Keun; Kang, Tae Soo; Jee, Young-Koo; Kim, You-Young

2017-01-01

The role of infectious agents in the etiology of inflammatory diseases once believed to be non-infectious is increasingly being recognized. Many bacterial components in the indoor dust can evoke inflammatory lung diseases. Bacteria secrete nanometer-sized vesicles into the extracellular milieu, so-called extracellular vesicles (EV). which are pathophysiologically related to inflammatory diseases. Microbiota compositions in the indoor dust revealed the presence of both Gram-negative and Gram-positive bacteria. Escherichia coli is a model organism of Gram-negative Enterobacteriaceae. The repeated inhalation of E. coli-derived EVs caused neutrophilic inflammation and emphysema in a dose-dependent manner. The emphysema induced by E. coli-derived EVs was partially eliminated by the absence of Interferon-gamma or interleukin-17, suggesting that Th1 and/or Th17 cell responses are important in the emphysema development. Meanwhile, the repeated inhalation of Staphylococcus aureus-derived EVs did not induce emphysema, although they induced neutrophilic inflammation in the lung. In terms of microbial EV compositions in the indoor dust, genera Pseudomonas, Acinetobacter, Enterobacter, and Staphylococcus were dominant. As for the clinical significance of sensitization to EVs in the indoor dust, EV sensitization was closely associated with asthma, chronic obstructive pulmonary disorder (COPD), and lung cancer. These data indicate that biological ultrafine particles in the indoor dust, which are mainly composed of microbial EVs, are important in the pathogenesis of chronic lung diseases associated with neutrophilic inflammation. Taken together, microbial EVs in the indoor dust are an important diagnostic and therapeutic target for the control of chronic lung diseases, such as asthma, COPD, and lung cancer.

Relationship of structure and function of the avian respiratory system to disease susceptibility.

PubMed

Fedde, M R

1998-08-01

The avian respiratory system exchanges oxygen and carbon dioxide between the gas and the blood utilizing a relatively small, rigid, flow-through lung, and a system of air sacs that act as bellows to move the gas through the lung. Gas movement through the paleopulmonic parabronchi, the main gas exchanging bronchi, in the lung is in the same direction during both inspiration and expiration, i.e., from the mediodorsal secondary bronchi to the medioventral secondary bronchi. During inspiration, acceleration of the gas at the segmentum accelerans of the primary bronchus increases gas velocity so it does not enter the medioventral secondary bronchi. During expiration, airway resistance is increased in he intrapulmonary primary bronchus because of dynamic compression causing gas to enter the mediodorsal secondary bronchi. Reduction in air flow velocity may decrease the efficiency of this aerodynamic valving and thereby decrease the efficiency of gas exchange. The convective gas flow in the avian parabronchus is orientated at a 90 degree angle with respect to the parabronchial blood flow; hence, the cross-current designation of this gas exchanger. With this design, the partial pressure of oxygen in the blood leaving the parabronchus can be higher than that in the gas exiting this structure, giving the avian lung a high gas exchange efficacy. The relationship of the partial pressure of oxygen in the moist inspired gas to that in the blood leaving the lung is dependent on he rate of ventilation. A low ventilation rate may produce a ow oxygen partial pressure in part of the parabronchus, thereby inducing hypoxic vasoconstriction in the pulmonary arterioles supplying this region. Inhaled foreign particles are removed by nasal mucociliary action, by escalator in the trachea, primary bronchi, and secondary bronchi. Small particles that enter parabronchi appear to be phagocytized by the epithelial cells in eh atria and infundibulum. These particles can e transported to interstitial macrophages but the disposition of the particles from this site is unknown. The predominant site of respiratory infections in the caudal air sacs, compared to other parts of the respiratory system, can be explained by the gas flow pathway and the mechanisms present in the parabronchi for particle removal.

Substance deposition assessment in obstructed pulmonary system through numerical characterization of airflow and inhaled particles attributes.

PubMed

Lalas, Antonios; Nousias, Stavros; Kikidis, Dimitrios; Lalos, Aris; Arvanitis, Gerasimos; Sougles, Christos; Moustakas, Konstantinos; Votis, Konstantinos; Verbanck, Sylvia; Usmani, Omar; Tzovaras, Dimitrios

2017-12-20

Chronic obstructive pulmonary disease (COPD) and asthma are considered as the two most widespread obstructive lung diseases, whereas they affect more than 500 million people worldwide. Unfortunately, the requirement for detailed geometric models of the lungs in combination with the increased computational resources needed for the simulation of the breathing did not allow great progress to be made in the past for the better understanding of inflammatory diseases of the airways through detailed modelling approaches. In this context, computational fluid dynamics (CFD) simulations accompanied by fluid particle tracing (FPT) analysis of the inhaled ambient particles are deemed critical for lung function assessment. Also they enable the understanding of particle depositions on the airways of patients, since these accumulations may affect or lead to inflammations. In this direction, the current study conducts an initial investigation for the better comprehension of particle deposition within the lungs. More specifically, accurate models of the airways obstructions that relate to pulmonary disease are developed and a thorough assessment of the airflow behavior together with identification of the effects of inhaled particle properties, such as size and density, is conducted. Our approach presents a first step towards an effective personalization of pulmonary treatment in regards to the geometric characteristics of the lungs and the in depth understanding of airflows within the airways. A geometry processing technique involving contraction algorithms is established and used to employ the different respiratory arrangements associated with lung related diseases that exhibit airways obstructions. Apart from the normal lung case, two categories of obstructed cases are examined, i.e. models with obstructions in both lungs and models with narrowings in the right lung only. Precise assumptions regarding airflow and deposition fraction (DF) over various sections of the lungs are drawn by simulating these distinct incidents through the finite volume method (FVM) and particularly the CFD and FPT algorithms. Moreover, a detailed parametric analysis clarifies the effects of the particles size and density in terms of regional deposition upon several parts of the pulmonary system. In this manner, the deposition pattern of various substances can be assessed. For the specific case of the unobstructed lung model most particles are detected on the right lung (48.56% of total, when the air flowrate is 12.6 L/min), a fact that is also true when obstructions arise symmetrically in both lungs (51.45% of total, when the air flowrate is 6.06 L/min and obstructions occur after the second generation). In contrast, when narrowings are developed on the right lung only, most particles are pushed on the left section (68.22% of total, when the air flowrate is 11.2 L/min) indicating that inhaled medication is generally deposited away from the areas of inflammation. This observation is useful when designing medical treatment of lung diseases. Furthermore, particles with diameters from 1 μm to 10 μm are shown to be mainly deposited on the lower airways, whereas particles with diameters of 20 μm and 30 μm are mostly accumulated in the upper airways. As a result, the current analysis indicates increased DF levels in the upper airways when the particle diameter is enlarged. Additionally, when the particles density increases from 1000 Kg/m 3 to 2000 Kg/m 3 , the DF is enhanced on every generation and for all cases investigated herein. The results obtained by our simulations provide an accurate and quantitative estimation of all important parameters involved in lung modeling. The treatment of respiratory diseases with inhaled medical substances can be advanced by the clinical use of accurate CFD and FPT simulations and specifically by evaluating the deposition of inhaled particles in a regional oriented perspective in regards to different particle sizes and particle densities. Since a drug with specific characteristics (i.e. particle size and density) exhibits maximum deposition on particular lung areas, the current study provides initial indications to a qualified physician for proper selection of medication.

Study on emission characteristics of hybrid bus under driving cycles in typical Chinese city

NASA Astrophysics Data System (ADS)

Xie, Yongdong; Xu, Guangju

2017-09-01

In this study, hybrid city bus was taken as the research object, through the vehicle drum test, the vehicle emissions of hybrid bus, the transient emissions of gas pollutants, as well as the particle size and number distribution were surveyed. The results of the studies are listed as follows: First, compared to traditional fuel bus, hybrid bus could reduce about 44% of the NOx emissions, 33% of the total hydrocarbon emissions, and 51% of the particles emissions. Furthermore, the distribution of particles number concentration of test vehicle became high in middle and low in both sides. More specifically, the particle number concentration was mainly concentrated in the range from 0.021 to 0.755μm, the maximum was 0.2μm, and particle size of particulate matter (PM) less than 1.2μm accounted for 95% of the total number concentration. Particulate mass concentration was increased with increment of particle size, and the maximum of particulate mass (PM) concentration was 6.2μm. On average, whether traditional fuel bus or hybrid bus, the particle size of particulate matter(PM) less than 2.5μm accounted for more than 98% in the particles emission. It is found that the particles are more likely to deposit to the lung, respiratory bronchioles and alveoli, causing respiratory and lung diseases. Therefore, how to control the PM emissions of hybrid bus is the key factor of the study.

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

NASA Astrophysics Data System (ADS)

Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

2016-06-01

Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

Role of inflammation in cardiopulmonary health effects of PM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donaldson, Ken; Mills, Nicholas; MacNee, William

2005-09-01

The relationship between increased exposure to PM and adverse cardiovascular effects is well documented in epidemiological studies. Inflammation in the lungs, caused by deposited particles, can be seen as a key process that could mediate adverse effects on the cardiovascular system. There are at least three potential pathways that could lead from pulmonary inflammation to adverse cardiovascular effects. Firstly, inflammation in the lung could lead to systemic inflammation, which is well known to be linked to sudden death from cardiovascular causes. Systemic inflammation can lead to destabilization by activation of inflammatory processes in atheromatous plaques. Secondly, inflammation can cause anmore » imbalance in coagulation factors that favor propagation of thrombi if thrombosis is initiated. Thirdly, inflammation could affect the autonomic nervous system activity in ways that could lead to alterations in the control of heart rhythm which could culminate in fatal dysrhythmia.« less

Biochemical studies of rat lung following exposure to potassium dichromate or chromium-rich welding fume particles.

PubMed

White, L R; Hunt, J; Richards, R J; Eik-Nes, K B

1982-04-01

Rats were examined for biochemical changes at the lung surface and in lung tissue 1, 4, and 13 weeks after a single instillation of the soluble of insoluble fraction of stainless steel welding particles, or potassium dichromate containing concentrations of hexavalent chromium (CrVI) equivalent to those found in the welding particles. Most of the toxicity of the welding particles 1 week after instillation could be related to the content of soluble CrVI, though the insoluble particles also produced changes at the alveolar surface. The regression of inflammatory changes 4 and 13 weeks after instillation was probably due to the removal of soluble components such as CrVI from the lung.

Acute and subacute pulmonary toxicity caused by a single intratracheal instillation of colloidal silver nanoparticles in mice: pathobiological changes and metallothionein responses.

PubMed

Kaewamatawong, Theerayuth; Banlunara, Wijit; Maneewattanapinyo, Pattwat; Thammachareon, Chuchaat; Ekgasit, Sanong

2014-01-01

To study the acute and subacute pulmonary toxicity of colloidal silver nanoparticles (Ag-NPs), 0 or 100 ppm of Ag-NPs were instilled intratracheally in mice. Cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF) and histological alterations were determined 1, 3, 7, 15, and 30 days after instillation. Ag-NPs induced moderate pulmonary inflammation and injury on BALF indices during the acute period; however, these changes gradually regressed in a time-dependent manner. Concomitant histopathological and laminin immunohistochemical findings generally correlated to BALF data. Superoxide dismutase and metallothionein expression occurred in particle-laden macrophages and alveolar epithelial cells, which correlated to lung lesions in mice treated with Ag-NPs. These findings suggest that instillation of Ag-NPs causes transient moderate acute lung inflammation and tissue damage. Oxidative stress may underlie the induction of injury to lung tissue. Moreover, the expression of metallothionein in tissues indicated the protective response to exposure to Ag-NPs.

The role of hypoxia inducible factor-1α in the increased MMP-2 and MMP-9 production by human monocytes exposed to nickel nanoparticles.

PubMed

Wan, Rong; Mo, Yiqun; Chien, Sufan; Li, Yihua; Li, Yixin; Tollerud, David J; Zhang, Qunwei

2011-12-01

Nickel is an important economic commodity, but it can cause skin sensitization and may cause lung diseases such as lung fibrosis, pneumonitis, bronchial asthma and lung cancer. With development of nanotechnology, nano-sized nickel (Nano-Ni) and nano-sized titanium dioxide (Nano-TiO₂) particles have been developed and produced for many years with new formulations and surface properties to meet novel demands. Our previous studies have shown that Nano-Ni instilled into rat lungs caused a greater inflammatory response as compared with standard-sized nickel (5 μm) at equivalent mass concentrations. Nano-Ni caused a persistent high level of inflammation in lungs even at low doses. Recently, several studies have shown that nanoparticles can translocate from the lungs to the circulatory system. To evaluate the potential systemic effects of metal nanoparticles, we compared the effects of Nano-Ni and Nano-TiO₂ on matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) gene expression and activity. Our results showed that exposure of human monocyte U937 to Nano-Ni caused dose- and time- dependent increase in MMP-2 and MMP-9 mRNA expression and pro-MMP-2 and pro-MMP-9 activity, but Nano-TiO₂ did not. Nano-Ni also caused dose- and time- related increase in tissue inhibitor of metalloproteinases 1 (TIMP-1), but Nano-TiO₂ did not. To determine the potential mechanisms involved, we measured the expression of hypoxia inducible factor 1α (HIF-1α) in U937 cells exposed to Nano-Ni and Nano-TiO₂. Our results showed that exposure to Nano-Ni caused HIF-1α accumulation in the nucleus. Furthermore, pre-treatment of U937 cells with heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), prior to exposure to Nano-Ni significantly abolished Nano-Ni-induced MMP-2 and MMP-9 mRNA upregulation and increased pro-MMP-2 and pro-MMP-9 activity. Our results suggest that HIF-1α accumulation may be involved in the increased MMP-2 and MMP-9 production in U937 cells exposed to Nano-Ni.

Particles from wood smoke and road traffic differently affect the innate immune system of the lung.

PubMed

Samuelsen, Mari; Cecilie Nygaard, Unni; Løvik, Martinus

2009-09-01

The effect of particles from road traffic and wood smoke on the innate immune response in the lung was studied in a lung challenge model with the intracellular bacterium Listeria monocytogenes. Female Balb/cA mice were instilled intratracheally with wood smoke particles, particles from road traffic collected during winter (studded tires used; St+), and during autumn (no studded tires; St-), or diesel exhaust particles (DEP). Simultaneously with, and 1 or 7 days after particle instillation, 10(5) bacteria were inoculated intratracheally. Bacterial numbers in the lungs and spleen 1 day after Listeria challenge were determined, as an indicator of cellular activation. In separate experiments, bronchoalveolar lavage (BAL) fluid was collected 4 h and 24 h after particle instillation. All particles tested reduced the numbers of bacteria in the lung 24 h after bacterial inoculation. When particles were given simultaneously with Listeria, the reduction was greatest for DEP, followed by St+ and St-, and least for wood smoke particles. Particle effects were no longer apparent after 7 days. Neutrophil numbers in BAL fluid were increased for all particle exposed groups. St+ and St- induced the highest levels of IL-1beta, MIP-2, MCP-1, and TNF-alpha, followed by DEP, which induced no TNF-alpha. In contrast, wood smoke particles only increased lactate dehydrogenase (LDH) activity, indicating a cytotoxic effect of these particles. In conclusion, all particles tested activated the innate immune system as determined with Listeria. However, differences in kinetics of anti-Listeria activity and levels of proinflammatory mediators point to cellular activation by different mechanisms.

In vitro particulate matter exposure causes direct and lung-mediated indirect effects on cardiomyocyte function.

PubMed

Gorr, Matthew W; Youtz, Dane J; Eichenseer, Clayton M; Smith, Korbin E; Nelin, Timothy D; Cormet-Boyaka, Estelle; Wold, Loren E

2015-07-01

Particulate matter (PM) exposure induces a pathological response from both the lungs and the cardiovascular system. PM is capable of both manifestation into the lung epithelium and entrance into the bloodstream. Therefore, PM has the capacity for both direct and lung-mediated indirect effects on the heart. In the present studies, we exposed isolated rat cardiomyocytes to ultrafine particulate matter (diesel exhaust particles, DEP) and examined their contractile function and calcium handling ability. In another set of experiments, lung epithelial cells (16HBE14o- or Calu-3) were cultured on permeable supports that allowed access to both the basal (serosal) and apical (mucosal) media; the basal media was used to culture cardiomyocytes to model the indirect, lung-mediated effects of PM on the heart. Both the direct and indirect treatments caused a reduction in contractility as evidenced by reduced percent sarcomere shortening and reduced calcium handling ability measured in field-stimulated cardiomyocytes. Treatment of cardiomyocytes with various anti-oxidants before culture with DEP was able to partially prevent the contractile dysfunction. The basal media from lung epithelial cells treated with PM contained several inflammatory cytokines, and we found that monocyte chemotactic protein-1 was a key trigger for cardiomyocyte dysfunction. These results indicate the presence of both direct and indirect effects of PM on cardiomyocyte function in vitro. Future work will focus on elucidating the mechanisms involved in these separate pathways using in vivo models of air pollution exposure. Copyright © 2015 the American Physiological Society.

Whole DNA methylome profiling in mice exposed to secondhand smoke

PubMed Central

Tommasi, Stella; Zheng, Albert; Yoon, Jae-In; Li, Arthur Xuejun; Wu, Xiwei; Besaratinia, Ahmad

2012-01-01

Aberration of DNA methylation is a prime epigenetic mechanism of carcinogenesis. Aberrant DNA methylation occurs frequently in lung cancer, with exposure to secondhand smoke (SHS) being an established risk factor. The causal role of SHS in the genesis of lung cancer, however, remains elusive. To investigate whether SHS can cause aberrant DNA methylation in vivo, we have constructed the whole DNA methylome in mice exposed to SHS for a duration of 4 mo, both after the termination of exposure and at ensuing intervals post-exposure (up to 10 mo). Our genome-wide and gene-specific profiling of DNA methylation in the lung of SHS-exposed mice revealed that all groups of SHS-exposed mice and controls share a similar pattern of DNA methylation. Furthermore, the methylation status of major repetitive DNA elements, including long-interspersed nuclear elements (LINE L1), intracisternal A particle long-terminal repeat retrotransposons (IAP-LTR), and short-interspersed nuclear elements (SINE B1), in the lung of all groups of SHS-exposed mice and controls remains comparable. The absence of locus-specific gain of DNA methylation and global loss of DNA methylation in the lung of SHS-exposed mice within a timeframe that precedes neoplastic-lesion formation underscore the challenges of lung cancer biomarker development. Identifying the initiating events that cause aberrant DNA methylation in lung carcinogenesis may help improve future strategies for prevention, early detection and treatment of this highly lethal disease. PMID:23051858

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-08-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles.

Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection.

PubMed Central

Castranova, V; Ma, J Y; Yang, H M; Antonini, J M; Butterworth, L; Barger, M W; Roberts, J; Ma, J K

2001-01-01

There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles. PMID:11544172

Radiation and Its Health Effects. AIO Red Paper #19.

ERIC Educational Resources Information Center

Duda, Terrie

Radiation has been a serious concern to individuals for over 100 years. A process by which an atomic nucleus emits particles to reach a more stable energy state, radiation harms living cells (usually by inhalation and absorption into the lungs) by causing abnormal cell function and structure. Man is constantly exposed to background radiation, both…

Mechanisms underlying the redistribution of particles among the lung's alveolar macrophages during alveolar phase clearance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lehnert, B.E.; Oritz, J.B.; Steinkamp, J.A.

1991-01-01

In order to obtain information about the particle redistribution phenomenon following the deposition of inhaled particles, as well as to obtain information about some of the mechanisms that may be operable in the redistribution of particles, lavaged lung free cell analyses and transmission electron microscopic (TEM) analyses of lung tissue and were performed using lungs from rats after they were subchronically exposed to aerosolized dioxide (TiO{sub 2}). TEM analyses indicated that the in situ autolysis of particle-containing Alveolar Macropages (AM) is one important mechanism involved in the redistribution of particles. Evidence was also obtained that indicated that the engulfment ofmore » one particle-containing phagocyte by another phagocyte also occurs. Another prominent mechanism of the particle redistribution phenomenon may be the in situ proliferation of particle-laden AM. We used the macrophage cell line J774A.1 as a surrogate for AM to investigate how different particulate loads in macrophages may affect their abilities to proliferate. These in vitro investigations indicated that the normal rate of proliferation of macrophages is essentially unaffected by the containment of relatively high particulate burdens. Overall, the results of our investigations suggest that in situ autolysis of particle-containing AM and the rephagocytosis of freed particles by other phagocytes, the phagocytosis of effete and disintegrating particle-containing phagocytes by other AM, and the in situ division of particle-containing AM are likely mechanisms that underlie the post-depositional redistribution of particles among the lung's AM during alveolar phase clearance. 19 refs., 8 figs., 2 tabs.« less

Impact of hydrogel nanoparticle size and functionalization on in vivo behavior for lung imaging and therapeutics

PubMed Central

Liu, Yongjian; Ibricevic-Richardson, Aida; Cohen, Joel A.; Cohen, Jessica L.; Gunsten, Sean P.; Fréchet, Jean M. J.; Walter, Michael J.; Welch, Michael J.; Brody, Steven L.

2009-01-01

Polymer chemistry offers the possibility of synthesizing multifunctional nanoparticles which incorporate moieties that enhance diagnostic and therapeutic targeting of cargo delivery to the lung. However, since rules for predicting particle behavior following modification are not well defined, it is essential that probes for tracking fate in vivo are also included. Accordingly, we designed polyacrylamide-based hydrogel particles of differing sizes, functionalized with a nona-arginine cell-penetrating peptide (Arg9), and labeled with imaging components to assess lung retention and cellular uptake after intratracheal administration. Radiolabeled microparticles (1–5 µm diameter) and nanoparticles (20–40 nm diameter) without and with Arg9 showed diffuse airspace distribution by positron emission tomography imaging. Biodistribution studies revealed that particle clearance and extrapulmonary distribution was, in part, size dependent. Microparticles were rapidly cleared by mucociliary routes but unexpectedly, also through the circulation. In contrast, nanoparticles had prolonged lung retention enhanced by Arg9 and were significantly restricted to the lung. For all particle types, uptake was predominant in alveolar macrophages, and, to a lesser extent, lung epithelial cells. In general, particles did not induce local inflammatory responses, with the exception of microparticles bearing Arg9. Whereas microparticles may be advantageous for short-term applications, nano-sized particles constitute an efficient high-retention and non-inflammatory vehicle for the delivery of diagnostic imaging agents and therapeutics to lung airspaces and alveolar macrophages that can be enhanced by Arg9. Importantly, our results show that minor particle modifications may significantly impact in vivo behavior within the complex environments of the lung, underscoring the need for animal modeling. PMID:19852512

The utility of electron microscopy in detecting asbestos fibers and particles in BALF in diffuse lung diseases.

PubMed

Kido, Takashi; Morimoto, Yasuo; Yatera, Kazuhiro; Ishimoto, Hiroshi; Ogoshi, Takaaki; Oda, Keishi; Yamasaki, Kei; Kawanami, Toshinori; Shimajiri, Shohei; Mukae, Hiroshi

2017-04-21

In patients with diffuse lung diseases, differentiating occupational lung diseases from other diseases is clinically important. However, the value of assessing asbestos and particles in bronchoalveolar lavage fluid (BALF) in diffuse lung diseases by electron microscopy (EM) remains unclear. We evaluated the utility of EM in detecting asbestos fibers and particles in patients with diffuse lung diseases. The BALF specimens of 107 patients with diffuse lung diseases were evaluated. First, detection of asbestos by EM and light microscopy (LM) were compared. Second, the detection of asbestos using surgically obtained lung tissues of 8 of 107 patients were compared with the results of EM and LM in BALF. Third, we compared the results of mineralogical components of particles in patients with (n = 48) and without (n = 59) a history of occupational exposure to inorganic dust. BALF asbestos were detected in 11 of 48 patients with a history of occupational exposure by EM; whereas asbestos as asbestos bodies (ABs) were detected in BALF in 4 of these 11 patients by LM. Eight of 107 patients in whom lung tissue samples were surgically obtained, EM detected BALF asbestos at a level of >1,000 fibers/ml in all three patients who had ABs in lung tissue samples by LM at a level of >1,000 fibers/g. The BALF asbestos concentration by EM and in lung tissue by LM were positively correlated. The particle fractions of iron and phosphorus were increased in patients with a history of occupational exposure and both correlated with a history of occupational exposure by a multiple regression analysis. EM using BALF seemed to be superior to LM using BALF and displayed a similar sensitivity to LM using surgically-obtained lung tissue samples in the detection of asbestos. Our results also suggest that detection of elements, such as iron and phosphorus in particles, is useful for evaluating occupational exposure. We conclude that the detection of asbestos and iron and phosphorus in particles in BALF by EM is very useful for the evaluation of occupational exposure.

Comparison of stainless and mild steel welding fumes in generation of reactive oxygen species.

PubMed

Leonard, Stephen S; Chen, Bean T; Stone, Samuel G; Schwegler-Berry, Diane; Kenyon, Allison J; Frazer, David; Antonini, James M

2010-11-03

Welding fumes consist of a wide range of complex metal oxide particles which can be deposited in all regions of the respiratory tract. The welding aerosol is not homogeneous and is generated mostly from the electrode/wire. Over 390,000 welders were reported in the U.S. in 2008 while over 1 million full-time welders were working worldwide. Many health effects are presently under investigation from exposure to welding fumes. Welding fume pulmonary effects have been associated with bronchitis, metal fume fever, cancer and functional changes in the lung. Our investigation focused on the generation of free radicals and reactive oxygen species from stainless and mild steel welding fumes generated by a gas metal arc robotic welder. An inhalation exposure chamber located at NIOSH was used to collect the welding fume particles. Our results show that hydroxyl radicals (.OH) were generated from reactions with H2O2 and after exposure to cells. Catalase reduced the generation of .OH from exposed cells indicating the involvement of H2O2. The welding fume suspension also showed the ability to cause lipid peroxidation, effect O2 consumption, induce H2O2 generation in cells, and cause DNA damage. Increase in oxidative damage observed in the cellular exposures correlated well with .OH generation in size and type of welding fumes, indicating the influence of metal type and transition state on radical production as well as associated damage. Our results demonstrate that both types of welding fumes are able to generate ROS and ROS-related damage over a range of particle sizes; however, the stainless steel fumes consistently showed a significantly higher reactivity and radical generation capacity. The chemical composition of the steel had a significant impact on the ROS generation capacity with the stainless steel containing Cr and Ni causing more damage than the mild steel. Our results suggest that welding fumes may cause acute lung injury. Since type of fume generated, particle size, and elapsed time after generation of the welding exposure are significant factors in radical generation and particle deposition these factors should be considered when developing protective strategies.

Comparison of stainless and mild steel welding fumes in generation of reactive oxygen species

PubMed Central

2010-01-01

Background Welding fumes consist of a wide range of complex metal oxide particles which can be deposited in all regions of the respiratory tract. The welding aerosol is not homogeneous and is generated mostly from the electrode/wire. Over 390,000 welders were reported in the U.S. in 2008 while over 1 million full-time welders were working worldwide. Many health effects are presently under investigation from exposure to welding fumes. Welding fume pulmonary effects have been associated with bronchitis, metal fume fever, cancer and functional changes in the lung. Our investigation focused on the generation of free radicals and reactive oxygen species from stainless and mild steel welding fumes generated by a gas metal arc robotic welder. An inhalation exposure chamber located at NIOSH was used to collect the welding fume particles. Results Our results show that hydroxyl radicals (.OH) were generated from reactions with H2O2 and after exposure to cells. Catalase reduced the generation of .OH from exposed cells indicating the involvement of H2O2. The welding fume suspension also showed the ability to cause lipid peroxidation, effect O2 consumption, induce H2O2 generation in cells, and cause DNA damage. Conclusion Increase in oxidative damage observed in the cellular exposures correlated well with .OH generation in size and type of welding fumes, indicating the influence of metal type and transition state on radical production as well as associated damage. Our results demonstrate that both types of welding fumes are able to generate ROS and ROS-related damage over a range of particle sizes; however, the stainless steel fumes consistently showed a significantly higher reactivity and radical generation capacity. The chemical composition of the steel had a significant impact on the ROS generation capacity with the stainless steel containing Cr and Ni causing more damage than the mild steel. Our results suggest that welding fumes may cause acute lung injury. Since type of fume generated, particle size, and elapsed time after generation of the welding exposure are significant factors in radical generation and particle deposition these factors should be considered when developing protective strategies. PMID:21047424

CFD simulation of aerosol delivery to a human lung via surface acoustic wave nebulization.

PubMed

Yousefi, Morteza; Pourmehran, Oveis; Gorji-Bandpy, Mofid; Inthavong, Kiao; Yeo, Leslie; Tu, Jiyuan

2017-12-01

Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier-Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes.

Particle Deposition in Human Lungs due to Varying Cross-Sectional Ellipticity of Left and Right Main Bronchi

NASA Astrophysics Data System (ADS)

Roth, Steven; Oakes, Jessica; Shadden, Shawn

2015-11-01

Particle deposition in the human lungs can occur with every breathe. Airbourne particles can range from toxic constituents (e.g. tobacco smoke and air pollution) to aerosolized particles designed for drug treatment (e.g. insulin to treat diabetes). The effect of various realistic airway geometries on complex flow structures, and thus particle deposition sites, has yet to be extensively investigated using computational fluid dynamics (CFD). In this work, we created an image-based geometric airway model of the human lung and performed CFD simulations by employing multi-domain methods. Following the flow simulations, Lagrangian particle tracking was used to study the effect of cross-sectional shape on deposition sites in the conducting airways. From a single human lung model, the cross-sectional ellipticity (the ratio of major and minor diameters) of the left and right main bronchi was varied systematically from 2:1 to 1:1. The influence of the airway ellipticity on the surrounding flow field and particle deposition was determined.

Lung cancer risk due to residential radon exposures: estimation and prevention.

PubMed

Truta, L A; Hofmann, W; Cosma, C

2014-07-01

Epidemiological studies proved that cumulative exposure to radon is the second leading cause of lung cancer, the world's most common cancer. The objectives of the present study are (i) to analyse lung cancer risk for chronic, low radon exposures based on the transformation frequency-tissue response (TF-TR) model formulated in terms of alpha particle hits in cell nuclei; (ii) to assess the percentage of attributable lung cancers in six areas of Transylvania where the radon concentration was measured and (iii) to point out the most efficient remediation measures tested on a pilot house in Stei, Romania. Simulations performed with the TF-TR model exhibit a linear dose-effect relationship for chronic, residential radon exposures. The fraction of lung cancer cases attributed to radon ranged from 9 to 28% for the investigated areas. Model predictions may represent a useful tool to complement epidemiological studies on lung cancer risk and to establish reasonable radiation protection regulations for human safety. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Correlation Analysis of PM10 and the Incidence of Lung Cancer in Nanchang, China.

PubMed

Zhou, Yi; Li, Lianshui; Hu, Lei

2017-10-19

Air pollution and lung cancer are closely related. In 2013, the World Health Organization listed outdoor air pollution as carcinogenic and regarded it as the most widespread carcinogen that humans are currently exposed to. Here, grey correlation and data envelopment analysis methods are used to determine the pollution factors causing lung cancer among residents in Nanchang, China, and identify population segments which are more susceptible to air pollution. This study shows that particulate matter with particle sizes below 10 micron (PM 10 ) is most closely related to the incidence of lung cancer among air pollution factors including annual mean concentrations of SO₂, NO₂, PM 10 , annual haze days, and annual mean Air Pollution Index/Air Quality Index (API/AQI). Air pollution has a greater impact on urban inhabitants as compared to rural inhabitants. When gender differences are considered, women are more likely to develop lung cancer due to air pollution. Smokers are more likely to suffer from lung cancer. These results provide a reference for the government to formulate policies to reduce air pollutant emissions and strengthen anti-smoking measures.

Correlation Analysis of PM10 and the Incidence of Lung Cancer in Nanchang, China

PubMed Central

Zhou, Yi; Li, Lianshui; Hu, Lei

2017-01-01

Air pollution and lung cancer are closely related. In 2013, the World Health Organization listed outdoor air pollution as carcinogenic and regarded it as the most widespread carcinogen that humans are currently exposed to. Here, grey correlation and data envelopment analysis methods are used to determine the pollution factors causing lung cancer among residents in Nanchang, China, and identify population segments which are more susceptible to air pollution. This study shows that particulate matter with particle sizes below 10 micron (PM10) is most closely related to the incidence of lung cancer among air pollution factors including annual mean concentrations of SO2, NO2, PM10, annual haze days, and annual mean Air Pollution Index/Air Quality Index (API/AQI). Air pollution has a greater impact on urban inhabitants as compared to rural inhabitants. When gender differences are considered, women are more likely to develop lung cancer due to air pollution. Smokers are more likely to suffer from lung cancer. These results provide a reference for the government to formulate policies to reduce air pollutant emissions and strengthen anti-smoking measures. PMID:29048397

Particulate pollution -- a biological dilemma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marrack, D.

Human epidemiological data from multiple studies on USA. and European populations have been reviewed extensively. The consensus supports a weak association between PM-10 particulate matter and cardio-pulmonary morbidity and mortality. It is consistent with factors in the particles comprising PM-10 causing the biological effects. PM-10 is treated as a precisely defined entity, which it is not! Ambient PM-10 particles have multiple sources, sizes 10m m, chemistry and surface area. The medical and biological effects are seen with the inhalation of a multi-media matrix of pollutants, often at elevated levels, a medical and biological problem. This paper addresses this biology, predominantlymore » determined by size and sources of PM reflecting particle chemistry and surface area, describing one mechanism by which inhaled fine particles provoke heart muscle dysfunction. Combustion-PM-2.5m m (C-PM-2.5) reach the alveoli with 70% + retention and are engulfed by pulmonary alveolar macrophages. These particles trigger chain reactions that lead to cardio-pulmonary morbidity. Their structure includes high absorptive capacity carbon, transition metal plaques, and silica components. PAH`s (Polyaromatic hydrocarbons) and other potentially toxic chemicals are extensively absorbed on them and are piggy-backed into macrophages without dilution by blood. PM-2.5`s trace amounts of soluble transition metal salts are important in the molecular and biological events leading to heart damage. Animal inhalation studies of C-PM-2.5 cause little cellular reaction in normal lungs. In lungs already irritated by other agents, C-PM-2.5 inhalation greatly aggravates the inflammatory response. The soluble transition-metals (Fe Salts) are the effector. The data are impressive and provides a robust scientific basis for more stringent regulations of ambient C-PM-2.5.« less

Environmental silica in badger lungs: a possible association with susceptibility to Mycobacterium bovis infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Higgins, D.A.; Kung, I.T.; Or, R.S.

1985-04-01

Badger lungs contain dark granular foci (0.2 to 2.0 mm) comprising aggregates of enlarged macrophages containing birefringent crystalline particles. Particles were examined from the lungs of three badgers; many were silicates and a significant number were pure silica (SiO/sub 2/). The particles and the accompanying pathology resembled mixed dust fibrosis and silicosis in humans, diseases associated with increased susceptibility to tuberculosis.

Activation of Transient Receptor Potential Ankyrin-1 (TRPA1) in Lung Cells by Wood Smoke Particulate Material

PubMed Central

Shapiro, Darien; Deering-Rice, Cassandra E.; Romero, Erin G.; Hughen, Ronald W.; Light, Alan R.; Veranth, John M.; Reilly, Christopher A.

2013-01-01

Cigarette smoke, diesel exhaust, and other combustion-derived particles activate the calcium channel transient receptor potential ankyrin-1 (TRPA1), causing irritation and inflammation in the respiratory tract. It was hypothesized that wood smoke particulate and select chemical constituents thereof would also activate TRPA1 in lung cells, potentially explaining the adverse effects of wood and other forms of biomass smoke on the respiratory system. TRPA1 activation was assessed using calcium imaging assays in TRPA1-overexpressing HEK-293 cells, mouse primary trigeminal neurons, and human adenocarcinoma (A549) lung cells. Particles from pine and mesquite smoke were less potent agonists of TRPA1 than an equivalent mass concentration of an ethanol extract of diesel exhaust particles; pine particles were comparable in potency to cigarette smoke condensate, and mesquite particles were the least potent. The fine particulate (PM<2.5 μm) of wood smoke were the most potent TRPA1 agonists and several chemical constituents of wood smoke particulate: 3,5-ditert-butylphenol, coniferaldehyde, formaldehyde, perinaphthenone, agathic acid, and isocupressic acid were TRPA1 agonists. Pine particulate activated TRPA1 in mouse trigeminal neurons and A549 cells in a concentration-dependent manner, which was inhibited by the TRPA1 antagonist HC-030031. TRPA1 activation by wood smoke particles occurred through the electrophile/oxidant-sensing domain (i.e., C621/C641/C665/K710), based on the inhibition of cellular responses when the particles were pre-treated with glutathione; a role for the menthol-binding site of TRPA1 (S873/T874) was demonstrated for 3,5-ditert-butylphenol. This study demonstrated that TRPA1 is a molecular sensor for wood smoke particulate and several chemical constituents thereof, in sensory neurons and A549 cells, suggesting that TRPA1 may mediate some of the adverse effects of wood smoke in humans. PMID:23541125

Isolation and Quantitative Estimation of Diesel Exhaust and Carbon Black Particles Ingested by Lung Epithelial Cells and Alveolar Macrophages In Vitro

EPA Science Inventory

A new procedure for isolating and estimating ingested carbonaceous diesel exhaust particles (DEP) or carbon black (CB) particles by lung epithelial cells and macrophages is described. Cells were incubated with DEP or CB to examine cell-particle interaction and ingestion. After va...

Air pollution as a determinant of rheumatoid arthritis.

PubMed

Sigaux, Johanna; Biton, Jérôme; André, Emma; Semerano, Luca; Boissier, Marie-Christophe

2018-03-07

Pollution has long been incriminated in many cardiovascular and respiratory diseases. More recently, studies evaluated the potential role for particulate pollutants in autoimmune diseases, including rheumatoid arthritis (RA). The incidence of RA was found to be higher in urban areas. Living near air pollution emitters was associated with higher risks of developing RA and of producing RA-specific autoantibodies. Nevertheless, no strong epidemiological evidence exists to link one or more specific air pollution particles to RA. The presence in the bronchi of lymphoid satellite islands (inducible bronchus-associated lymphoid tissue, iBALT) is strongly associated with both inflammatory lung disease and RA-associated lung disease. Diesel exhaust particles can stimulate iBALT formation. The induction by air pollution of an inflammatory environment with high citrullination levels in the lung may induce iBALT formation, thereby causing a transition toward a more specific immune response via the production of anti-citrullinated peptide antibodies. Air pollution not only triggers innate immune responses at the molecular level, increasing the levels of proinflammatory cytokines and reactive oxygen species, but is also involved in adaptive immune responses. Thus, via the aryl hydrocarbon receptor (AHR), diesel exhaust particles can trigger a T-cell switch to the Th17 profile. Finally, in the murine collagen-induced arthritis model, animals whose lymphocytes lack the AHR develop milder arthritis. Copyright © 2018. Published by Elsevier SAS.

Deposition of aerosol particles in human lungs: in vivo measurements and modeling

EPA Science Inventory

The deposition dose and site of inhaled particles within the lung are the key determinants in health risk assessment of particulate pollutants. Accurate dose estimation, however, is a formidable task because aerosol transport and deposition in the lung are governed by many factor...

Applicability of avidin protein coated mesoporous silica nanoparticles as drug carriers in the lung

NASA Astrophysics Data System (ADS)

van Rijt, S. H.; Bölükbas, D. A.; Argyo, C.; Wipplinger, K.; Naureen, M.; Datz, S.; Eickelberg, O.; Meiners, S.; Bein, T.; Schmid, O.; Stoeger, T.

2016-04-01

Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery.Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery. Electronic supplementary information (ESI) available: Synthesis of MSN particles. Characterisation of MSN particles (Fig. S1 and S2), DLS measurements of MSNs over time, lymphocyte and PMN cell count after MSN exposure (Fig. S3). Toxicity in BAL cytospins controls, phalloidin staining on BAL cytospins of MSN-NH2 exposed mice (Fig. S4), nanoparticle distribution in lung cryo-slices of Balb/c mice exposed to 100 μg MSNs (Fig. S5). Balb/c mice cryo-slices exposed to MSN-AVI for 1 or 7 days, co-stained with alveolar epithelial cell type 1 marker or with alveolar epithelial cell type 2 marker (Fig. S6), DiD selective labeling in a co-culture set-up (Fig. S7). See DOI: 10.1039/c5nr04119h

Association with Amino Acids Does Not Enhance Efficacy of Polymerized Liposomes As a System for Lung Gene Delivery

PubMed Central

Bandeira, Elga; Lopes-Pacheco, Miquéias; Chiaramoni, Nadia; Ferreira, Débora; Fernandez-Ruocco, Maria J.; Prieto, Maria J.; Maron-Gutierrez, Tatiana; Perrotta, Ramiro M.; de Castro-Faria-Neto, Hugo C.; Rocco, Patricia R. M.; Alonso, Silvia del Valle; Morales, Marcelo M.

2016-01-01

Development of improved drug and gene delivery systems directly into the lungs is highly desirable given the important burden of respiratory diseases. We aimed to evaluate the safety and efficacy of liposomes composed of photopolymerized lipids [1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine] associated with amino acids as vectors for gene delivery into the lungs of healthy animals. Lipopolymer vesicles, in particular, are more stable than other types of liposomes. In this study, lipopolymers were associated with l-arginine, l-tryptophan, or l-cysteine. We hypothesized that the addition of these amino acids would enhance the efficacy of gene delivery to the lungs by the lipopolymers. l-Arginine showed the highest association efficiency due to its positive charge and better surface interactions. None of the formulations caused inflammation or altered lung mechanics, suggesting that these lipopolymers can be safely administered as aerosols. All formulations were able to induce eGFP mRNA expression in lung tissue, but the addition of amino acids reduced delivery efficacy when compared with the simple lipopolymer particle. These results indicate that this system could be further explored for gene or drug delivery targeting lung diseases. PMID:27199766

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

PubMed

Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

2016-06-01

Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

Varied dose exposures to ultrafine particles in the motorcycle smoke cause kidney cell damages in male mice.

PubMed

Wardoyo, Arinto Y P; Juswono, Unggul P; Noor, Johan A E

2018-01-01

Ultrafine particles (UFPs) are one of motorcycle exhaust emissions which can penetrate the lung alveoli and deposit in the kidney. This study was aimed to investigate mice kidney cell physical damage (deformation) due to motorcycle exhaust emission exposures. The motorcycle exhaust emissions were sucked from the muffler with the rate of 33 cm 3 /s and passed through an ultrafine particle filter system before introduced into the mice exposure chamber. The dose concentration of the exhaust emissions was varied by setting the injected time of the 20s, 40s, 60s, 80s, and 100s. The mice were exposed to the smoke in the chamber for 100 s twice a day. The impact of the ultrafine particles on the kidney was observed by identifying the histological image of the kidney cell deformation using a microscope. The exposure was conducted for 10 days. The kidney observations were carried out on day 11. The results showed that there was a significant linear correlation between the total concentration of ultrafine particles deposited in the kidneys and the physical damage percentages. The increased concentrations of ultrafine particles caused larger cell deformation to the kidneys.

Relative effectiveness of HZE iron-56 particles for the induction of cytogenetic damage in vivo

NASA Technical Reports Server (NTRS)

Brooks, A.; Bao, S.; Rithidech, K.; Couch, L. A.; Braby, L. A.

2001-01-01

One of the risks of prolonged manned space flight is the exposure of astronauts to radiation from galactic cosmic rays, which contain heavy ions such as (56)Fe. To study the effects of such exposures, experiments were conducted at the Brookhaven National Laboratory by exposing Wistar rats to high-mass, high-Z, high-energy (HZE) particles using the Alternating Gradient Synchrotron (AGS). The biological effectiveness of (56)Fe ions (1000 MeV/nucleon) relative to low-LET gamma rays and high-LET alpha particles for the induction of chromosome damage and micronuclei was determined. The mitotic index and the frequency of chromosome aberrations were evaluated in bone marrow cells, and the frequency of micronuclei was measured in cells isolated from the trachea and the deep lung. A marked delay in the entry of cells into mitosis was induced in the bone marrow cells that decreased as a function of time after the exposure. The frequencies of chromatid aberrations and micronuclei increased as linear functions of dose. The frequency of chromosome aberrations induced by HZE particles was about 3.2 times higher than that observed after exposure to (60)Co gamma rays. The frequency of micronuclei in rat lung fibroblasts, lung epithelial cells, and tracheal epithelial cells increased linearly, with slopes of 7 x 10(-4), 12 x 10(-4), and 11 x 10(-4) micronuclei/binucleated cell cGy(-1), respectively. When genetic damage induced by radiation from (56)Fe ions was compared to that from exposure to (60)Co gamma rays, (56)Fe-ion radiation was between 0.9 and 3.3 times more effective than (60)Co gamma rays. However, the HZE-particle exposures were only 10-20% as effective as radon in producing micronuclei in either deep lung or tracheal epithelial cells. Using microdosimetric techniques, we estimated that 32 cells were hit by delta rays for each cell that was traversed by the primary HZE (56)Fe particle. These calculations and the observed low relative effectiveness of the exposure to HZE particles suggest that at least part of the cytogenetic damage measured was caused by the delta rays. Much of the energy deposited by the primary HZE particles may result in cell killing and may therefore be "wasted" as far as production of detectable micronuclei is concerned. The role of wasted energy in studies of cancer induction may be important in risk estimates for exposure to HZE particles.

Physicochemical properties and ability to generate free radicals of ambient coarse, fine, and ultrafine particles in the atmosphere of Xuanwei, China, an area of high lung cancer incidence

NASA Astrophysics Data System (ADS)

Lu, Senlin; Yi, Fei; Hao, Xiaojie; Yu, Shang; Ren, Jingjing; Wu, Minghong; Jialiang, Feng; Yonemochi, Shinich; Wang, Qingyue

2014-11-01

The link between the high incidence of lung cancer and harmful pollutants emitted by local coal combustion in Xuanwei, Yunnan province, China, has been a focus of study since the 1980s. However, the mechanisms responsible for the high lung cancer rate remain unclear, necessitating further study. Since a close relationship between ambient air particle pollution and respiratory diseases exists, we sampled size-resolved ambient particles from the atmosphere of Xuanwei. In our indoor experiment, cutting-edge methods, including scanning electron microscopy coupled with energy dispersive X-ray detection (SEM/EDX), particle-induced X-ray emission (PIXE), electronic paramagnetic resonance (EPR) and the cell-free DCFH-DA assay, were employed to investigate the physicochemical properties, the potential to generate free radicals and the oxidative potential of ambient coarse (diameter, 1.8-10 μm), fine (diameter, 0.1-1.8 μm), and ultrafine (diameter, <0.1 μm) particles. We found the total mass concentrations of the size-resolved particles collected in spring were higher than that in early winter. Mass percentage of fine particles accounted for 68% and 61% of the total particulate mass in spring and in early winter samples, respectively, indicating that fine particles were the major component of the Xuanwei ambient particulate matters. On the other hand, the results of SEM/EDX analysis showed that the coarse particles were dominated by minerals, the fine particles by soot aggregates and fly ashes, and the ultrafine particles by soot particles and unidentified particles. Our PIXE results revealed that crustal elements (Ca, Ti Si, Fe) were mainly distributed in coarse particles, while trace metals (Cr, Mn, Ni, Cu, Zn, Pb) dominated in the fine particle fraction, and S, a typical element emitted by coal combustion, mainly resided in fine particles collected from the winter atmosphere. EPR results indicated that the magnitude of free radical intensity caused by size-resolved particles followed these patterns: fine particles > coarse particles > ultrafine particles for spring samples and ultrafine particles > fine particles > coarse particles for winter samples. Cell-free DCFH assay results conclusively showed that all of the measured particle suspensions displayed a higher oxidative potential than the negative control. The correlation coefficient (R2) between free radical intensity and fluorescent intensity generated by the size-resolved particles was 0.535 and 0.507 for the spring and winter seasons, respectively, implying that ambient air particles in the Xuanwei atmosphere have the ability to generate free radicals, and fine and ultrafine particles could be hazardous to local residents.

Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye

A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, andmore » infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. - Highlights: • Combined RSV FFG VLP vaccine is effective in inducing F specific responses. • FFG VLP vaccine confers RSV neutralizing activity and viral control in cotton rats. • Cotton rats with RSV FFG VLP vaccination do not show vaccine-enhanced disease. • Cotton rats with FFG VLP vaccine induce F specific antibody secreting cell responses. • Cotton rats with FFG VLP do not induce lung cellular infiltrates and Th2 cytokine.« less

Physico-chemical properties and biological effects of diesel and biomass particles.

PubMed

Longhin, Eleonora; Gualtieri, Maurizio; Capasso, Laura; Bengalli, Rossella; Mollerup, Steen; Holme, Jørn A; Øvrevik, Johan; Casadei, Simone; Di Benedetto, Cristiano; Parenti, Paolo; Camatini, Marina

2016-08-01

Diesel combustion and solid biomass burning are the major sources of ultrafine particles (UFP) in urbanized areas. Cardiovascular and pulmonary diseases, including lung cancer, are possible outcomes of combustion particles exposure, but differences in particles properties seem to influence their biological effects. Here the physico-chemical properties and biological effects of diesel and biomass particles, produced under controlled laboratory conditions, have been characterized. Diesel UFP were sampled from a Euro 4 light duty vehicle without DPF fuelled by commercial diesel and run over a chassis dyno. Biomass UFP were collected from a modern automatic 25 kW boiler propelled by prime quality spruce pellet. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images of both diesel and biomass samples showed aggregates of soot particles, but in biomass samples ash particles were also present. Chemical characterization showed that metals and PAHs total content was higher in diesel samples compared to biomass ones. Human bronchial epithelial (HBEC3) cells were exposed to particles for up to 2 weeks. Changes in the expression of genes involved in xenobiotic metabolism were observed after exposure to both UFP already after 24 h. However, only diesel particles modulated the expression of genes involved in inflammation, oxidative stress and epithelial-to-mesenchymal transition (EMT), increased the release of inflammatory mediators and caused phenotypical alterations, mostly after two weeks of exposure. These results show that diesel UFP affected cellular processes involved in lung and cardiovascular diseases and cancer. Biomass particles exerted low biological activity compared to diesel UFP. This evidence emphasizes that the study of different emission sources contribution to ambient PM toxicity may have a fundamental role in the development of more effective strategies for air quality improvement. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tentative explanatory variable of lung dust concentration in gold miners exposed to crystalline silica.

PubMed

Dufresne, A; Loosereewanich, P; Bégin, R; Dion, C; Ecobichon, D; Muir, D C; Ritchie, A C; Perrault, G

1998-01-01

The first objective of the study was to investigate the relationships between quantitative lung mineral dust burdens, dust exposure history, and pathological fibrosis grading in silicotic workers. The second objective was to evaluate the association between particle size parameters, concentration of retained silica particles and the severity of the silicosis. Sixty-seven paraffin-embedded lung tissue samples of silicotic patients were analyzed. The cases of silicosis included 39 non-lung cancer patients and 28 patients with lung cancer. All of the cases were gold miners in the Province of Ontario, Canada. Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. Total particles, silica, clay, and quartz also increase in concentration with increased age at death, although the trends are not statistically significant. Quartz concentration has a statistically significant correlation with the silicosis severity score (r = +0.45, p < 0.001), with the geometric mean concentration increasing from 2.24 micrograms/mg in the group having silicosis severity score less than 1 to 4.80 micrograms/mg in group with highest score. Quartz concentration is the only significant explanatory variable of the silicosis severity with a regression coefficient of +0.41 (p < 0.001). Among several dust exposure variables extracted from the work history of the miners, the calendar year of first exposure was the primary significant determinant of lung retained total particles, silica, and clay minerals, except for quartz. A statistically significant linear relationship between lung quartz concentration and silicosis severity in the gold miners was observed (p < 0.001). Among the several types of lung particles detected, quartz was the only significant determinant of the silicosis severity in the gold miners in this study and vice versa, although it explained only 20% of the variation in the severity. This study suggested no significant linear relationship between the duration of dust exposure and the lung burden of any particle types in the gold miners.

Creation of Lung-Targeted Dexamethasone Immunoliposome and Its Therapeutic Effect on Bleomycin-Induced Lung Injury in Rats

PubMed Central

Li, Nan; Hu, Yang; Zhang, Yuan; Xu, Jin-Fu; Li, Xia; Ren, Jie; Su, Bo; Yuan, Wei-Zhong; Teng, Xin-Rong; Zhang, Rong-Xuan; Jiang, Dian-hua; Mulet, Xavier; Li, Hui-Ping

2013-01-01

Objective Acute lung injury (ALI), is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM)-loaded immunoliposome (NLP) functionalized with pulmonary surfactant protein A (SP-A) antibody (SPA-DXM-NLP) in an animal model. Methods DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. Results The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. Conclusions The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice. PMID:23516459

MICRO DOSE ASESSMENT OF INHALED PARTICLES IN HUMAN LUNGS: A STEP CLOSER TOWARDS THE TARGET TISSUE DOSE

EPA Science Inventory

Rationale: Inhaled particles deposit inhomogeneously in the lung and this may result in excessive deposition dose at local regions of the lung, particularly at the anatomic sites of bifurcations and junctions of the airways, which in turn leads to injuries to the tissues and adve...

Air pollution ultrafine particles: toxicity beyond the lung.

PubMed

Terzano, C; Di Stefano, F; Conti, V; Graziani, E; Petroianni, A

2010-10-01

Ultrafine particles or nanoparticles (UFPs or PM0.1) are the fraction of ambient particulates with an aerodynamic diameter smaller than 0.1 microm. Currently UFPs are emerging as the most abundant particulate pollutants in urban and industrial areas, as their exposures have increased dramatically because of anthropogenic sources such as internal combustion engines, power plants, incinerators and many other sources of thermo-degradation. Ultrafine particles have been less studied than PM2.5 and PM10 particulates, mass concentrations of particles smaller than 2.5 and 10 microm, respectively. OBJECTIVE, EVIDENCE AND INFORMATION SOURCES: We examined the current scientific literature about the health effects of ultrafine particles exposure. UFPs are able to inhibit phagocytosis, and to stimulate inflammatory responses, damaging epithelial cells and potentially gaining access to the interstitium. They could be responsible for consistent reductions in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in patients with asthma. Chronic exposure to UFPs can produce deleterious effects on the lung, also causing oxidative stress and enhancing pro-inflammatory effects in airways of COPD patients. Cardiovascular detrimental consequences due to UFPs exposure have observed in epidemiological studies, and could likely be explained by translocation of UFPs from the respiratory epithelium towards circulation and subsequent toxicity to vascular endothelium; alteration of blood coagulation; triggering of autonomic nervous system reflexes eventually altering the cardiac frequency and function. Once deposited deeply into the lung, UFPs--in contrast to larger-sized particles--appear to access to the blood circulation by different transfer routes and mechanisms, resulting in distribution throughout the body, including the brain, with potential neurotoxic consequences. UFPs represent an area of toxicology of emerging concern. A new concept of environmental medicine would help in understanding not only the environmental mechanisms of disease, but also in developing specific preventive or therapeutic strategies for minimizing the dangerous influence of pollution on health.

Lung retention and metabolic fate of inhaled benzo(a)pyrene associated with diesel exhaust particles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, J.D.; Wolff, R.K.; Kanapilly, G.M.

The effect of ultrafine, insoluble, carrier particles on the lung retention and metabolic fate of inhaled PAHs was investigated with a radiolabeled model PAH, (/sup 3/H)benzo(a)pyrene (/sup 3/H-BaP). Fischer-344 rats were exposed (30 min) by nose-only inhalation to /sup 3/H-BaP adsorbed (approximately 0.1% by mass) onto diesel engine exhaust particles. The total mass concentration of these aerosols was 4-6 micrograms/liter of air with a mass median diameter of 0.14 micron. Lung clearance of the inhaled particle-associated /sup 3/H radioactivity occurred in two phases. The initially rapid clearance of this inhaled radiolabel had a half-time of less than 1 hr. Themore » second, long-term component of lung clearance had a half-time of 18 +/- 2 days and represented 50 +/- 2% of the /sup 3/H radioactivity that had initially deposited in lungs. In contrast, previous inhalation studies with a pure /sup 3/H-BaP aerosol showed that greater than 99% of the /sup 3/H radioactivity deposited in lungs was cleared within 2 hr after exposure. By HPLC analysis, the majority of diesel soot-associated /sup 3/H radioactivity retained in lungs was BaP (65-76%) with smaller amounts of BaP-phenol (13-17%) and BaP-quinone (5-18%) metabolites also being detected. No other metabolites of BaP were detected in lungs of exposed rats. Tissue distribution and excretion patterns of /sup 3/H radioactivity were qualitatively similar to previous inhalation studies with /sup 3/H-BaP coated Ga2O3 aerosols. These findings suggest that inhaled PAHs may be retained in lungs for a greater period of time when these compounds are associated with diesel engine exhaust particles. These results may have significant implications for the health risks that may be involved with human exposure to particle-associated organic pollutants.« less

DIFFERENTIAL GENE EXPRESSION BY CHAPEL HILL FINE PARTICLES IN HUMAN ALVEOLAR MACHROPHAGES

EPA Science Inventory

Pollutant particles (PM) induce systemic and lung inflammation. Alveolar macrophages (AM) are one of the lung cells directly exposed to PM that may initiate these responses. In this study, we determined the gene expression profile induced by Chapel Hill fine particles (PM2.5) in ...

Real-time non-invasive detection of inhalable particulates delivered into live mouse airways.

PubMed

Donnelley, Martin; Morgan, Kaye S; Fouras, Andreas; Skinner, William; Uesugi, Kentaro; Yagi, Naoto; Siu, Karen K W; Parsons, David W

2009-07-01

Fine non-biological particles small enough to be suspended in the air are continually inhaled as we breathe. These particles deposit on airway surfaces where they are either cleared by airway defences or can remain and affect lung health. Pollutant particles from vehicles, building processes and mineral and industrial dusts have the potential to cause both immediate and delayed health problems. Because of their small size, it has not been possible to non-invasively examine how individual particles deposit on live airways, or to consider how they behave on the airway surface after deposition. In this study, synchrotron phase-contrast X-ray imaging (PCXI) has been utilized to detect and monitor individual particle deposition. The in vitro detectability of a range of potentially respirable particulates was first determined. Of the particulates tested, only asbestos, quarry dust, fibreglass and galena (lead sulfate) were visible in vitro. These particulates were then examined after delivery into the nasal airway of live anaesthetized mice; all were detectable in vivo but each exhibited different surface appearances and behaviour along the airway surface. The two fibrous particulates appeared as agglomerations enveloped by fluid, while the non-fibrous particulates were present as individual particles. Synchrotron PCXI provides the unique ability to non-invasively detect and track deposition of individual particulates in live mouse airways. With further refinement of particulate sizing and delivery techniques, PCXI should provide a novel approach for live animal monitoring of airway particulates relevant to lung health.

Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells

NASA Astrophysics Data System (ADS)

Lin, Weisheng; Xu, Yi; Huang, Chuan-Chin; Ma, Yinfa; Shannon, Katie B.; Chen, Da-Ren; Huang, Yue-Wern

2009-01-01

This is the first comprehensive study to evaluate the cytotoxicity, biochemical mechanisms of toxicity, and oxidative DNA damage caused by exposing human bronchoalveolar carcinoma-derived cells (A549) to 70 and 420 nm ZnO particles. Particles of either size significantly reduced cell viability in a dose- and time-dependent manner within a rather narrow dosage range. Particle mass-based dosimetry and particle-specific surface area-based dosimetry yielded two distinct patterns of cytotoxicity in both 70 and 420 nm ZnO particles. Elevated levels of reactive oxygen species (ROS) resulted in intracellular oxidative stress, lipid peroxidation, cell membrane leakage, and oxidative DNA damage. The protective effect of N-acetylcysteine on ZnO-induced cytotoxicity further implicated oxidative stress in the cytotoxicity. Free Zn2+ and metal impurities were not major contributors of ROS induction as indicated by limited free Zn2+ cytotoxicity, extent of Zn2+ dissociation in the cell culture medium, and inductively-coupled plasma-mass spectrometry metal analysis. We conclude that (1) exposure to both sizes of ZnO particles leads to dose- and time-dependent cytotoxicity reflected in oxidative stress, lipid peroxidation, cell membrane damage, and oxidative DNA damage, (2) ZnO particles exhibit a much steeper dose-response pattern unseen in other metal oxides, and (3) neither free Zn2+ nor metal impurity in the ZnO particle samples is the cause of cytotoxicity.

Multiscale Airflow Model and Aerosol Deposition in Healthy and Emphysematous Rat Lungs

NASA Astrophysics Data System (ADS)

Oakes, Jessica; Marsden, Alison; Grandmont, Celine; Darquenne, Chantal; Vignon-Clementel, Irene

2012-11-01

The fate of aerosol particles in healthy and emphysematic lungs is needed to determine the toxic or therapeutic effects of inhalable particles. In this study we used a multiscale numerical model that couples a 0D resistance and capacitance model to 3D airways generated from MR images. Airflow simulations were performed using an in-house 3D finite element solver (SimVascular, simtk.org). Seven simulations were performed; 1 healthy, 1 uniform emphysema and 5 different cases of heterogeneous emphysema. In the heterogeneous emphysema cases the disease was confined to a single lobe. As a post processing step, 1 micron diameter particles were tracked in the flow field using Lagrangian particle tracking. The simulation results showed that the inhaled flow distribution was equal for the healthy and uniform emphysema cases. However, in the heterogeneous emphysema cases the delivery of inhaled air was larger in the diseased lobe. Additionally, there was an increase in delivery of aerosol particles to the diseased lobe. This suggests that as the therapeutic particles would reach the diseased areas of the lung, while toxic particles would increasingly harm the lung. The 3D-0D model described here is the first of its kind to be used to study healthy and emphysematic lungs. NSF Graduate Fellowship (Oakes), Burroughs Wellcome Fund (Marsden, Oakes) 1R21HL087805-02 from NHLBI at NIH, INRIA Team Grant.

Comparative microscopic study of human and rat lungs after overexposure to welding fume.

PubMed

Antonini, James M; Roberts, Jenny R; Schwegler-Berry, Diane; Mercer, Robert R

2013-11-01

Welding is a common industrial process used to join metals and generates complex aerosols of potentially hazardous metal fumes and gases. Most long-time welders experience some type of respiratory disorder during their time of employment. The use of animal models and the ability to control the welding fume exposure in toxicology studies have been helpful in developing a better understanding of how welding fumes affect health. There are no studies that have performed a side-by-side comparison of the pulmonary responses from an animal toxicology welding fume study with the lung responses associated with chronic exposure to welding fume by a career welder. In this study, post-mortem lung tissue was donated from a long-time welder with a well-characterized work background and a history of extensive welding fume exposure. To simulate a long-term welding exposure in an animal model, Sprague-Dawley rats were treated once a week for 28 weeks by intratracheal instillation with 2mg of a stainless steel, hard-surfacing welding fume. Lung tissues from the welder and the welding fume-treated rats were examined by light and electron microscopy. Pathological analysis of lung tissue collected from the welder demonstrated inflammatory cell influx and significant pulmonary injury. The poor and deteriorating lung condition observed in the welder examined in this study was likely due to exposure to very high levels of potentially toxic metal fumes and gases for a significant number of years due to work in confined spaces. The lung toxicity profile for the rats treated with welding fume was similar. For tissue samples from both the welder and treated rats, welding particle accumulations deposited and persisted in lung structures and were easily visualized using light microscopic techniques. Agglomerates of deposited welding particles mostly were observed within lung cells, particularly alveolar macrophages. Analysis of individual particles within the agglomerates showed that these particles were metal complexes with iron, chromium, and nickel being the most common metals present. In conclusion, long-term exposure to specific welding fume can lead to serious chronic lung disease characterized by significant particle deposition and persistence as demonstrated in both a human case study and rat model. Not only were the lung responses similar in the human and rat lungs, as evidenced by inflammatory cell influx and pulmonary disease, but the composition of individual welding particles and agglomerations in situ was comparable.

Pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides following 4-week inhalation exposure of rats: toxic effects are determined by agglomerated, not primary particle size.

PubMed

Pauluhn, Jürgen

2009-05-01

Inhaled polydisperse micronsized agglomerated particulates composed of nanosized primary particles may exert their pulmonary toxicity in either form, depending on whether these tightly associated structures are disintegrated within the biological system or not. This hypothesis was tested in a rat bioassay using two calcined aluminum oxyhydroxides (AlOOH) consisting of primary particles in the range of 10-40 nm. Male Wistar rats were nose-only exposed to 0.4, 3, and 28 mg/m(3) in two 4-week (6 h/day, 5 days/week) inhalation studies followed by a 3-month postexposure period. The respective mass median aerodynamic diameter (MMAD) of agglomerated particles in inhalation chambers was 1.7 and 0.6 mum. At serial sacrifices, pulmonary toxicity was characterized by bronchoalveolar lavage (BAL) and histopathology. The retention kinetics of aluminum (Al) was determined in lung tissue, BAL cells, and selected extrapulmonary organs, including lung-associated lymph nodes (LALNs). Significant changes in BAL, lung, and LALN weights occurred at 28 mg/m(3). Histopathology revealed alveolar macrophages with enlarged and foamy appearance, increased epithelial cells, inflammatory cells, and focal septal thickening. The determination of aluminum in lung tissue shows that the cumulative lung dose was higher following exposure to AlOOH-40 nm/MMAD-0.6 mum than to AlOOH-10 nm/MMAD-1.7 mum, despite identical exposure concentrations. The associated pulmonary inflammatory response appears to be principally dependent on the agglomerated rather than primary particle size. Despite high lung burdens, conclusively increased extrapulmonary organ burdens did not occur at any exposure concentration and postexposure time point. Particle-induced pulmonary inflammation was restricted to cumulative doses exceeding approximately 1 mg AlOOH/g lung following 4-week exposure at 28 mg/m(3). It is concluded that the pulmonary toxicity of nanosized, agglomerated AlOOH particles appears to be determined by the size of agglomerated rather than primary particles, whereas the clearance half-time of particles appears to increase with decreased primary particle size. However, in regard to toxicokinetics, this outcome is highly contingent upon the total lung burden and especially whether overloading or non-overloading conditions were attained or not. In order to reliably demonstrate retention-related different characteristics in toxicity and fate of poorly soluble (nano)particles postexposure periods of at least 3 months appear to be indispensible.

International Airport Impacts to Air Quality: Size and Related Properties of Large Increases in Ultrafine Particle Number Concentrations.

PubMed

Hudda, N; Fruin, S A

2016-04-05

We measured particle size distributions and spatial patterns of particle number (PN) and particle surface area concentrations downwind from the Los Angeles International Airport (LAX) where large increases (over local background) in PN concentrations routinely extended 18 km downwind. These elevations were mostly comprised of ultrafine particles smaller than 40 nm. For a given downwind distance, the greatest increases in PN concentrations, along with the smallest mean sizes, were detected at locations under the landing jet trajectories. The smaller size of particles in the impacted area, as compared to the ambient urban aerosol, increased calculated lung deposition fractions to 0.7-0.8 from 0.5-0.7. A diffusion charging instrument (DiSCMini), that simulates alveolar lung deposition, measured a fivefold increase in alveolar-lung deposited surface area concentrations 2-3 km downwind from the airport (over local background), decreasing steadily to a twofold increase 18 km downwind. These ratios (elevated lung-deposited surface area over background) were lower than the corresponding ratios for elevated PN concentrations, which decreased from tenfold to twofold over the same distance, but the spatial patterns of elevated concentrations were similar. It appears that PN concentration can serve as a nonlinear proxy for lung deposited surface area downwind of major airports.

Radiation exposure and lung disease in today's nuclear world.

PubMed

Deas, Steven D; Huprikar, Nikhil; Skabelund, Andrew

2017-03-01

Ionizing radiation poses important health risks. The per capita annual dose rate has increased in the United States and there is increasing concern for the risks posed by low-dose occupational exposure among workers in nuclear industries and healthcare. Recent nuclear accidents and concern for terrorism have heightened concern for catastrophic, high-dose ionizing radiation exposure. This review will highlight recent research into the risks to lung health posed by ionizing radiation exposure and into potential treatments. Angiotensin-converting enzyme inhibitors and some antioxidants have shown promise as mitigators, to decrease pneumonitis and fibrosis when given after exposure. Studies of survivors of nuclear catastrophes have shown increased risk for lung cancer, especially in nonsmokers. There is evidence for increased lung cancer risk in industrial radiation workers, especially those who process plutonium and may inhale radioactive particles. There does not seem to be an increased risk of lung cancer in healthcare workers who perform fluoroscopic procedures. High-dose ionizing radiation exposure causes pneumonitis and fibrosis, and more research is needed to develop mitigators to improve outcomes in nuclear catastrophes. Long-term, low-dose occupational radiation may increase lung cancer risk. More research to better define this risk could lead to improved safety protocols and screening programs.

Coal Mine Dust Desquamative Chronic Interstitial Pneumonia: A Precursor of Dust-Related Diffuse Fibrosis and of Emphysema.

PubMed

Jelic, Tomislav M; Estalilla, Oscar C; Sawyer-Kaplan, Phyllis R; Plata, Milton J; Powers, Jeremy T; Emmett, Mary; Kuenstner, John T

2017-07-01

Diseases associated with coal mine dust continue to affect coal miners. Elucidation of initial pathological changes as a precursor of coal dust-related diffuse fibrosis and emphysema, may have a role in treatment and prevention. To identify the precursor of dust-related diffuse fibrosis and emphysema. Birefringent silica/silicate particles were counted by standard microscope under polarized light in the alveolar macrophages and fibrous tissue in 25 consecutive autopsy cases of complicated coal worker's pneumoconiosis and in 21 patients with tobacco-related respiratory bronchiolitis. Coal miners had 331 birefringent particles/high power field while smokers had 4 (p<0.001). Every coal miner had intra-alveolar macrophages with silica/silicate particles and interstitial fibrosis ranging from minimal to extreme. All coal miners, including those who never smoked, had emphysema. Fibrotic septa of centrilobular emphysema contained numerous silica/silicate particles while only a few were present in adjacent normal lung tissue. In coal miners who smoked, tobacco-associated interstitial fibrosis was replaced by fibrosis caused by silica/silicate particles. The presence of silica/silicate particles and anthracotic pigment-laden macrophages inside the alveoli with various degrees of interstitial fibrosis indicated a new disease: coal mine dust desquamative chronic interstitial pneumonia, a precursor of both dust-related diffuse fibrosis and emphysema. In studied coal miners, fibrosis caused by smoking is insignificant in comparison with fibrosis caused by silica/silicate particles. Counting birefringent particles in the macrophages from bronchioalveolar lavage may help detect coal mine dust desquamative chronic interstitial pneumonia, and may initiate early therapy and preventive measures.

Experimental determination of the respiratory tract deposition of diesel combustion particles in patients with chronic obstructive pulmonary disease

PubMed Central

2012-01-01

Background Air pollution, mainly from combustion, is one of the leading global health risk factors. A susceptible group is the more than 200 million people worldwide suffering from chronic obstructive pulmonary disease (COPD). There are few data on lung deposition of airborne particles in patients with COPD and none for combustion particles. Objectives To determine respiratory tract deposition of diesel combustion particles in patients with COPD during spontaneous breathing. Methods Ten COPD patients and seven healthy subjects inhaled diesel exhaust particles generated during idling and transient driving in an exposure chamber. The respiratory tract deposition of the particles was measured in the size range 10–500 nm during spontaneous breathing. Results The deposited dose rate increased with increasing severity of the disease. However, the deposition probability of the ultrafine combustion particles (< 100 nm) was decreased in COPD patients. The deposition probability was associated with both breathing parameters and lung function, but could be predicted only based on lung function. Conclusions The higher deposited dose rate of inhaled air pollution particles in COPD patients may be one of the factors contributing to their increased vulnerability. The strong correlations between lung function and particle deposition, especially in the size range of 20–30 nm, suggest that altered particle deposition could be used as an indicator respiratory disease. PMID:22839109

Oxidative and cytotoxic stress induced by inorganic granular and fibrous particles.

PubMed

Helmig, Simone; Walter, Dirk; Putzier, Julia; Maxeiner, Hagen; Wenzel, Sibylle; Schneider, Joachim

2018-06-01

The hazards of granular and fibrous particles have been associated with the generation of reactive oxygen species (ROS), which in turn is often associated with physicochemical properties exhibited by these particles. In the present study, the ability of various types of fibrous and granular dusts to generate oxidative stress, and their cytotoxicity, was investigated. Biopersistent granular dusts employed in the present study included micro‑ and nanosized titanium dioxide with rutile or anatase crystal structure modifications. Additionally, glass fibres, chrysotile and crocidolite asbestos representative of fibrous dust were selected. Detailed characterisation of particles was performed using scanning electron microscopy, and the effect of exposure to these particles on cell viability and intracellular ROS generation was assessed by PrestoBlue and 2',7'‑dichlorofluorescein assays, respectively. A549 human lung epithelial adenocarcinoma cells were exposed to increasing concentrations (0.1‑10 µg/cm2) of particles and fibres for 24 h. Subsequently, the gene expression of X‑linked inhibitor of apoptosis (XIAP), superoxide dismutase (SOD)1 and SOD2 were analysed by reverse transcription‑quantitative polymerase chain reaction. All investigated granular particles induce ROS production in A549 lung carcinoma cells within 24 h. Hematite increased ROS production in a dose‑dependent manner. A concentration of >1 µg/cm2 TiO2 na with its disordered surface, demonstrated the greatest ability to generate ROS. Therefore, the crystalline surface structure of the particle may be considered as a determinant of the extent of ROS induction by the particle. Fibrous particle compared with granular particles were associated with a lower ability to generate ROS. Glass fibres did not significantly increase ROS production in A549 cells, but elevated gene expression of SOD2 was observed. The results demonstrated that in general, the ability of particles to generate ROS depends on their number and crystal phase. Therefore, the present study helps to understand the cause of particle toxicity.

Overview of Silica-Related Clusters in the United States: Will Fracking Operations Become the Next Cluster?

PubMed

Quail, M Thomas

2017-01-01

Silicosis is the oldest know occupational pulmonary disease. It is a progressive disease and any level of exposure to respirable crystalline silica particles or dust has the potential to develop into silicosis. Silicosis is caused by silica particles or dust entering the lungs and damaging healthy lung tissue. The damage restricts the ability to breathe. Exposure to silica increases a worker’s risk of developing cancer or tuberculosis. This special report will provide background history of silicosis in the U.S., including the number of workers affected and their common industries. Over the years, these industries have impeded government oversight, resulting in silicosis exposure clusters. The risk of acquiring silicosis is diminished when industry implements safety measures with oversight by governmental agencies. Reputable authorities believe that the current innovative drilling techniques such as fracking will generate future cases of silicosis in the U.S. if safety measures to protect workers are ignored.

Presence of nanosilica (E551) in commercial food products: TNF-mediated oxidative stress and altered cell cycle progression in human lung fibroblast cells.

PubMed

Athinarayanan, Jegan; Periasamy, Vaiyapuri Subbarayan; Alsaif, Mohammed A; Al-Warthan, Abdulrahman A; Alshatwi, Ali A

2014-04-01

Silica (E551) is commonly used as an anti-caking agent in food products. The morphology and the dimension of the added silica particles are not, however, usually stated on the food product label. The food industry has adapted nanotechnology using engineered nanoparticles to improve the quality of their products. However, there has been increased debate regarding the health and safety concerns related to the use of engineered nanoparticles in consumer products. In this study, we investigated the morphology and dimensions of silica (E551) particles in food. The silica content of commercial food products was determined using inductively coupled plasma optical emission spectrometry. The result indicates that 2.74-14. 45 μg/g silica was found in commercial food products; however, the daily dietary intake in increase causes adverse effects on human health. E551 was isolated from food products and the morphology, particle size, crystalline nature, and purity of the silica particles were analyzed using XRD, FTIR, TEM, EDX and DLS. The results of these analyses confirmed the presence of spherical silica nanoparticles (of amorphous nature) in food, approximately 10-50 nm in size. The effects of E551 on human lung fibroblast cell viability, intracellular ROS levels, cell cycle phase, and the expression levels of metabolic stress-responsive genes (CAT, GSTA4, TNF, CYP1A, POR, SOD1, GSTM3, GPX1, and GSR1) were studied. The results suggest that E551 induces a dose-dependent cytotoxicity and changes in ROS levels and alters the gene expression and cell cycle. Treatment with a high concentration of E551 caused significant cytotoxic effects on WI-38 cells. These findings have implications for the use of these nanoparticles in the food industry.

Contribution of metals to respiratory cancer.

PubMed Central

Peters, J M; Thomas, D; Falk, H; Oberdörster, G; Smith, T J

1986-01-01

This paper reviews studies on the adverse health effects of exposure to metals, using arsenic and cadmium as examples. The carcinogenic potential of arsenic has been studied in various settings. Inhalation is clearly related to the development of lung cancer in (copper) smelting and arsenical pesticide manufacturing, and also in heavily exposed wine merchants who had an additional source of exposure by ingestion. Animal studies have shown cadmium to be a lung carcinogen, while a study by Thun et al. provides the best evidence to date that cadmium inhaled as CdO particles may be a human lung carcinogen. On the basis of this latter study, EPA estimates the risk due to cadmium at 1.8 X 10(-3) cases/micrograms/m3, which results in more than 100,000 excess lung cancers (lifetime). For arsenic, the risk estimate of 4.29 cases/1,000 micrograms/m3, based on epidemiologic data also results in more than 100,000 lung cancers (lifetime). This paper reviews the bases for these estimates and presents recommendations for further research. Lung cancer risks also exist for other metals such as nickel, chromium, and beryllium. Further study is required before a definitive conclusion can be reached about the significance and magnitude of environmental exposures to metals as a cause of lung cancer. PMID:3830115

Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs.

PubMed

Garbuzenko, Olga B; Winkler, Jennifer; Tomassone, M Silvina; Minko, Tamara

2014-11-04

The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

PubMed Central

Wu, Xiao; Hayes, Don; Zwischenberger, Joseph B; Kuhn, Robert J; Mansour, Heidi M

2013-01-01

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine. PMID:23403805

Intramuscular and intranasal immunization with an H7N9 influenza virus-like particle vaccine protects mice against lethal influenza virus challenge.

PubMed

Ren, Zhiguang; Zhao, Yongkun; Liu, Jing; Ji, Xianliang; Meng, Lingnan; Wang, Tiecheng; Sun, Weiyang; Zhang, Kun; Sang, Xiaoyu; Yu, Zhijun; Li, Yuanguo; Feng, Na; Wang, Hualei; Yang, Songtao; Yang, Zhengyan; Ma, Yuanfang; Gao, Yuwei; Xia, Xianzhu

2018-05-01

The H7N9 influenza virus epidemic has been associated with a high mortality rate in China. Therefore, to prevent the H7N9 virus from causing further damage, developing a safe and effective vaccine is necessary. In this study, a vaccine candidate consisting of virus-like particles (VLPs) based on H7N9 A/Shanghai/2/2013 and containing hemagglutinin (HA), neuraminidase (NA), and matrix protein (M1) was successfully produced using a baculovirus (BV) expression system. Immunization experiments showed that strong humoral and cellular immune responses could be induced by the developed VLPs when administered via either the intramuscular (IM) or intranasal (IN) immunization routes. Notably, VLPs administered via both immunization routes provided 100% protection against lethal infection caused by the H7N9 virus. The IN immunization with 40μg of H7N9 VLPs induced strong lung IgA and lung tissue resident memory (TRM) cell-mediated local immune responses. These results provide evidence for the development of an effective preventive vaccine against the H7N9 virus based on VLPs administered through both the IM and IN immunization routes. Copyright © 2017. Published by Elsevier B.V.

Polycyclic Aromatic Hydrocarbon Exposure in Household Air Pollution from Solid Fuel Combustion among the Female Population of Xuanwei and Fuyuan Counties, China

PubMed Central

2015-01-01

Exposure to polycyclic aromatic hydrocarbons (PAHs) from burning “smoky” (bituminous) coal has been implicated as a cause of the high lung cancer incidence in the counties of Xuanwei and Fuyuan, China. Little is known about variations in PAH exposure from throughout the region nor how fuel source and stove design affects exposure. Indoor and personal PAH exposure resulting from solid fuel combustion in Xuanwei and Fuyuan was investigated using repeated 24 h particle bound and gas-phase PAH measurements, which were collected from 163 female residents of Xuanwei and Fuyuan. 549 particle bound (283 indoor and 266 personal) and 193 gas phase (all personal) PAH measurements were collected. Mixed effect models indicated that PAH exposure was up to 6 times higher when burning smoky coal than smokeless coal and varied by up to a factor of 3 between different smoky coal geographic sources. PAH measurements from unventilated firepits were up to 5 times that of ventilated stoves. Exposure also varied between different room sizes and season of measurement. These findings indicate that PAH exposure is modulated by a variety of factors, including fuel type, coal source, and stove design. These findings may provide valuable insight into potential causes of lung cancer in the area. PMID:25393345

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

PubMed

Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

2016-01-01

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 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.

Toxicity of Mineral Dusts and a Proposed Mechanism for the Pathogenesis of Particle-Induced Lung Diseases

NASA Technical Reports Server (NTRS)

Lam, C.-W.; Zeidler-Erdely, P.; Scully, R.R.; Meyers, V.; Wallace, W.; Hunter, R.; Renne, R.; McCluskey, R.; Castranova, V.; Barger, M.;

Comparative Microscopic Study of Human and Rat Lungs After Overexposure to Welding Fume

PubMed Central

ANTONINI, JAMES M.; ROBERTS, JENNY R.; SCHWEGLER-BERRY, DIANE; MERCER, ROBERT R.

2015-01-01

Welding is a common industrial process used to join metals and generates complex aerosols of potentially hazardous metal fumes and gases. Most long-time welders experience some type of respiratory disorder during their time of employment. The use of animal models and the ability to control the welding fume exposure in toxicology studies have been helpful in developing a better understanding of how welding fumes affect health. There are no studies that have performed a side-by-side comparison of the pulmonary responses from an animal toxicology welding fume study with the lung responses associated with chronic exposure to welding fume by a career welder. In this study, post-mortem lung tissue was donated from a long-time welder with a well-characterized work background and a history of extensive welding fume exposure. To simulate a long-term welding exposure in an animal model, Sprague-Dawley rats were treated once a week for 28 weeks by intratracheal instillation with 2 mg of a stainless steel, hard-surfacing welding fume. Lung tissues from the welder and the welding fume-treated rats were examined by light and electron microscopy. Pathological analysis of lung tissue collected from the welder demonstrated inflammatory cell influx and significant pulmonary injury. The poor and deteriorating lung condition observed in the welder examined in this study was likely due to exposure to very high levels of potentially toxic metal fumes and gases for a significant number of years due to work in confined spaces. The lung toxicity profile for the rats treated with welding fume was similar. For tissue samples from both the welder and treated rats, welding particle accumulations deposited and persisted in lung structures and were easily visualized using light microscopic techniques. Agglomerates of deposited welding particles mostly were observed within lung cells, particularly alveolar macrophages. Analysis of individual particles within the agglomerates showed that these particles were metal complexes with iron, chromium, and nickel being the most common metals present. In conclusion, long-term exposure to specific welding fume can lead to serious chronic lung disease characterized by significant particle deposition and persistence as demonstrated in both a human case study and rat model. Not only were the lung responses similar in the human and rat lungs, as evidenced by inflammatory cell influx and pulmonary disease, but the composition of individual welding particles and agglomerations in situ was comparable. PMID:23798603

Pulmonary macrophages: Phenomena associated with the particle ``overload`` condition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lehnert, B.E.; Sebring, R.J.; Oberdoerster, G.

1993-05-01

Numerous lines of evidence support the generalization that alveolar macrophage (AM)-mediated particle clearance, or the transport of particle-containing AM from the alveoli out of the lung via the mucociliary apparatus, is a prominent mechanism that determines the pulmonary retention characteristics of relatively insoluble particles. Studies have also shown that the alveolar deposition of excessive burdens of particles with even low intrinsic cytotoxicity can result in impairments of the AM-mediated panicle clearance mechanism and the development of pathologic disorders including pulmonary fibrosis and lung cancer, at least in the lungs of rats. We briefly review evidence consistent with the idea thatmore » the high volumetric loads of particles contained in AM during particle overload conditions underlies their inabilities to translocate from the lung. Using a condition of particle overload brought about by subchronic exposure of rats to ultra-fine titanium dioxide as an experimental model, we have obtained ultrastructural and other evidence that indicates an association between particle overload and: The occurrence of aggregates of particle-containing AM in alveoli, Type II cell hyperplasia in alveoli that contain the AM aggregates, a loss in patent pores of Kohn in alveoli that contain the AM aggregates and show Type II cell hyperplasia, the interstitialization of particles at the sites where these phenomena collectively occur, and the development of fibrosis in alveolar regions where particle interstitialization occurs. The loss of pores of Kohn in the alveoli that contain aggregates of particle-laden AM suggests that these interalveolar pores normally serve as passageways through which AM may migrate to neighboring alveoli as they perform their function of phagocytizing particles that have deposited on the alveolar surface. The pores of Kohn also serve as short-cut pathways for AM to reach the mucociliary apparatus from more distal alveoli.« less

Pulmonary macrophages: Phenomena associated with the particle overload'' condition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lehnert, B.E.; Sebring, R.J.; Oberdoerster, G.

1993-01-01

Numerous lines of evidence support the generalization that alveolar macrophage (AM)-mediated particle clearance, or the transport of particle-containing AM from the alveoli out of the lung via the mucociliary apparatus, is a prominent mechanism that determines the pulmonary retention characteristics of relatively insoluble particles. Studies have also shown that the alveolar deposition of excessive burdens of particles with even low intrinsic cytotoxicity can result in impairments of the AM-mediated panicle clearance mechanism and the development of pathologic disorders including pulmonary fibrosis and lung cancer, at least in the lungs of rats. We briefly review evidence consistent with the idea thatmore » the high volumetric loads of particles contained in AM during particle overload conditions underlies their inabilities to translocate from the lung. Using a condition of particle overload brought about by subchronic exposure of rats to ultra-fine titanium dioxide as an experimental model, we have obtained ultrastructural and other evidence that indicates an association between particle overload and: The occurrence of aggregates of particle-containing AM in alveoli, Type II cell hyperplasia in alveoli that contain the AM aggregates, a loss in patent pores of Kohn in alveoli that contain the AM aggregates and show Type II cell hyperplasia, the interstitialization of particles at the sites where these phenomena collectively occur, and the development of fibrosis in alveolar regions where particle interstitialization occurs. The loss of pores of Kohn in the alveoli that contain aggregates of particle-laden AM suggests that these interalveolar pores normally serve as passageways through which AM may migrate to neighboring alveoli as they perform their function of phagocytizing particles that have deposited on the alveolar surface. The pores of Kohn also serve as short-cut pathways for AM to reach the mucociliary apparatus from more distal alveoli.« less

Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.

PubMed

Ung, Keith T; Rao, Nagaraja; Weers, Jeffry G; Huang, Daniel; Chan, Hak-Kim

2016-09-25

Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat. Copyright © 2016 Elsevier B.V. All rights reserved.

Potential health effects of fume particles on the crew of spacecrafts

NASA Technical Reports Server (NTRS)

Ferin, Juraj; Oberdorster, Gunter

1992-01-01

The effect of the size of polymer (e.g., Teflon) particles in fumes inhaled by spacecraft personnel on the condition of the lung tissue and on the recovery of the exposed subjects was investigated in rats receiving a single intrapulmonary instillation, or repeated inhalation exposures to either TiO2 particles with primary particle diameter 20 nm, or TiO2 particles with primary particle diameter 250 nm. It was found that rats exposed to 20-nm-diam particles showed a dramatically higher toxicity and slower recovery compared to the group exposed to the 250-nm-diam particles, due to a larger extent of penetration of the interstitium of the lung by the finer particles.

Particle Therapy for Non-Small Cell Lung Tumors: Where Do We Stand? A Systematic Review of the Literature

PubMed Central

Wink, Krista C. J.; Roelofs, Erik; Solberg, Timothy; Lin, Liyong; Simone, Charles B.; Jakobi, Annika; Richter, Christian; Lambin, Philippe; Troost, Esther G. C.

2014-01-01

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed. PMID:25401087

BIOMARKERS OF HEALTH EFFECTS IN THE HUMAN LUNG

EPA Science Inventory

Little information exists about retained particle/metal burden in human lung and associated biomarkers of internal dose/indicators of health effects. We have shown that anatomical remodeling of the terminal and respiratory bronchioles occur at sites of particle deposition. We ext...

Biokinetics and effects of titania nano-material after inhalation and i.v. injection

NASA Astrophysics Data System (ADS)

Landsiedel, Robert; Fabian, Eric; Ma-Hock, Lan; Wiench, Karin; van Ravenzwaay, Bennard

2009-05-01

Within NanoSafe2 we developed a special inhalation model to investigate deposition of inhaled particles in the lung and the further distribution in the body after. Concurrently, the effects of the inhaled materials in the lung were examined. The results for nano-Titania were compared to results from inhalation studies with micron-sized (non-nano) Titania particles and to quartz particles (DQ12, known to be potent lung toxicants). To build a PBPK model for nano-Titania the tissue distribution of the material was also examined following intravenous (i.v.) administration.

Exposure to ultrafine particles in asphalt work.

PubMed

Elihn, Karine; Ulvestad, Bente; Hetland, Siri; Wallen, Anna; Randem, Britt Grethe

2008-12-01

An epidemiologic study has demonstrated that asphalt workers show increased loss of lung function and an increase of biomarkers of inflammation over the asphalt paving season. The aim of this study was to investigate which possible agent(s) causes the inflammatory reaction, with emphasis on ultrafine particles. The workers' exposure to total dust, polycyclic aromatic hydrocarbons, and NO(2) was determined by personal sampling. Exposure to ultrafine particles was measured by means of particle counters and scanning mobility particle sizer mounted on a van following the paving machine. The fractions of organic and elemental carbon were determined. Asphalt paving workers were exposed to ultrafine particles with medium concentration of about 3.4 x 10(4)/cm(3). Ultrafine particles at the paving site originated mainly from asphalt paving activities and traffic exhaust; most seemed to originate from asphalt fumes. Oil mist exceeded occupational limits on some occasions. Diesel particulate matter was measured as elemental carbon, which was low, around 3 microg/m(3). NO(2) and total dust did not exceed limits. Asphalt pavers were exposed to relatively high concentrations of ultrafine particles throughout their working day, with possible adverse health effects.

Thermal degradation events as health hazards: Particle vs gas phase effects, mechanistic studies with particles

NASA Astrophysics Data System (ADS)

Oberdörster, G.; Ferin, J.; Finkelstein, J.; Soderholm, S.

Exposure to thermal degradation products arising from fire or smoke could be a major concern for manned space missions. Severe acute lung damage has been reported in people after accidental exposure to fumes from plastic materials, and animal studies revealed the extremely high toxicity of freshly generated fumes whereas a decrease in toxicity of aged fumes has been found. This and the fact that toxicity of the freshly generated fumes can be prevented with filters raises the question whether the toxicity may be due to the particulate rather than the gas phase components of the thermodegradation products. Indeed, results from recent studies implicate ultrafine particles (particle diameter in the nm range) as potential severe pulmonary toxicants. We have conducted a number of in vivo (inhalation and instillation studies in rats) and in vitro studies to test the hypothesis that ultrafine particles possess an increased potential to injure the lung compared to larger-sized particles. We used as surrogate particles ultrafine TiO 2 particles (12 and 20 nm diameter). Results in exposed rats showed that the ultrafine TiO 2 particles not only induce a greater acute inflammatory reaction in the lung than larger-sized TiO 2 particles, but can also lead to persistent chronic effects, as indicated by an adverse effect on alveolar macrophage mediated clearance function of particles. Release of mediators from alveolar macrophages during phagocytosis of the ultrafine particles and an increased access of the ultrafine particles to the pulmonary interstitium are likely factors contributing to their pulmonary toxicity. In vitro studies with lung cells (alveolar macrophages) showed, in addition, that ultrafine TiO 2 particles have a greater potential to induce cytokines than larger-sized particles. We conclude from our present studies that ultrafine particles have a significant potential to injure the lung and that their occurrence in thermal degradation events can play a major role in the highly acute toxicity of fumes. Future studies will include adsorption of typical gas phase components (HCl, HF) on surrogate particles to differentiate between gas and particle phase effects and to perform mechanistic studies aimed at introducing therapeutic/preventive measures. These studies will be complemented by a comparison with actual thermal degradation products.

Intratracheal instillation of coal and coal fly ash particles in mice induces DNA damage and translocation of metals to extrapulmonary tissues.

PubMed

León-Mejía, Grethel; Machado, Mariana Nascimento; Okuro, Renata Tiemi; Silva, Luis F O; Telles, Claudia; Dias, Johnny; Niekraszewicz, Liana; Da Silva, Juliana; Henriques, João Antônio Pêgas; Zin, Walter Araujo

2018-06-01

Continuous exposure to coal mining particles can cause a variety of lung diseases. We aimed to evaluate the outcomes of exposure to detailed characterized coal and coal fly ash (CFA) particles on DNA, lung and extrapulmonary tissues. Coal samples (COAL11 and COAL16) and CFA samples (CFA11 and CFA16) were included in this study. Intending to enhance the combustion process COAL16 was co-fired with a mixture of fuel oil and diesel oil, producing CFA16. Male BALB/c mice were intratracheally instilled with coal and CFA particles. Measurements were done 24h later. Results showed significant rigidity and obstruction of the central airways only for animals acutely exposed to coal particles. The COAL16 group also showed obstruction of the peripheral airways. Mononuclear cells were recruited in all treatment groups and expression of cytokines, particularly TNF-α and IL-1β, was observed. Only animals exposed to COAL16 showed a significant expression of IL-6 and recruitment of polymorphonuclear cells. DNA damage was demonstrated by Comet assay for all groups. Cr, Fe and Ni were detected in liver, spleen and brain, showing the efficient translocation of metals from the bloodstream to extrapulmonary organs. These effects were associated with particle composition (oxides, hydroxides, phosphates, sulfides, sulphates, silciates, organic-metalic compounds, and polycyclic aromatic hidrocarbons) rather than their size. This work provides state of knowledge on the effects of acute exposure to coal and CFA particles on respiratory mechanics, DNA damage, translocation of metals to other organs and related inflammatory processes. Copyright © 2018 Elsevier B.V. All rights reserved.

Distribution of aerosolized particles in healthy and emphysematous rat lungs: comparison between experimental and numerical studies.

PubMed

Oakes, Jessica M; Marsden, Alison L; Grandmont, Céline; Darquenne, Chantal; Vignon-Clementel, Irene E

2015-04-13

In silico models of airflow and particle deposition in the lungs are increasingly used to determine the therapeutic or toxic effects of inhaled aerosols. While computational methods have advanced significantly, relatively few studies have directly compared model predictions to experimental data. Furthermore, few prior studies have examined the influence of emphysema on particle deposition. In this work we performed airflow and particle simulations to compare numerical predictions to data from our previous aerosol exposure experiments. Employing an image-based 3D rat airway geometry, we first compared steady flow simulations to coupled 3D-0D unsteady simulations in the healthy rat lung. Then, in 3D-0D simulations, the influence of emphysema was investigated by matching disease location to the experimental study. In both the healthy unsteady and steady simulations, good agreement was found between numerical predictions of aerosol delivery and experimental deposition data. However, deposition patterns in the 3D geometry differed between the unsteady and steady cases. On the contrary, satisfactory agreement was not found between the numerical predictions and experimental data for the emphysematous lungs. This indicates that the deposition rate downstream of the 3D geometry is likely proportional to airflow delivery in the healthy lungs, but not in the emphysematous lungs. Including small airway collapse, variations in downstream airway size and tissue properties, and tracking particles throughout expiration may result in a more favorable agreement in future studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Combustion derived ultrafine particles induce cytochrome P-450 expression in specific lung compartments in the developing neonatal and adult rat

PubMed Central

Chan, Jackie K. W.; Vogel, Christoph F.; Baek, Jaeeun; Kodani, Sean D.; Uppal, Ravi S.; Bein, Keith J.; Anderson, Donald S.

2013-01-01

Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAH) and can be a dominant contributor to ultrafine urban particulate matter (PM). Exposure to ultrafine PM is correlated with respiratory infections and asthmatic symptoms in young children. The lung undergoes substantial growth, alveolarization, and cellular maturation within the first years of life, which may be impacted by environmental pollutants such as PM. PAHs in PM can serve as ligands for the aryl hydrocarbon receptor (AhR) that induces expression of certain isozymes in the cytochrome P-450 superfamily, such as CYP1A1 and CYP1B1, localized in specific lung cell types. Although AhR activation and induction has been widely studied, its context within PM exposure and impact on the developing lung is poorly understood. In response, we have developed a replicable ultrafine premixed flame particle (PFP) generating system and used in vitro and in vivo models to define PM effects on AhR activation in the developing lung. We exposed 7-day neonatal and adult rats to a single 6-h PFP exposure and determined that PFPs cause significant parenchymal toxicity in neonates. PFPs contain weak AhR agonists that upregulate AhR-xenobiotic response element activity and expression and are capable inducers of CYP1A1 and CYP1B1 expression in both ages with different spatial and temporal patterns. Neonatal CYP1A1 expression was muted and delayed compared with adults, possibly because of differences in the enzyme maturation. We conclude that the inability of neonates to sufficiently adapt in response to PFP exposure may, in part, explain their susceptibility to PFP and urban ultrafine PM. PMID:23502512

Quantification of inhaled aerosol particles composed of toxic household disinfectant using radioanalytical method.

PubMed

Shim, Ha Eun; Lee, Jae Young; Lee, Chang Heon; Mushtaq, Sajid; Song, Ha Yeon; Song, Lee; Choi, Seong-Jin; Lee, Kyuhong; Jeon, Jongho

2018-05-25

To assess the risk posed by a toxic chemical to human health, it is essential to quantify its uptake in a living subject. This study aims to investigate the biological distribution of inhaled polyhexamethylene guanidine (PHMG) aerosol particle, which is known to cause severe pulmonary damage. By labeling with indium-111 ( 111 In), we quantified the uptake of PHMG for up to 7 days after inhalation exposure in rats. The data demonstrate that PHMG is only slowly cleared, with approximately 74% of inhaled particles persisting in the lungs after 168 h. Approximately 5.3% of inhaled particles were also translocated to the liver after 168 h, although the level of redistribution to other tissues, including the kidneys and spleen, was minimal. These observations suggest that large uptake and slow clearance may underlie the fatal inhalation toxicity of PHMG in humans. Copyright © 2018 Elsevier Ltd. All rights reserved.

[The influence of spray drying process conditions on physical, chemical properties and lung inhaling performance of Panax notoginseng saponins - tanshinone II A composite particles].

PubMed

Wang, Hua-Mei; Fu, Ting-Ming; Guo, Li-Wei

2013-06-01

This study is to report the influence of conditions in spray drying process on physical and chemical properties and lung inhaling performance of Panax notoginseng Saponins - Tanshinone II A composite particles. According to the physical and chemical properties of the two types of components within the composite particles, three solvent systems were selected including ethanol, ethanol : acetone (9 : 1, v/v) and ethanol : acetone (4 : 1, v/v), and three inlet temperature: 110 degrees C, 120 degrees C, 130 degrees C to prepare seven different composite particle samples; each sample was characterized using laser diffraction, scanning electron microscopy (SEM), dynamic vapour sorption (DVS) and atomic force microscope (AFM), and their aerodynamic behavior was evaluated by a Next Generation Impactor (NGI). The results indicate that under the conditions of using the mixed solvent system of ethanol--acetone volume ratio of 9 : 1, and the inlet temperature of 110 degrees C, the resulting composite particles showed rough surface, with more tanshinone II A distributing in the outer layer, such composite particles have the best lung inhaling performance and the fine particle fraction (FPF) close to 60%. Finally it is concluded that by adjusting the conditions in co-spray drying process, the distribution amount and existence form of tanshinone II A in the outer layer of the particles can be changed so that to enhance lung inhaling performance of the drug composite particles.

Inhalable Magnetic Nanoparticles for Targeted Hyperthermia in Lung Cancer Therapy

PubMed Central

Sadhukha, Tanmoy; Wiedmann, Timothy Scott; Panyam, Jayanth

2015-01-01

Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. PMID:23591395

Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy.

PubMed

Sadhukha, Tanmoy; Wiedmann, Timothy S; Panyam, Jayanth

2013-07-01

Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

PubMed Central

Schneider, Craig S.; Xu, Qingguo; Boylan, Nicholas J.; Chisholm, Jane; Tang, Benjamin C.; Schuster, Benjamin S.; Henning, Andreas; Ensign, Laura M.; Lee, Ethan; Adstamongkonkul, Pichet; Simons, Brian W.; Wang, Sho-Yu S.; Gong, Xiaoqun; Yu, Tao; Boyle, Michael P.; Suk, Jung Soo; Hanes, Justin

2017-01-01

Mucoadhesive particles (MAP) have been widely explored for pulmonary drug delivery because of their perceived benefits in improving particle residence in the lungs. However, retention of particles adhesively trapped in airway mucus may be limited by physiologic mucus clearance mechanisms. In contrast, particles that avoid mucoadhesion and have diameters smaller than mucus mesh spacings rapidly penetrate mucus layers [mucus-penetrating particles (MPP)], which we hypothesized would provide prolonged lung retention compared to MAP. We compared in vivo behaviors of variously sized, polystyrene-based MAP and MPP in the lungs following inhalation. MAP, regardless of particle size, were aggregated and poorly distributed throughout the airways, leading to rapid clearance from the lungs. Conversely, MPP as large as 300 nm exhibited uniform distribution and markedly enhanced retention compared to size-matched MAP. On the basis of these findings, we formulated biodegradable MPP (b-MPP) with an average diameter of <300 nm and examined their behavior following inhalation relative to similarly sized biodegradable MAP (b-MAP). Although b-MPP diffused rapidly through human airway mucus ex vivo, b-MAP did not. Rapid b-MPP movements in mucus ex vivo correlated to a more uniform distribution within the airways and enhanced lung retention time as compared to b-MAP. Furthermore, inhalation of b-MPP loaded with dexamethasone sodium phosphate (DP) significantly reduced inflammation in a mouse model of acute lung inflammation compared to both carrier-free DP and DP-loaded MAP. These studies provide a careful head-to-head comparison of MAP versus MPP following inhalation and challenge a long-standing dogma that favored the use of MAP for pulmonary drug delivery. PMID:28435870

Attenuation by intravenous 2-chloroadenosine of acute lung injury induced by live escherichia coli or latex particles added to endotoxin in the neutropenic state.

PubMed

Sakamaki, Fumio; Ishizaka, Akitoshi; Urano, Tetsuya; Sayama, Koichi; Nakamura, Hidetoshi; Terashima, Takeshi; Waki, Yasuhiro; Soejima, Kenzo; Tasaka, Sadatomo; Sawafuji, Makoto; Kobayashi, Kouichi; Yamaguchi, Kazuhiro; Kanazawa, Minoru

2003-08-01

Although neutrophil depletion can reduce the level of acute lung injury (ALI) induced by Escherichia coli endotoxin, that induced by live E coli cannot be attenuated even in neutropenia. This suggests that live E coli cause ALI by way of an mechanism independent of circulating neutrophil. Tumor necrosis factor-alpha (TNF-alpha), which is released from monocytes and macrophages, is a proinflammatory cytokine that is recognized as a central mediator of several forms of inflammation. In this controlled experimental study, we examined the effects of an adenosine-receptor agonist, 2-chloroadenosine (2CA), that has suppressive effects on various cell types and TNF-alpha, on endotoxin plus latex particles, and on ALI induced by live E coli in the neutropenic state. We studied 42 guinea pigs rendered neutropenic by means of intraperitoneal cyclophosphamide administration. Experimental groups consisted of (1) a saline-solution control group; (2) an endotoxin (0.2 mg/kg)-treated group; (3) a group treated with endotoxin plus 2CA (10 micro g/kg); (4) a group treated with latex (2 x 10(9)/kg); (5) a group exposed to endotoxin and latex; (6) a group exposed to endotoxin, latex, and 2CA; (7) a group exposed to E coli (2 x 10(9)/kg); and (8) a group exposed to E coli and 2CA. The injection of endotoxin alone in neutropenic animals did not increase the indexes of ALI (lung tissue/plasma ratio [T/P] and lung wet weight/dry weight ratio [W/D], calculated with the use of iodine 125-labeled albumin). In contrast, these indexes were increased in the endotoxin-and-latex groups compared with those of the control group. ALI in the endotoxin-and-latex group was attenuated by intravenous 2CA. The intravenous injection of live E coli also caused increases in T/P, W/D, and plasma TNF-alpha, but thse were limited by 2CA. In summary, ALI induced by latex particles added to endotoxin and live E coli in the neutropenic state was attenuated by 2CA, suggesting a partial contribution of various cell types or humoral mediators as a neutrophil-independent pathway in its pathogenesis.

Total deposition of ultrafine particles in the lungs of healthy men and women: experimental and theoretical results

PubMed Central

2016-01-01

Background Inhaled ultrafine particles (UFP) may induce greater adverse respiratory effects than larger particles occurring in the ambient atmosphere. Due to this potential of UFP to act as triggers for diverse lung injuries medical as well as physical research has been increasingly focused on the exact deposition behavior of the particles in lungs of various probands. Main purpose of the present study was the presentation of experimental and theoretical data of total, regional, and local UFP deposition in the lungs of men and women. Methods Both experiments and theoretical simulations were carried out by using particle sizes of 0.04, 0.06, 0.08, and 0.10 µm [number median diameters (NMD)]. Inhalation of UFP took place by application of predefined tidal volumes (500, 750, and 1,000 mL) and respiratory flow rates (150, 250, 375, and 500 mL·s−1). For male subjects a functional residual capacity (FRC) of 3,911±892 mL was measured, whereas female probands had a FRC of 3,314±547 mL. Theoretical predictions were based on (I) a stochastic model of the tracheobronchial tree; (II) particle transport computations according to a random walk algorithm; and (III) empirical formulae for the description of UFP deposition. Results Total deposition fractions (TDF) are marked by a continuous diminution with increasing particle size. Whilst particles measuring 0.04 µm in size deposit in the respiratory tract by 40–70%, particles with a size of 0.10 µm exhibit deposition values ranging from 20% to 45%. Except for the largest particles studied here TDF of female probands are higher than those obtained for male probands. Differences between experimental and theoretical results are most significant for 0.10 µm particles, but never exceed 20%. Predictions of regional (extrathoracic, tracheobronchial, alveolar) UFP deposition show clearly that females tend to develop higher tracheobronchial and alveolar deposition fractions than males. This discrepancy is also confirmed by airway generation-specific deposition, which is permanently higher in women than in men. Conclusions From the experimental data and modeling predictions it can be concluded that females bear a slightly higher potential to develop lung insufficiencies after exposure to UFP than males. Besides higher deposition fractions occurring in female subjects, also total lung deposition dose is noticeably enhanced. PMID:27429960

Total deposition of ultrafine particles in the lungs of healthy men and women: experimental and theoretical results.

PubMed

Sturm, Robert

2016-06-01

Inhaled ultrafine particles (UFP) may induce greater adverse respiratory effects than larger particles occurring in the ambient atmosphere. Due to this potential of UFP to act as triggers for diverse lung injuries medical as well as physical research has been increasingly focused on the exact deposition behavior of the particles in lungs of various probands. Main purpose of the present study was the presentation of experimental and theoretical data of total, regional, and local UFP deposition in the lungs of men and women. Both experiments and theoretical simulations were carried out by using particle sizes of 0.04, 0.06, 0.08, and 0.10 µm [number median diameters (NMD)]. Inhalation of UFP took place by application of predefined tidal volumes (500, 750, and 1,000 mL) and respiratory flow rates (150, 250, 375, and 500 mL·s(-1)). For male subjects a functional residual capacity (FRC) of 3,911±892 mL was measured, whereas female probands had a FRC of 3,314±547 mL. Theoretical predictions were based on (I) a stochastic model of the tracheobronchial tree; (II) particle transport computations according to a random walk algorithm; and (III) empirical formulae for the description of UFP deposition. Total deposition fractions (TDF) are marked by a continuous diminution with increasing particle size. Whilst particles measuring 0.04 µm in size deposit in the respiratory tract by 40-70%, particles with a size of 0.10 µm exhibit deposition values ranging from 20% to 45%. Except for the largest particles studied here TDF of female probands are higher than those obtained for male probands. Differences between experimental and theoretical results are most significant for 0.10 µm particles, but never exceed 20%. Predictions of regional (extrathoracic, tracheobronchial, alveolar) UFP deposition show clearly that females tend to develop higher tracheobronchial and alveolar deposition fractions than males. This discrepancy is also confirmed by airway generation-specific deposition, which is permanently higher in women than in men. From the experimental data and modeling predictions it can be concluded that females bear a slightly higher potential to develop lung insufficiencies after exposure to UFP than males. Besides higher deposition fractions occurring in female subjects, also total lung deposition dose is noticeably enhanced.

Comparison of lung burdens of inhaled particles of rats exposed during the day or night

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hesseltine, G.R.; Wolff, R.K.; Hanson, R.L.

Inhalation studies frequently involve daytime exposures of nocturnal animals to toxicants. Such exposures may result in different respiratory tract depositions than would be obtained if rodents were exposed at night. Our study assessed the effect of night versus day exposures on lung burdens of particles inhaled by Fischer 344 rats. One group of 15 female rats was exposed to 0.3 micron volume median diameter particles of gallium oxide (Ga2O3) for 11.2 h during the day and a second group of 15 female rats was exposed to the same aerosol for 11.2 h at night. Gallium in the lungs at themore » end of exposure was measured by electrothermal atomic absorption spectrometry. Rats exposed during the night had significantly (p less than 0.05) higher lung burdens than day-exposed rats when burdens were expressed as either microgram Ga2O3/lung (mean +/- SD = 896 +/- 175 versus 698 +/- 150) or microgram Ga2O3/g lung (mean +/- SD = 683 +/- 134 versus 465 +/- 103). The greater amount of material in lungs of rats exposed at night probably reflected increased ventilation accompanying nocturnal activity.« less

Lung volume is a determinant of aerosol bolus dispersion.

PubMed

Schulz, Holger; Eder, Gunter; Heyder, Joachim

2003-01-01

The technique of inhaling a small volume element labeled with particles ("aerosol bolus") can be used to assess convective gas mixing in the lung. While a bolus undergoes mixing in the lung, particles are dispersed in an increasing volume of the respired air. However, determining factors of bolus dispersion are not yet completely understood. The present study tested the hypothesis that bolus dispersion is related, among others, to the total volume in which the bolus is allowed to mix--i.e., to the individual lung size. Bolus dispersion was measured in 32 anesthetized, mechanically ventilated dogs with total lung capacities (TLCs) of 1.1-2.5 L. Six-milliliter aerosol boluses were introduced at various preselected time-points during inspiration to probe different volumetric lung depths. Dispersion (SD) was determined by moment analysis of particle concentrations in the expired air. We found linear correlations between SD at a given lung depth and the individual end-inspiratory lung volume (V(L)). The relationship was tightest for boluses inhaled deepest into the lungs: SD(40) = 0.068 V(L) - 1.77, r(2) = 0.59. Normalizing SD to V(L) abolished this dependency and resulted in a considerable reduction of inter-individual variability as compared to the uncorrected measurements. These data indicate that lung size influences measurements of bolus dispersion. It therefore appears reasonable to apply a normalization procedure before interpreting the data. Apart from a reduction in measurement variability, this should help to separate the effects on bolus dispersion of altered lung volumes and altered mixing processes in diseased lungs.

MATHEMATICAL ANALYSIS OF PARTICLE TRANSPORT AND DEPOSITION IN HUMAN LUNGS

EPA Science Inventory

MATHEMATICAL ANALYSIS OF PARTICLE TRANSPORT AND DEPOSITION IN HUMAN LUNGS. Jung-il Choi*, Center for Environmental Medicine, University of North Carolina, Chapel Hill, NC 27599; C. S. Kim, USEPA National Health and Environmental Effects Research Lab. RTP, NC 27711

Partic...

A Lagrangian Approach for Calculating Microsphere Deposition in a One-Dimensional Lung-Airway Model.

PubMed

Vaish, Mayank; Kleinstreuer, Clement

2015-09-01

Using the open-source software openfoam as the solver, a novel approach to calculate microsphere transport and deposition in a 1D human lung-equivalent trumpet model (TM) is presented. Specifically, for particle deposition in a nonlinear trumpetlike configuration a new radial force has been developed which, along with the regular drag force, generates particle trajectories toward the wall. The new semi-empirical force is a function of any given inlet volumetric flow rate, micron-particle diameter, and lung volume. Particle-deposition fractions (DFs) in the size range from 2 μm to 10 μm are in agreement with experimental datasets for different laminar and turbulent inhalation flow rates as well as total volumes. Typical run times on a single processor workstation to obtain actual total deposition results at comparable accuracy are 200 times less than that for an idealized whole-lung geometry (i.e., a 3D-1D model with airways up to 23rd generation in single-path only).

Automatic lung lobe segmentation using particles, thin plate splines, and maximum a posteriori estimation.

PubMed

Ross, James C; San José Estépar, Rail; Kindlmann, Gordon; Díaz, Alejandro; Westin, Carl-Fredrik; Silverman, Edwin K; Washko, George R

2010-01-01

We present a fully automatic lung lobe segmentation algorithm that is effective in high resolution computed tomography (CT) datasets in the presence of confounding factors such as incomplete fissures (anatomical structures indicating lobe boundaries), advanced disease states, high body mass index (BMI), and low-dose scanning protocols. In contrast to other algorithms that leverage segmentations of auxiliary structures (esp. vessels and airways), we rely only upon image features indicating fissure locations. We employ a particle system that samples the image domain and provides a set of candidate fissure locations. We follow this stage with maximum a posteriori (MAP) estimation to eliminate poor candidates and then perform a post-processing operation to remove remaining noise particles. We then fit a thin plate spline (TPS) interpolating surface to the fissure particles to form the final lung lobe segmentation. Results indicate that our algorithm performs comparably to pulmonologist-generated lung lobe segmentations on a set of challenging cases.

Automatic Lung Lobe Segmentation Using Particles, Thin Plate Splines, and Maximum a Posteriori Estimation

PubMed Central

Ross, James C.; Estépar, Raúl San José; Kindlmann, Gordon; Díaz, Alejandro; Westin, Carl-Fredrik; Silverman, Edwin K.; Washko, George R.

2011-01-01

We present a fully automatic lung lobe segmentation algorithm that is effective in high resolution computed tomography (CT) datasets in the presence of confounding factors such as incomplete fissures (anatomical structures indicating lobe boundaries), advanced disease states, high body mass index (BMI), and low-dose scanning protocols. In contrast to other algorithms that leverage segmentations of auxiliary structures (esp. vessels and airways), we rely only upon image features indicating fissure locations. We employ a particle system that samples the image domain and provides a set of candidate fissure locations. We follow this stage with maximum a posteriori (MAP) estimation to eliminate poor candidates and then perform a post-processing operation to remove remaining noise particles. We then fit a thin plate spline (TPS) interpolating surface to the fissure particles to form the final lung lobe segmentation. Results indicate that our algorithm performs comparably to pulmonologist-generated lung lobe segmentations on a set of challenging cases. PMID:20879396

Comparison of non-crystalline silica nanoparticles in IL-1β release from macrophages

PubMed Central

2012-01-01

Background Respirable crystalline silica (silicon dioxide; SiO2, quartz) particles are known to induce chronic inflammation and lung disease upon long-term inhalation, whereas non-crystalline (amorphous) SiO2 particles in the submicrometre range are regarded as less harmful. Several reports have demonstrated that crystalline, but also non-crystalline silica particles induce IL-1β release from macrophages via the NALP3-inflammasome complex (caspase-1, ASC and NALP3) in the presence of lipopolysaccharide (LPS) from bacteria. Our aim was to study the potential of different non-crystalline SiO2 particles from the nano- to submicro-sized range to activate IL-1β responses in LPS-primed RAW264.7 macrophages and primary rat lung macrophages. The role of the NALP3-inflammasome and up-stream mechanisms was further explored in RAW264.7 cells. Results In the present study, we have shown that 6 h exposure to non-crystalline SiO2 particles in nano- (SiNPs, 5–20 nm, 50 nm) and submicro-sizes induced strong IL-1β responses in LPS-primed mouse macrophages (RAW264.7) and primary rat lung macrophages. The primary lung macrophages were more sensitive to Si-exposure than the RAW-macrophages, and responded more strongly. In the lung macrophages, crystalline silica (MinUsil 5) induced IL-1β release more potently than the non-crystalline Si50 and Si500, when adjusted to surface area. This difference was much less pronounced versus fumed SiNPs. The caspase-1 inhibitor zYVAD and RNA silencing of the NALP3 receptor reduced the particle-induced IL-1β release in the RAW264.7 macrophages. Furthermore, inhibitors of phagocytosis, endosomal acidification, and cathepsin B activity reduced the IL-1β responses to the different particles to a similar extent. Conclusions In conclusion, non-crystalline silica particles in the nano- and submicro-size ranges seemed to induce IL-1β release from LPS-primed RAW264.7 macrophages via similar mechanisms as crystalline silica, involving particle uptake, phagosomal leakage and activation of the NALP3 inflammasome. Notably, rat primary lung macrophages were more sensitive with respect to silica-induced IL-1β release. The differential response patterns obtained suggest that silica-induced IL-1β responses not only depend on the particle surface area, but on factors and/or mechanisms such as particle reactivity or particle uptake. These findings may suggest that bacterial infection via LPS may augment acute inflammatory effects of non-crystalline as well as crystalline silica particles. PMID:22882971

Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery

NASA Astrophysics Data System (ADS)

Zhou, Jihan; Li, Dong; Wen, Hao; Zheng, Shuquan; Su, Cuicui; Yi, Fan; Wang, Jue; Liang, Zicai; Tang, Tao; Zhou, Demin; Zhang, Li-He; Liang, Dehai; Du, Quan

2016-03-01

Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.

The movement and deposition of PM2.5 in the upper respiratory tract for the patients with heart failure: an elementary CFD study.

PubMed

Zhang, Tiantian; Gao, Bin; Zhou, Zhixiang; Chang, Yu

2016-12-28

PM2.5 is an important factor to affect the patients with respiratory and cardiovascular diseases. Clinical studies have found that the morbidity and mortality of patients with heart failure (HF) have a close relationship with the movement and deposition state of PM2.5. One reason is that the breathing pattern of patients with HF has obvious difference with healthy people, however the effect caused by these differences on the distribution regularity of PM2.5 in the respiratory tract is still unclear. Hence, a computational fluid dynamics simulation was conducted to clarify the aerodynamic effect of breathing pattern of patients with HF on respiratory system. Ideal upper respiratory tract geometric model was established based on standardized aerosol research laboratory of Alberta and Weibel A dimension. The discrete phase method is used to calculate the movement of the airflow and particles. The flow rate were chosen as the inlet boundary conditions, and the outlets are set at a constant pressure. The rate of particle deposition, distribution location, wall pressure, flow velocity and wall shear stress are obtained, and compared to the normal control. The results demonstrated that the rate of escaped particles in every bronchial outlet of the patients with HF was more than the normal controls, meanwhile the trapped was less (1024 < 1160). There was higher by 12.9% possibility that the PM2.5 entered the lungs than the normal control. The aerodynamic performances of HF patients are different from normal control. Compared to the normal control, under similar environment, there is higher possibility of PM2.5 moving into lungs, and these particles could affect the function of the respiratory system, resulting in the deterioration of the state of cardiovascular system. In short, it's necessary to pay more attention to the living environment of HF patients, to reduce the content of PM2.5 particles in the air, and reduce the damage of PM2.5 particles caused by breathing patterns.

Diesel exhaust particles induce the over expression of tumor necrosis factor-alpha (TNF-alpha) gene in alvelor machrophage and failed to induce apoptosis through activation of nuclear factor-kappaB (NF-kappaB)

EPA Science Inventory

Exposure to particulate matter (PM2.5-10), including diesel exhaust particles (DEP) has been reported to induce lung injury and exacerbation of asthma and chronic obstructive pulmonary disease. Alveolar macrophages play a major role in the lung's response to inhaled particles and...

Global Gene Expression Profiling in Lung Tissues of Rat Exposed to Lunar Dust Particles

NASA Technical Reports Server (NTRS)

Yeshitla, Samrawit A.; Lam, Chiu-Wing; Kidane, Yared H.; Feiveson, Alan H.; Ploutz-Snyder, Robert; Wu, Honglu; James, John T.; Meyers, Valerie E.; Zhang, Ye

2014-01-01

The Moon's surface is covered by a layer of fine, potential reactive dust. Lunar dust contain about 1-2% respirable very fine dust (less than 3 micrometers). The habitable area of any lunar landing vehicle and outpost would inevitably be contaminated with lunar dust that could pose a health risk. The purpose of the study is to analyze the dynamics of global gene expression changes in lung tissues of rats exposed to lunar dust particles. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.8, 21, and 61 mg/m3 of lunar dust. Animals were euthanized at 1 day and 13 weeks after the last inhalation exposure. After being lavaged, lung tissue from each animal was collected and total RNA was isolated. Four samples of each dose group were analyzed using Agilent Rat GE v3 microarray to profile global gene expression of 44K transcripts. After background subtraction, normalization, and log transformation, t tests were used to compare the mean expression levels of each exposed group to the control group. Correction for multiple testing was made using the method of Benjamini, Krieger, and Yekuteli (1) to control the false discovery rate. Genes with significant changes of at least 1.75 fold were identified as genes of interest. Both low and high doses of lunar dust caused dramatic, dose-dependent global gene expression changes in the lung tissues. However, the responses of lung tissue to low dose lunar dust are distinguished from those of high doses, especially those associated with 61mg/m3 dust exposure. The data were further integrated into the Ingenuity system to analyze the gene ontology (GO), pathway distribution and putative upstream regulators and gene targets. Multiple pathways, functions, and upstream regulators have been identified in response to lunar dust induced damage in the lung tissue.

Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation.

PubMed

Abid, Aamir D; Anderson, Donald S; Das, Gautom K; Van Winkle, Laura S; Kennedy, Ian M

2013-01-10

The deposition, clearance and translocation of europium-doped gadolinium oxide nanoparticles in a mouse lung were investigated experimentally. Nanoparticles were synthesized by spray flame pyrolysis. The particle size, crystallinity and surface properties were characterized. Following instillation, the concentrations of particles in organs were determined with inductively coupled plasma mass spectrometry. The protein corona coating the nanoparticles was found to be similar to the coating on more environmentally relevant nanoparticles such as iron oxide. Measurements of the solubility of the nanoparticles in surrogates of biological fluids indicated very little propensity for dissolution, and the elemental ratio of particle constituents did not change, adding further support to the contention that intact nanoparticles were measured. The particles were intratracheally instilled into the mouse lung. After 24 hours, the target organs were harvested, acid digested and the nanoparticle mass in each organ was measured by inductively coupled plasma mass spectrometry (ICP-MS). The nanoparticles were detected in all the studied organs at low ppb levels; 59% of the particles remained in the lung. A significant amount of particles was also detected in the feces, suggesting fast clearance mechanisms. The nanoparticle system used in this work is highly suitable for quantitatively determining deposition, transport and clearance of nanoparticles from the lung, providing a quantified measure of delivered dose.

A new method for measuring lung deposition efficiency of airborne nanoparticles in a single breath

NASA Astrophysics Data System (ADS)

Jakobsson, Jonas K. F.; Hedlund, Johan; Kumlin, John; Wollmer, Per; Löndahl, Jakob

2016-11-01

Assessment of respiratory tract deposition of nanoparticles is a key link to understanding their health impacts. An instrument was developed to measure respiratory tract deposition of nanoparticles in a single breath. Monodisperse nanoparticles are generated, inhaled and sampled from a determined volumetric lung depth after a controlled residence time in the lung. The instrument was characterized for sensitivity to inter-subject variability, particle size (22, 50, 75 and 100 nm) and breath-holding time (3-20 s) in a group of seven healthy subjects. The measured particle recovery had an inter-subject variability 26-50 times larger than the measurement uncertainty and the results for various particle sizes and breath-holding times were in accordance with the theory for Brownian diffusion and values calculated from the Multiple-Path Particle Dosimetry model. The recovery was found to be determined by residence time and particle size, while respiratory flow-rate had minor importance in the studied range 1-10 L/s. The instrument will be used to investigate deposition of nanoparticles in patients with respiratory disease. The fast and precise measurement allows for both diagnostic applications, where the disease may be identified based on particle recovery, and for studies with controlled delivery of aerosol-based nanomedicine to specific regions of the lungs.

A feasibility study on the use of phantoms with statistical lung masses for determining the uncertainty in the dose absorbed by the lung from broad beams of incident photons and neutrons

PubMed Central

Khankook, Atiyeh Ebrahimi; Hakimabad, Hashem Miri

2017-01-01

Abstract Computational models of the human body have gradually become crucial in the evaluation of doses absorbed by organs. However, individuals may differ considerably in terms of organ size and shape. In this study, the authors sought to determine the energy-dependent standard deviations due to lung size of the dose absorbed by the lung during external photon and neutron beam exposures. One hundred lungs with different masses were prepared and located in an adult male International Commission on Radiological Protection (ICRP) reference phantom. Calculations were performed using the Monte Carlo N-particle code version 5 (MCNP5). Variation in the lung mass caused great uncertainty: ~90% for low-energy broad parallel photon beams. However, for high-energy photons, the lung-absorbed dose dependency on the anatomical variation was reduced to <1%. In addition, the results obtained indicated that the discrepancy in the lung-absorbed dose varied from 0.6% to 8% for neutron beam exposure. Consequently, the relationship between absorbed dose and organ volume was found to be significant for low-energy photon sources, whereas for higher energy photon sources the organ-absorbed dose was independent of the organ volume. In the case of neutron beam exposure, the maximum discrepancy (of 8%) occurred in the energy range between 0.1 and 5 MeV. PMID:28077627

Developing an in vitro technology to study the inflammation potential of ambient particle types

NASA Astrophysics Data System (ADS)

Haddrell, Allen E.

Elevated levels of suspended particles in the troposphere, termed particulate matter, elicit a myriad of adverse health effects in humans, ranging from shortness of breath and wheezing to myocardial infarction and death. It is currently believed that the adverse health effects associated with particulate matter are mediated by the inflammatory response initiated by the lung following particulate matter inhalation. What remains an area of much interest is elucidating the specific properties of particulate matter, physical or chemical, that cause the upregulation of proinflammatory mediators. The basic premise of this thesis was to identify the specific chemical components of particulate matter responsible for its adverse health effects. To address this issue, instrumentation and methodology were developed wherein one could design, create, levitate and deposit particles of both known chemical composition and size onto lung cells, in vitro, followed by the monitoring of the downstream biological response. An initial study focused on the role of the endotoxin component in particulate matter toxicity. Through a series of blocking studies we found that endotoxin acted synergistically with the particle core to elicit upregulation of proinflammatory mediators, including IL-1beta, TNF-alpha and ICAM-1; all of which are associated with the NF-kappaB pathway. Through characterizing this relatively simple system, one observation became apparent: the presence of the insoluble particle core had a profound effect on the cellular response; that is to say, the particle core was not simply a delivery vector, but a determinant factor in the final intracellular location of the toxic chemical. The latter observation held true as other particle types were studied and in addition, it was found that the nature of the actual chemical species itself plays a dual role in particle toxicity; first by retaining its toxic properties and second by altering the physical properties of the particle. It stems from these findings that the toxicity of the chemical components must be studied in concert and not as individual entities.

Variation in Extracellular Detoxification Is a Link to Different Carcinogenicity among Chromates in Rodent and Human Lungs.

PubMed

Krawic, Casey; Luczak, Michal W; Zhitkovich, Anatoly

2017-09-18

Inhalation of soluble chromium(VI) is firmly linked with higher risks of lung cancer in humans. However, comparative studies in rats have found a high lung tumorigenicity for moderately soluble chromates but no tumors for highly soluble chromates. These major species differences remain unexplained. We investigated the impact of extracellular reducers on responses of human and rat lung epithelial cells to different Cr(VI) forms. Extracellular reduction of Cr(VI) is a detoxification process, and rat and human lung lining fluids contain different concentrations of ascorbate and glutathione. We found that reduction of chromate anions in simulated lung fluids was principally driven by ascorbate with only minimal contribution from glutathione. The addition of 500 μM ascorbate (∼rat lung fluid concentration) to culture media strongly inhibited cellular uptake of chromate anions and completely prevented their cytotoxicity even at otherwise lethal doses. While proportionally less effective, 50 μM extracellular ascorbate (∼human lung fluid concentration) also decreased uptake of chromate anions and their cytotoxicity. In comparison to chromate anions, uptake and cytotoxicity of respirable particles of moderately soluble CaCrO 4 and SrCrO 4 were much less sensitive to suppression by extracellular ascorbate, especially during early exposure times and in primary bronchial cells. In the absence of extracellular ascorbate, chromate anions and CaCrO 4 /SrCrO 4 particles produced overall similar levels of DNA double-stranded breaks, with less soluble particles exhibiting a slower rate of breakage. Our results indicate that a gradual extracellular dissolution and a rapid internalization of calcium chromate and strontium chromate particles makes them resistant to detoxification outside the cells, which is extremely effective for chromate anions in the rat lung fluid. The detoxification potential of the human lung fluid is significant but much lower and insufficient to provide a threshold-type dose dependence for soluble chromates.

Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial?

PubMed

Marcus, Pamela M; Doria-Rose, Vincent Paul; Gareen, Ilana F; Brewer, Brenda; Clingan, Kathy; Keating, Kristen; Rosenbaum, Jennifer; Rozjabek, Heather M; Rathmell, Joshua; Sicks, JoRean; Miller, Anthony B

2016-08-01

Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55-74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2-25.0), as compared with the published finding of 20% (95% confidence interval: 6.7-26.7). Death review may not be necessary for primary-outcome analyses in lung cancer screening trials. If deemed necessary, researchers should strive to streamline the death review process as much as possible. © The Author(s) 2016.

Surface reactivity of volcanic ash from the eruption of Soufrière Hills volcano, Montserrat, West Indies with implications for health hazards.

PubMed

Horwell, Claire J; Fenoglio, Ivana; Vala Ragnarsdottir, K; Sparks, R Steve J; Fubini, Bice

2003-10-01

The fine-grained character of volcanic ash generated in the long-lived eruption of the Soufrière Hills volcano, Montserrat, West Indies, raises the issue of its possible health hazards. Surface- and free-radical production has been closely linked to bioreactivity of dusts within the lung. In this study, electron paramagnetic resonance (EPR) techniques have been used, for the first time, on volcanic ash to measure the production of radicals from the surface of particles. Results show that concentrations of hydroxyl radicals (HO*) in respirable ash are two to three times higher than a toxic quartz standard. The dome-collapse ash contains cristobalite, a crystalline silica polymorph that may cause adverse health effects. EPR experiments indicate, however, that cristobalite in the ash does not contribute to HO* generation. Our results show that the main cause of reactivity is removable divalent iron (Fe2+), which is present in abundance on the surfaces of the particles and is very reactive in the lung. Our analyses show that fresh ash generates more HO* than weathered ash (which has undergone progressive oxidation and leaching of iron from exposed surfaces), an effect replicated experimentally by incubating fresh ash in dilute acid. HO* production experiments also indicate that iron-rich silicate minerals are responsible for surface reactivity in the Soufrière Hills ash.

Deposition efficiency of inhaled particles (15-5000 nm) related to breathing pattern and lung function: an experimental study in healthy children and adults.

PubMed

Rissler, Jenny; Gudmundsson, Anders; Nicklasson, Hanna; Swietlicki, Erik; Wollmer, Per; Löndahl, Jakob

2017-04-08

Exposure to airborne particles has a major impact on global health. The probability of these particles to deposit in the respiratory tract during breathing is essential for their toxic effects. Observations have shown that there is a substantial variability in deposition between subjects, not only due to respiratory diseases, but also among individuals with healthy lungs. The factors determining this variability are, however, not fully understood. In this study we experimentally investigate factors that determine individual differences in the respiratory tract depositions of inhaled particles for healthy subjects at relaxed breathing. The study covers particles of diameters 15-5000 nm and includes 67 subjects aged 7-70 years. A comprehensive examination of lung function was performed for all subjects. Principal component analyses and multiple regression analyses were used to explore the relationships between subject characteristics and particle deposition. A large individual variability in respiratory tract deposition efficiency was found. Individuals with high deposition of a certain particle size generally had high deposition for all particles <3500 nm. The individual variability was explained by two factors: breathing pattern, and lung structural and functional properties. The most important predictors were found to be breathing frequency and anatomical airway dead space. We also present a linear regression model describing the deposition based on four variables: tidal volume, breathing frequency, anatomical dead space and resistance of the respiratory system (the latter measured with impulse oscillometry). To understand why some individuals are more susceptible to airborne particles we must understand, and take into account, the individual variability in the probability of particles to deposit in the respiratory tract by considering not only breathing patterns but also adequate measures of relevant structural and functional properties.

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation.

PubMed

Bar-Shai, Amir; Alcalay, Yifat; Sagiv, Adi; Rotem, Michal; Feigelson, Sara W; Alon, Ronen; Fireman, Elizabeth

2015-01-01

Acute lung inflammation can be monitored by various biochemical readouts of bronchoalveolar lavage fluid (BALF). To analyze the BALF content of ultrafine particles (UFP; <100 nm) as an inflammatory biomarker in early diagnosis of acute and chronic lung diseases. Mice were exposed to different stress conditions and inflammatory insults (acute lipopolysaccharide inhalation, tobacco smoke and lethal dose of total body irradiation, i.e. 950 rad). After centrifugation, the cellular pellet was assessed while cytokines and ultrafine particles were measured in the soluble fraction of the BALF. A characteristic UFP distribution with a D50 (i.e. the dimension of the 50th UFP percentile) was shared by all tested mouse strains in the BALF of resting lungs. All tested inflammatory insults similarly shifted this size distribution, resulting in a unique UFP fingerprint with an averaged D50 of 58.6 nm, compared with the mean UFP D50 of 23.7 nm for resting BALF (p < 0.0001). This UFP profile was highly reproducible and independent of the intensity or duration of the inflammatory trigger. It returned to baseline after resolution of the inflammation. Neither total body irradiation nor induction of acute cough induced this fingerprint. The UFP fingerprint in the BALF of resting and inflamed lungs can serve as a binary biomarker of healthy and acutely inflamed lungs. This marker can be used as a novel readout for the onset of inflammatory lung diseases and for complete lung recovery from different insults.

Respiratory Health Effects of Volcanic Ash - a new Approach

NASA Astrophysics Data System (ADS)

Horwell, C. J.; Fenoglio, I.; Sparks, R. J.; Ragnarsdottir, K. V.; Fubini, B.

2003-12-01

Attempts to characterise the toxicity of volcanic ash have focused on the presence of the crystalline silica polymorph cristobalite, which is known to cause silicosis and lung cancer in industrial settings. Within the lung, it is the surface of the particles which will react with endogenous molecules. Free radicals, produced on particle surfaces, can react with DNA and other cellular components, instigating a chain of toxic events. For the first time, the ability of volcanic ash to form free radicals has been assessed using Electron Paramagnetic Resonance techniques specific to the hydroxyl radical. Respirable (< 4 microns) crystalline silica, separated from volcanic ash from the Soufriere Hills volcano, Montserrat, West Indies, did not produce hydroxyl free radicals or surface radicals. However, the ash, itself, generated up to 3 times more hydroxyl radicals than a quartz of known toxicity. The cause of the reactivity is reduced iron on the surface of iron-rich minerals such as amphiboles and pyroxenes. Fresh volcanic ash generates more free radicals than weathered volcanic ash which will have oxidised (and leached away) surface iron. These results have implications for volcanic health hazard research as it was previously assumed that volcanoes which did not produce respirable crystalline silica presented a lesser respiratory health hazard. The International Volcanic Health Hazard Network (IVHHN) promotes research into the health effects of volcanic emissions. Under the auspices of IVHHN, volcanic ash samples from volcanoes world-wide are being analysed for surface reactivity, grain-size distribution and composition to form a comprehensive database for use by volcano observatories, emergency managers, medical practitioners and researchers. The results will highlight volcanoes which have the potential to cause a respiratory health hazard through generation of iron-catalysed free radicals, as well as more conventional markers such as concentration of respirable particles. At the onset of new eruptions, the database will be used to aid the rapid assessment of health hazard from volcanic ash.

Lung Cancer—Patient Version

Cancer.gov

The two main types of lung cancer are non-small cell lung cancer and small cell lung cancer. Smoking causes most lung cancers, but nonsmokers can also develop lung cancer. Start here to find information on lung cancer treatment, causes and prevention, screening, research, and statistics on lung cancer.

The effects of selected air pollutants on clearance of titanic oxide particles from the lungs of rats.

PubMed

Ferin, J; Leach, L J

1975-09-01

A procedure utilizing the lung clearance kinetics of titanic oxide (TiO2) particles was used to determine the effects of inhaled sulphur dioxide (SO2) and nitrogen oxides (NO x) on particle clearance. The procedure is reproducible and mainly tests clearance mechanisms involving alveolar macrophages and the mucociliary transport system at the alveolobronchial clearance pathway. At low SO2 or NOx exposures enhanced particle clearance was observed. Lung clearance was depressed at 15 and 24 ppm of NO2 after 22 exposures as well as at 20 ppm of SO2 after 11 exposures, and also at 1 ppm of SO2 after 25 exposures. Dose-response curves for the SO2 and NOx exposures showed differences explainable by the routes by which these gases reach the alveolar macrophages.

Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

NASA Technical Reports Server (NTRS)

Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

2010-01-01

Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

REGIONAL DEPOSITION DOSE OF INHALED NANO-SIZE PARTICLES IN HUMAN LUNGS DURING CONTROLLED NORMAL BREATHING

EPA Science Inventory

INTRODUCTION

One of the key factors for affecting respiratory

deposition of particles is the breathing pattern of

individual subjects. Although idealized breathing

patterns (square or sine wave form) are frequently used

for studying lung deposit...

Effect of Phase Lag on Fluid Flow and Particle Dispersion in a Single Human Alveolus

NASA Astrophysics Data System (ADS)

Chhabra, Sudhaker; Prasad, Ajay

2007-11-01

The human lung can be divided into (1) the conducting airways, and (2) the acini. The acini are responsible for gas exchange and consist of alveoli and bronchioles. The acini are useful delivery sites for inhaled therapeutic aerosols. In normal lung function the alveolus expands and contracts in phase with the bronchiole airflow oscillation. Lung diseases such as emphysema compromise the elasticity of the lung. Consequently, the alveolus may not oscillate in-phase with the oscillating bronchiole airflow. We have previously studied flow and particle transport in an alveolus for in-phase flow. The current work focuses on measuring out-of-phase airflow patterns and particle transport in an in-vitro model of a single expanding/contracting human alveolus. The model consists of a transparent, elastic, oscillating alveolus (represented by a 5/6th hemisphere) attached to a rigid circular tube. Realistic tidal breathing conditions were achieved by matching Reynolds and Womersley numbers. Flow patterns were measured using PIV; these velocity maps were subsequently used to calculate particle transport and deposition on the alveolar wall.

Impact of acute exposure to WTC dust on ciliated and goblet cells in lungs of rats

PubMed Central

Cohen, Mitchell D.; Vaughan, Joshua M.; Garrett, Brittany; Prophete, Colette; Horton, Lori; Sisco, Maureen; Ghio, Andrew; Zelikoff, Judith; Lung-chi, Chen

2015-01-01

Clinical studies and the World Trade Center (WTC) Health Registry have revealed increases in the incidence of chronic (non-cancer) lung disorders among first responders (FR) who were at Ground Zero during the initial 72 h after the collapse. Our previous analyses of rats exposed to building-derived WTC dusts using exposure scenarios/levels that mimicked FR mouth-breathing showed that a single WTC dust exposure led to changes in expression of genes whose products could be involved in the lung ailments, but few other significant pathologies. We concluded that rather than acting as direct inducers of many of the FR health effects, it was more likely inhaled WTC dusts instead may have impacted on toxicities induced by other rescue-related co-pollutants present in Ground Zero air. To allow for such effects to occur, we hypothesized that the alkaline WTC dusts induced damage to the normal ability of the lungs to clear inhaled particles. To validate this, rats were exposed on two consecutive days (2 h/d, by intratracheal inhalation) to WTC dust (collected 12–13 September 2001) and examined over a 1-yr period thereafter for changes in the presence of ciliated cells in the airways and hyperplastic goblet cells in the lungs. WTC dust levels in the lungs were assessed in parallel to verify that any changes in levels of these cells corresponded with decreases in host ability to clear the particles themselves. Image analyses of the rat lungs revealed a significant decrease in ciliated cells and increase in hyperplastic goblet cells due to the single series of WTC dust exposures. The study also showed there was only a nominal non-significant decrease (6–11%) in WTC dust burden over a 1-yr period after the final exposure. These results provide support for our current hypothesis that exposure to WTC dusts caused changes in airway morphology/cell composition; such changes could, in turn, have led to potential alterations in the clearance/toxicities of other pollutants inhaled at Ground Zero in the critical initial 72-h period. PMID:26194034

Impact of acute exposure to WTC dust on ciliated and goblet cells in lungs of rats.

PubMed

Cohen, Mitchell D; Vaughan, Joshua M; Garrett, Brittany; Prophete, Colette; Horton, Lori; Sisco, Maureen; Ghio, Andrew; Zelikoff, Judith; Lung-chi, Chen

2015-01-01

Clinical studies and the World Trade Center (WTC) Health Registry have revealed increases in the incidence of chronic (non-cancer) lung disorders among first responders (FR) who were at Ground Zero during the initial 72 h after the collapse. Our previous analyses of rats exposed to building-derived WTC dusts using exposure scenarios/levels that mimicked FR mouth-breathing showed that a single WTC dust exposure led to changes in expression of genes whose products could be involved in the lung ailments, but few other significant pathologies. We concluded that rather than acting as direct inducers of many of the FR health effects, it was more likely inhaled WTC dusts instead may have impacted on toxicities induced by other rescue-related co-pollutants present in Ground Zero air. To allow for such effects to occur, we hypothesized that the alkaline WTC dusts induced damage to the normal ability of the lungs to clear inhaled particles. To validate this, rats were exposed on two consecutive days (2 h/d, by intratracheal inhalation) to WTC dust (collected 12-13 September 2001) and examined over a 1-yr period thereafter for changes in the presence of ciliated cells in the airways and hyperplastic goblet cells in the lungs. WTC dust levels in the lungs were assessed in parallel to verify that any changes in levels of these cells corresponded with decreases in host ability to clear the particles themselves. Image analyses of the rat lungs revealed a significant decrease in ciliated cells and increase in hyperplastic goblet cells due to the single series of WTC dust exposures. The study also showed there was only a nominal non-significant decrease (6-11%) in WTC dust burden over a 1-yr period after the final exposure. These results provide support for our current hypothesis that exposure to WTC dusts caused changes in airway morphology/cell composition; such changes could, in turn, have led to potential alterations in the clearance/toxicities of other pollutants inhaled at Ground Zero in the critical initial 72-h period.

Physicochemical characterization of Capstone depleted uranium aerosols III: morphologic and chemical oxide analyses.

PubMed

Krupka, Kenneth M; Parkhurst, Mary Ann; Gold, Kenneth; Arey, Bruce W; Jenson, Evan D; Guilmette, Raymond A

2009-03-01

The impact of depleted uranium (DU) penetrators against an armored target causes erosion and fragmentation of the penetrators, the extent of which is dependent on the thickness and material composition of the target. Vigorous oxidation of the DU particles and fragments creates an aerosol of DU oxide particles and DU particle agglomerations combined with target materials. Aerosols from the Capstone DU aerosol study, in which vehicles were perforated by DU penetrators, were evaluated for their oxidation states using x-ray diffraction (XRD), and particle morphologies were examined using scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS). The oxidation state of a DU aerosol is important as it offers a clue to its solubility in lung fluids. The XRD analysis showed that the aerosols evaluated were a combination primarily of U3O8 (insoluble) and UO3 (relatively more soluble) phases, though intermediate phases resembling U4O9 and other oxides were prominent in some samples. Analysis of particle residues in the micrometer-size range by SEM/EDS provided microstructural information such as phase composition and distribution, fracture morphology, size distribution, and material homogeneity. Observations from SEM analysis show a wide variability in the shapes of the DU particles. Some of the larger particles were spherical, occasionally with dendritic or lobed surface structures. Others appear to have fractures that perhaps resulted from abrasion and comminution, or shear bands that developed from plastic deformation of the DU material. Amorphous conglomerates containing metals other than uranium were also common, especially with the smallest particle sizes. A few samples seemed to contain small bits of nearly pure uranium metal, which were verified by EDS to have a higher uranium content exceeding that expected for uranium oxides. Results of the XRD and SEM/EDS analyses were used in other studies described in this issue of Health Physics to interpret the results of lung solubility studies and in selecting input parameters for dose assessments.

Physicochemical Characterization of Capstone Depleted Uranium Aerosols III: Morphologic and Chemical Oxide Analyses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupka, Kenneth M.; Parkhurst, MaryAnn; Gold, Kenneth

2009-03-01

The impact of depleted uranium (DU) penetrators against an armored target causes erosion and fragmentation of the penetrators, the extent of which is dependent on the thickness and material composition of the target. Vigorous oxidation of the DU particles and fragments creates an aerosol of DU oxide particles and DU particle agglomerations combined with target materials. Aerosols from the Capstone DU aerosol study, in which vehicles were perforated by DU penetrators, were evaluated for their oxidation states using X-ray diffraction (XRD) and particle morphologies using scanning electron microscopy/energy dispersive spectrometry (SEM/EDS). The oxidation state of a DU aerosol is importantmore » as it offers a clue to its solubility in lung fluids. The XRD analysis showed that the aerosols evaluated were a combination primarily of U3O8 (insoluble) and UO3 (relatively more soluble) phases, though intermediate phases resembling U4O9 and other oxides were prominent in some samples. Analysis of particle residues in the micrometer-size range by SEM/EDS provided microstructural information such as phase composition and distribution, fracture morphology, size distribution, and material homogeneity. Observations from SEM analysis show a wide variability in the shapes of the DU particles. Some of the larger particles appear to have been fractured (perhaps as a result of abrasion and comminution); others were spherical, occasionally with dendritic or lobed surface structures. Amorphous conglomerates containing metals other than uranium were also common, especially with the smallest particle sizes. A few samples seemed to contain small chunks of nearly pure uranium metal, which were verified by EDS to have a higher uranium content exceeding that expected for uranium oxides. Results of the XRD and SEM/EDS analyses were used in other studies described in this issue of The Journal of Health Physics to interpret the results of lung solubility studies and in selecting input parameters for dose assessments.« less

In vitro effects of coal fly ashes: hydroxyl radical generation, iron release, and DNA damage and toxicity in rat lung epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

van Maanen, J.M.; Borm, P.J.; Knaapen, A

1999-12-15

The authors measured iron release, acellular generation of hydroxyl radicals, and oxidative DNA damage and cytotoxicity in rat lung epithelial (RLE) cells by different coal fly ashes (CFA) that contain both quartz and iron. Seven samples of CFA with different particle size and quartz content (up to 14.1%) were tested along with silica (alpha-quartz), ground coal, and coal mine dust (respirable) as positive control particles, and fine TiO{sub 2} (anatase) as a negative control. Five test samples were pulverized fuel ashes (PFA), two samples were coal gasification (SCG) ashes (quartz content {lt} 0.1%), and one sample was a ground coal.more » No marked differences between SCG and PFA fly ashes were observed, and toxicity did not correlate with physicochemical characteristics or effect parameters. Stable surface radicals were only detected in the reference particles silica and coal mine dust, but not in CFA. On the other hand, hydroxyl radical generation by all fly ashes was observed in the presence of hydrogen peroxide. Also a relationship between acellular hydroxyl radical generation and oxidative DNA damage in RLE cells by CFA was observed. The respirable ashes (MAT023, 38, and 41) showed an extensive level of hydroxyl radical generation in comparison to nonrespirable fly ashes and respirable references. This was related to the iron mobilization from these particles. Themechanisms by which CFA and the positive references (silica, coal mine dust) affect rat lung epithelial cells seem to be different, and the data suggest that quartz in CFA does not act the same as quartz in silica or coal mine dust. However, the results indicate an important role for size and iron release in generation and subsequent effects of reactive oxygen species caused by CFA.« less

Effects of nitrogen dioxide on respiratory tract clearance in the ferret

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rasmussen, R.E.; Mannix, R.C.; Oldham, M.J.

1994-01-01

During growth and development, young children are periodically exposed to relatively high concentrations of various air contaminants, including tobacco smoke and environmental pollutants generated by fossil fuel use. The effects of these exposures on respiratory function and lung development are difficult to determine because of interindividual variation and lack of accurate dosimetry. To provide information on the effects of chronic exposure to a common indoor and outdoor pollutant during lung development, a study was performed to assess the effects of exposure to two concentrations of nitrogen dioxide (NO[sub 2]; 0.5 or 10 ppm) on tracer particle clearance from the airwaysmore » of ferrets exposed during postnatal respiratory tract development. Separate groups of ferrets were exposed nose-only to the test atmospheres or clean air 4 h/d, 5 d/wk, for either 8 or 15 wk. Those animals exposed for 8 wk were subsequently housed in a filtered air environment until the particle clearance measurements commenced at 3 wk prior to the end of the 15-wk exposure protocol. Radiolabeled ([sup 51]Cr) tracer particles were deposited in the respiratory tract of all animals by inhalation, and the clearance rates from the head and thoracic regions were separately monitored for 18 d. No significant effects of the NO[sub 2] exposure on head airways clearance were seen. In contrast, the rates of particle clearance from the thorax of both the 8- and 15-wk groups exposed to 10 ppm NO[sub 2] were significantly reduced, and did not differ from each other. Thoracic clearance was also reduced in animals exposed to 0.5 ppm, but the rate was not significantly different from that of the clean air exposed controls. These results show that NO[sub 2] at moderate concentrations caused highly significant changes in the deep lung of the juvenile ferret, and suggest that impairment of the clearance function may be only slowly recovered after chronic exposure. 35 refs., 1 fig., 1 tab.« less

Respiratory Effects of Fine and Ultrafine Particles from Indoor Sources—A Randomized Sham-Controlled Exposure Study of Healthy Volunteers

PubMed Central

Soppa, Vanessa J.; Schins, Roel P. F.; Hennig, Frauke; Hellack, Bryan; Quass, Ulrich; Kaminski, Heinz; Kuhlbusch, Thomas A. J.; Hoffmann, Barbara; Weinmayr, Gudrun

2014-01-01

Particulate air pollution is linked to impaired respiratory health. We analyzed particle emissions from common indoor sources (candles burning (CB), toasting bread (TB), frying sausages (FS)) and lung function in 55 healthy volunteers (mean age 33.0 years) in a randomized cross-over controlled exposure study. Lung-deposited particle surface area concentration (PSC), size-specific particle number concentration (PNC) up to 10 µm, and particle mass concentration (PMC) of PM1, PM2.5 and PM10 were determined during exposure (2 h). FEV1, FVC and MEF25%–75% was measured before, 4 h and 24 h after exposure. Wilcoxon-rank sum tests (comparing exposure scenarios) and mixed linear regression using particle concentrations and adjusting for personal characteristics, travel time and transportation means before exposure sessions were performed. While no effect was seen comparing the exposure scenarios and in the unadjusted model, inverse associations were found for PMC from CB and FS in relation to FEV1 and MEF25%–75%. with a change in 10 µg/m3 in PM2.5 from CB being associated with a change in FEV1 of −19 mL (95%-confidence interval:−43; 5) after 4 h. PMC from TB and PNC of UFP were not associated with lung function changes, but PSC from CB was. Elevated indoor fine particles from certain sources may be associated with small decreases in lung function in healthy adults. PMID:25000149

Evaluation of an exposure setup for studying effects of diesel exhaust in humans.

PubMed

Rudell, B; Sandström, T; Hammarström, U; Ledin, M L; Hörstedt, P; Stjernberg, N

1994-01-01

Diesel exhaust is a common air pollutant and work exposure has been reported to cause discomfort and affect lung function. The aim of this study was to develop an experimental setup which would allow investigation of acute effects on symptoms and lung function in humans exposed to diluted diesel exhaust. Diluted diesel exhaust was fed from an idling lorry through heated tubes into an exposure chamber. During evaluations of the setup we found the size and the shape of the exhaust particles to appear unchanged during the transport from the tail pipe to the exposure chamber. The composition of the diesel exhaust expressed as the ratios CO/NO, total hydrocarbons/NO, particles/NO, NO2/NO, and formaldehyde/NO were almost constant at different dilutions. The concentrations of NO2 and particles in the exposure chamber showed no obvious gradients. New steady state concentrations in the exposure chamber were obtained within 5-7 min. In a separate experiment eight healthy nonsmoking subjects were exposed to diluted exhaust at a median steady state concentration of 1.6 ppm NO2 for the duration of 1 h in the exposure chamber. All subjects experienced unpleasant smell, eye irritation, and nasal irritation. Throat irritation, headache, dizziness, nausea, tiredness, and coughing were experienced by some subjects. Lung function was not found to be affected during the exposure. The experimental setup was found to be appropriate for creating different predetermined steady state concentrations in the exposure chamber of diluted exhaust from a continuously idling vehicle. The acute symptoms reported by the subjects were relatively similar to what patients reported at different workplaces.

A new method for measuring lung deposition efficiency of airborne nanoparticles in a single breath

PubMed Central

Jakobsson, Jonas K. F.; Hedlund, Johan; Kumlin, John; Wollmer, Per; Löndahl, Jakob

2016-01-01

Assessment of respiratory tract deposition of nanoparticles is a key link to understanding their health impacts. An instrument was developed to measure respiratory tract deposition of nanoparticles in a single breath. Monodisperse nanoparticles are generated, inhaled and sampled from a determined volumetric lung depth after a controlled residence time in the lung. The instrument was characterized for sensitivity to inter-subject variability, particle size (22, 50, 75 and 100 nm) and breath-holding time (3–20 s) in a group of seven healthy subjects. The measured particle recovery had an inter-subject variability 26–50 times larger than the measurement uncertainty and the results for various particle sizes and breath-holding times were in accordance with the theory for Brownian diffusion and values calculated from the Multiple-Path Particle Dosimetry model. The recovery was found to be determined by residence time and particle size, while respiratory flow-rate had minor importance in the studied range 1–10 L/s. The instrument will be used to investigate deposition of nanoparticles in patients with respiratory disease. The fast and precise measurement allows for both diagnostic applications, where the disease may be identified based on particle recovery, and for studies with controlled delivery of aerosol-based nanomedicine to specific regions of the lungs. PMID:27819335

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part I: Theory and model validation.

PubMed

Kolanjiyil, Arun V; Kleinstreuer, Clement

2016-12-01

Computational predictions of aerosol transport and deposition in the human respiratory tract can assist in evaluating detrimental or therapeutic health effects when inhaling toxic particles or administering drugs. However, the sheer complexity of the human lung, featuring a total of 16 million tubular airways, prohibits detailed computer simulations of the fluid-particle dynamics for the entire respiratory system. Thus, in order to obtain useful and efficient particle deposition results, an alternative modeling approach is necessary where the whole-lung geometry is approximated and physiological boundary conditions are implemented to simulate breathing. In Part I, the present new whole-lung-airway model (WLAM) represents the actual lung geometry via a basic 3-D mouth-to-trachea configuration while all subsequent airways are lumped together, i.e., reduced to an exponentially expanding 1-D conduit. The diameter for each generation of the 1-D extension can be obtained on a subject-specific basis from the calculated total volume which represents each generation of the individual. The alveolar volume was added based on the approximate number of alveoli per generation. A wall-displacement boundary condition was applied at the bottom surface of the first-generation WLAM, so that any breathing pattern due to the negative alveolar pressure can be reproduced. Specifically, different inhalation/exhalation scenarios (rest, exercise, etc.) were implemented by controlling the wall/mesh displacements to simulate realistic breathing cycles in the WLAM. Total and regional particle deposition results agree with experimental lung deposition results. The outcomes provide critical insight to and quantitative results of aerosol deposition in human whole-lung airways with modest computational resources. Hence, the WLAM can be used in analyzing human exposure to toxic particulate matter or it can assist in estimating pharmacological effects of administered drug-aerosols. As a practical WLAM application, the transport and deposition of asthma drugs from a commercial dry-powder inhaler is discussed in Part II. Copyright © 2016 Elsevier Ltd. All rights reserved.

Particle characteristics and lung deposition patterns in a human airway replica of a dry powder formulation of polylactic acid produced using supercritical fluid technology.

PubMed

Cheng, Y S; Yazzie, D; Gao, J; Muggli, D; Etter, J; Rosenthal, G J

2003-01-01

Polylactic acid (PLA) powders have been used as vector particles to carry pharmaceutical material. Drugs incorporated in the PLA powder can be retained in the lung for a longer period and may be more effective than free-form drugs. A new formulation of L-PLA dry powder, which was easy to disperse in the air, was produced by using a supercritical technology. The L-PLA powder was characterized in terms of physical particle size and aerodynamic size as generated with a Turbuhaler dry powder inhaler (DPI). Electron microscopy analysis of the particles indicated that they were individual particles in bulk form and became aggregate particles after generation by the Turbuhaler. Aerodynamic particle size analysis using both an Aerodynamic Particle Sizer (APS) aerosol spectrometer and Andersen impactor showed that the aerodynamic size decreased as the flow rate in the Turbuhaler increased from 28.3 to 90 L min(-1). Deposition patterns in the human respiratory tract were estimated using a realistic physical replica of human airways. Deposition of the L-PLA was high (80.8%) in the oral airway at 28.3 L min(-1) and an average of 73.4% at flow rates of 60 and 90 L min(-1). In the lung region, the deposition totaled 7.2% at 28.3 L min(-1), 18.3% at 60 L min(-1), and 17.6% at 90 L min(-1). These deposition patterns were consistent with aerodynamic size measurement, which showed 76 to 86% deposition in the USP/EP (US Pharmacopoeia/European Pharmacopoeia) induction port. As the flow rate increased, fewer aggregates were formed resulting in the smaller aerodynamic particles. As a result, more particles penetrated the oral airways and were available for deposition in the lung. Our results showed that L-PLA particles as manufactured by the supercritical technology could be used in a DPI that does not require the use of carrier particles to facilitate aerosol delivery.

In vitro and in vivo lung deposition of coated magnetic aerosol particles.

PubMed

Xie, Yuanyuan; Longest, P Worth; Xu, Yun Hao; Wang, Jian Ping; Wiedmann, Timothy Scott

2010-11-01

The magnetic induced deposition of polydispersed aerosols composed of agglomerated superparamagnetic particles was measured with an in vitro model system and in the mouse trachea and deep lung for the purpose of investigating the potential of site specific respiratory drug delivery. Oleic acid coated superparamagnetic particles were prepared and characterized by TEM, induced magnetic moment, and iron content. The particles were dispersed in cyclohexane, aerosolized with an ultrasonic atomizer and dried by sequential reflux and charcoal columns. The fraction of iron deposited on glass tubes increased with particle size and decreasing flow rate. High deposition occurred with a small diameter tube, but the deposition fraction was largely independent of tube size at larger diameters. Results from computational fluid dynamics qualitatively agreed with the experimental results. Enhanced deposition was observed in the mouse lung but not in the trachea consistent with the analysis of the aerodynamic time allowed for deposition and required magnetic deposition time. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Improvements in lung lavage to increase its effectiveness in removing inhaled radionuclides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muggenburg, B.A.; Guilmette, R.A.; Romero, L.M.

Lung lavage has been shown to be an effective method to remove insoluble radionuclides deposited and retained in the lung, but the treatment has been limited to the effective removal of only about 50% of the retained material. Reported here is change in lavage technique that slightly increases the effectiveness and the addition of high-frequency chest wall oscillation. The latter increased the effectiveness of the lavage procedure but also caused significant physiological complications. These studies were conducted in adult male and female beagles. The aerosol in the first study was {sup 239}PuO{sub 2} heat-treated at 850{degrees}C, obtained as powder frommore » a commercial V-blending process. The dogs briefly inhaled the aerosol per nasi. The tissue content at death and the amount of {sup 239}Pu excreted and in the recovered lung lavage fluid was determined by radiochemical methods{sup 5}. These values were used to reconstruct the initial pulmonary burden of {sup 239} and the amount of {sup 239}Pu removed by lavage. In the second study, with the HFCWO, the aerosol was {sup 85}Sr fused in aluminosilicate particles. The IPB of {sup 85}Sr was determined by whole-body counting. The excreta and recovered lung lavage fluids were also assayed for {sup 85}Sr activity.« less

Lung burden of a glass fiber by inhalation.

PubMed

Tanaka, I; Akiyama, T; Kido, M

1991-01-01

Pulmonary deposition and clearance of deposited particles from lungs are very important factors in order to induce pneumoconioses. In this paper, five Wistar male rats were exposed to glass fiber particles (mass median aerodynamic diameter (MMAD), 2.8 microns) for 6 hrs/day, 5 days/week for 4 weeks. The average exposure concentration was controlled by a continuous fluidized bed with a screw feeder and an overflow pipe at 0.79 mg/m3 during the exposure period. The fibrous particles concentrations in the exposure chamber were monitored by a light scattering method and showed to be constant during the exposure. The rats were sacrificed at 24 hours after the termination of the exposure and then the wet lung weight and the silica concentration in the lungs were measured. The lungs were treated for low temperature ashing (ca. 150 degrees C) by a plasma asher. After ashing, these samples were melted with sodium carbonate in platinum pot for the measurement of the silica content by the absorption spectrophotometry. The maximum content of SiO2 was 45 micrograms in the exposed rats and 20 micrograms in the control. The deposited amount of SiO2 by the exposure to glass fiber was 25 micrograms. The apparent deposition fraction defined as the deposited amount in the lungs to the amount of the inhaled glass fiber during the exposure was 6.8%. There was no significant difference of the apparent deposition fraction at same MMAD between glass fiber in this study and non-fibrous particles.

Possible role of ammonia on the deposition, retention, and absorption of nicotine in humans while smoking.

PubMed

Seeman, Jeffrey I

2007-03-01

This perspective presents an overview of the properties of tobacco smoke aerosol and the possible effect of ammonia on the deposition location, retention and the amount and rate of nicotine absorption during cigarette smoking. Three main mechanisms describe the absorption of smoke constituents: (A) gas-phase constituents deposit directly; (B) particles deposit and the constituents then diffuse through the particle into the biological buffer and then into the tissue; and (C) particulate phase constituents evaporate from the particles and then deposit from the gas phase. Nicotine from smoking deposits and is absorbed predominately in the lungs. When particles deposit on the lung-blood interfaces, nicotine is absorbed rapidly, regardless of the acid-base nature of the particles. This is due to the buffering capacity of the lung-blood interfaces and the small mass of nicotine per puff distributed over a large number of particles depositing onto a huge lung surface. The composition of both tobacco smoke aerosol particles and the gas phase are time dependent. Ammonia in mainstream smoke evaporates faster from particles than nicotine. It is, therefore, unlikely that ammonia can significantly affect the volatility of MS smoke nicotine from particles in the smoke aerosol. It is certain that no single measurement of tobacco or of smoke, especially one made under equilibrium conditions, can adequately characterize the time-dependent properties of mainstream smoke aerosol. Thus, the fraction of nonprotonated freebase nicotine in trapped, aged smoke particulate matter has not been shown to be a useful predictor of the amount or total rate of nicotine uptake in human smokers. Similarly, "smoke pH" and "pHeff" are not useful practical parameters for providing understanding or predictability of tobacco smoke chemistry or nicotine bioavailability.

Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids.

PubMed

Sonnappa, Samatha; Martin, Richard; Israel, Elliot; Postma, Dirkje; van Aalderen, Wim; Burden, Annie; Usmani, Omar S; Price, David B

2017-01-01

Regular use of inhaled corticosteroids (ICS) in patients with obstructive lung diseases has been associated with a higher risk of pneumonia, particularly in COPD. The risk of pneumonia has not been previously evaluated in relation to ICS particle size and dose used. Historical cohort, UK database study of 23,013 patients with obstructive lung disease aged 12-80 years prescribed extra-fine or fine-particle ICS. The endpoints assessed during the outcome year were diagnosis of pneumonia, acute exacerbations and acute respiratory events in relation to ICS dose. To determine the association between ICS particle size, dose and risk of pneumonia in unmatched and matched treatment groups, logistic and conditional logistic regression models were used. 14788 patients were stepped-up to fine-particle ICS and 8225 to extra-fine ICS. On unmatched analysis, patients stepping-up to extra-fine ICS were significantly less likely to be coded for pneumonia (adjusted odds ratio [aOR] 0.60; 95% CI 0.37, 0.97]); experience acute exacerbations (adjusted risk ratio [aRR] 0.91; 95%CI 0.85, 0.97); and acute respiratory events (aRR 0.90; 95%CI 0.86, 0.94) compared with patients stepping-up to fine-particle ICS. Patients prescribed daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) had a significantly higher risk of pneumonia (OR [95%CI] 2.38 [1.17, 4.83]) compared with patients prescribed lower doses, irrespective of particle size. These findings suggest that patients with obstructive lung disease on extra-fine particle ICS have a lower risk of pneumonia than those on fine-particle ICS, with those receiving higher ICS doses being at a greater risk.

Multiscale image-based modeling and simulation of gas flow and particle transport in the human lungs

PubMed Central

Tawhai, Merryn H; Hoffman, Eric A

2013-01-01

Improved understanding of structure and function relationships in the human lungs in individuals and sub-populations is fundamentally important to the future of pulmonary medicine. Image-based measures of the lungs can provide sensitive indicators of localized features, however to provide a better prediction of lung response to disease, treatment and environment, it is desirable to integrate quantifiable regional features from imaging with associated value-added high-level modeling. With this objective in mind, recent advances in computational fluid dynamics (CFD) of the bronchial airways - from a single bifurcation symmetric model to a multiscale image-based subject-specific lung model - will be reviewed. The interaction of CFD models with local parenchymal tissue expansion - assessed by image registration - allows new understanding of the interplay between environment, hot spots where inhaled aerosols could accumulate, and inflammation. To bridge ventilation function with image-derived central airway structure in CFD, an airway geometrical modeling method that spans from the model ‘entrance’ to the terminal bronchioles will be introduced. Finally, the effects of turbulent flows and CFD turbulence models on aerosol transport and deposition will be discussed. CFD simulation of airflow and particle transport in the human lung has been pursued by a number of research groups, whose interest has been in studying flow physics and airways resistance, improving drug delivery, or investigating which populations are most susceptible to inhaled pollutants. The three most important factors that need to be considered in airway CFD studies are lung structure, regional lung function, and flow characteristics. Their correct treatment is important because the transport of therapeutic or pollutant particles is dependent on the characteristics of the flow by which they are transported; and the airflow in the lungs is dependent on the geometry of the airways and how ventilation is distributed to the peripheral tissue. The human airway structure spans more than 20 generations, beginning with the extra-thoracic airways (oral or nasal cavity, and through the pharynx and larynx to the trachea), then the conducting airways, the respiratory airways, and to the alveoli. The airways in individuals and sub-populations (by gender, age, ethnicity, and normal vs. diseased states) may exhibit different dimensions, branching patterns and angles, and thickness and rigidity. At the local level, one would like to capture detailed flow characteristics, e.g. local velocity profiles, shear stress, and pressure, for prediction of particle transport in an airway (lung structure) model that is specific to the geometry of an individual, to understand how inter-subject variation in airway geometry (normal or pathological) influences the transport and deposition of particles. In a systems biology – or multiscale modeling – approach, these local flow characteristics can be further integrated with epithelial cell models for the study of mechanotransduction. At the global (organ) level, one would like to match regional ventilation (lung function) that is specific to the individual, thus ensuring that the flow that transports inhaled particles is appropriately distributed throughout the lung model. Computational models that do not account for realistic distribution of ventilation are not capable of predicting realistic particle distribution or targeted drug deposition. Furthermore, the flow in the human lung can be transitional or turbulent in the upper and proximal airways, and becomes laminar in the distal airways. The flows in the laminar, transitional and turbulent regimes have different temporal and spatial scales. Therefore, modeling airway structure and predicting gas flow and particle transport at both local and global levels require image-guided multiscale modeling strategies. In this article, we will review the aforementioned three key aspects of CFD studies of the human lungs: airway structure (conducting airways), lung function (regional ventilation and boundary conditions), and flow characteristics (modeling of turbulent flow and its effect on particle transport). For modeling airway structure, we will focus on the conducting airways, and review both symmetric vs. asymmetric airway models, idealized vs. CT-based airway models, and multiscale subject-specific airway models. Imposition of physiological subject-specific boundary conditions (BCs) in CFD is essential to match regional ventilation in individuals, which is also critical in studying preferential deposition of inhaled aerosols in sub-populations, e.g. normals vs. asthmatics that may exhibit different ventilation patterns. Subject-specific regional ventilation defines flow distributions and characteristics in airway segments and bifurcations, which subsequently determines the transport and deposition of aerosols in the entire lungs. Turbulence models are needed to capture the transient and turbulent nature of the gas flow in the human lungs. Thus, the advantages and disadvantages of different turbulence models as well as their effects on particle transport will be discussed. The ultimate goal of the development is to identify sensitive structural and functional variables in sub-populations of normal and diseased lungs for potential clinical applications. PMID:23843310

Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein.

PubMed

Tomono, Takumi; Kajita, Masahiro; Yano, Kentaro; Ogihara, Takuo

2016-08-05

P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNA expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment. Copyright © 2016 Elsevier Inc. All rights reserved.

Aerosol Deposition in Health and Disease

PubMed Central

2012-01-01

Abstract The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. This article reviews the main mechanisms affecting the transport and deposition of inhaled aerosol in the human lung. Aerosol deposition in both the healthy and diseased lung is described mainly based on the results of human studies using nonimaging techniques. This is followed by a discussion of the effect of flow regime on aerosol deposition. Finally, the link between therapeutic effects of inhaled drugs and their deposition pattern is briefly addressed. Data show that total lung deposition is a poor predictor of clinical outcome, and that regional deposition needs to be assessed to predict therapeutic effectiveness. Indeed, spatial distribution of deposited particles and, as a consequence, drug efficiency is strongly affected by particle size. Large particles (>6 μm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region and are probably the most apt to act systemically, whereas the particle in the size range 2–6 μm are be best suited to treat the central and small airways. PMID:22686623

High-Resolution Phase-Contrast Imaging of Submicron Particles in Unstained Lung Tissue

NASA Astrophysics Data System (ADS)

Schittny, J. C.; Barré, S. F.; Mokso, R.; Haberthür, D.; Semmler-Behnke, M.; Kreyling, W. G.; Tsuda, A.; Stampanoni, M.

2011-09-01

To access the risks and chances of deposition of submicron particles in the gas-exchange area of the lung, a precise three-dimensional (3D)-localization of the sites of deposition is essential—especially because local peaks of deposition are expected in the acinar tree and in individual alveoli. In this study we developed the workflow for such an investigation. We administered 200-nm gold particles to young adult rats by intratracheal instillation. After fixation and paraffin embedding, their lungs were imaged unstained using synchrotron radiation x-ray tomographic microscopy (SRXTM) at the beamline TOMCAT (Swiss Light Source, Villigen, Switzerland) at sample detector distances of 2.5 mm (absorption contrast) and of 52.5 mm (phase contrast). A segmentation based on a global threshold of grey levels was successfully done on absorption-contrast images for the gold and on the phase-contrast images for the tissue. The smallest spots containing gold possessed a size of 1-2 voxels of 370-nm side length. We conclude that a combination of phase and absorption contrast SRXTM imaging is necessary to obtain the correct segmentation of both tissue and gold particles. This method will be used for the 3D localization of deposited particles in the gas-exchange area of the lung.

A feasibility study on the use of phantoms with statistical lung masses for determining the uncertainty in the dose absorbed by the lung from broad beams of incident photons and neutrons.

PubMed

Khankook, Atiyeh Ebrahimi; Hakimabad, Hashem Miri; Motavalli, Laleh Rafat

2017-05-01

Computational models of the human body have gradually become crucial in the evaluation of doses absorbed by organs. However, individuals may differ considerably in terms of organ size and shape. In this study, the authors sought to determine the energy-dependent standard deviations due to lung size of the dose absorbed by the lung during external photon and neutron beam exposures. One hundred lungs with different masses were prepared and located in an adult male International Commission on Radiological Protection (ICRP) reference phantom. Calculations were performed using the Monte Carlo N-particle code version 5 (MCNP5). Variation in the lung mass caused great uncertainty: ~90% for low-energy broad parallel photon beams. However, for high-energy photons, the lung-absorbed dose dependency on the anatomical variation was reduced to <1%. In addition, the results obtained indicated that the discrepancy in the lung-absorbed dose varied from 0.6% to 8% for neutron beam exposure. Consequently, the relationship between absorbed dose and organ volume was found to be significant for low-energy photon sources, whereas for higher energy photon sources the organ-absorbed dose was independent of the organ volume. In the case of neutron beam exposure, the maximum discrepancy (of 8%) occurred in the energy range between 0.1 and 5 MeV. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Rheumatoid lung disease

MedlinePlus

Lung disease - rheumatoid arthritis; Rheumatoid nodules; Rheumatoid lung ... Lung problems are common in rheumatoid arthritis. They often cause no symptoms. The cause of lung disease associated with rheumatoid arthritis is unknown. Sometimes, the medicines used to ...

Novel multi-functional europium-doped gadolinium oxide nanoparticle aerosols facilitate the study of deposition in the developing rat lung.

PubMed

Das, Gautom K; Anderson, Donald S; Wallis, Chris D; Carratt, Sarah A; Kennedy, Ian M; Van Winkle, Laura S

2016-06-02

Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg m(-3) of ∼30 nm europium doped gadolinium oxide nanoparticles (Gd2O3:Eu(3+)) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng per g body weight compared to 1.47 ng per g and 0.097 ng per g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution.

Novel multi-functional europium-doped gadolinium oxide nanoparticle aerosols facilitate the study of deposition in the developing rat lung

NASA Astrophysics Data System (ADS)

Das, Gautom K.; Anderson, Donald S.; Wallis, Chris D.; Carratt, Sarah A.; Kennedy, Ian M.; van Winkle, Laura S.

2016-06-01

Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg m-3 of ~30 nm europium doped gadolinium oxide nanoparticles (Gd2O3:Eu3+) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng per g body weight compared to 1.47 ng per g and 0.097 ng per g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution.Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg m-3 of ~30 nm europium doped gadolinium oxide nanoparticles (Gd2O3:Eu3+) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng per g body weight compared to 1.47 ng per g and 0.097 ng per g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr00897f

[A lung abscess caused by bad teeth].

PubMed

van Brummelen, S E; Melles, D; van der Eerden, M

2017-01-01

An odontogenic cause of a lung abscess can easily be overlooked. A 61-year-old man presented at the emergency department with a productive cough and dyspnoea. He was admitted to the pulmonary ward with a suspected odontogenic lung abscess. A thorax CT scan confirmed the diagnosis 'lung abscess', following which the dental surgeon confirmed that the lung abscess probably had an odontogenic cause. The patient made a full recovery following a 6-week course of antibiotics, and he received extensive dental treatment. Poor oral hygiene can be a cause of a lung abscess. A patient with a lung abscess can be treated successfully with a 6-week course of antibiotics; however, if the odontogenic cause is not recognised the abscess can recur.

Research of transport and deposition of aerosol in human airway replica

NASA Astrophysics Data System (ADS)

Lizal, Frantisek; Jedelsky, Jan; Elcner, Jakub; Durdina, Lukas; Halasova, Tereza; Mravec, Filip; Jicha, Miroslav

2012-04-01

Growing concern about knowledge of aerosol transport in human lungs is caused by great potential of use of inhaled pharmaceuticals. Second substantial motive for the research is an effort to minimize adverse effects of particular matter emitted by traffic and industry on human health. We created model geometry of human lungs to 7th generation of branching. This model geometry was used for fabrication of two physical models. The first one is made from thin walled transparent silicone and it allows a measurement of velocity and size of aerosol particles by Phase Doppler Anemometry (PDA). The second one is fabricated by stereolithographic method and it is designed for aerosol deposition measurements. We provided a series of measurements of aerosol transport in the transparent model and we ascertained remarkable phenomena linked with lung flow. The results are presented in brief. To gather how this phenomena affects aerosol deposition in human lungs we used the second model and we developed a technique for deposition fraction and deposition efficiency assessment. The results confirmed that non-symmetric and complicated shape of human airways essentially affects transport and deposition of aerosol. The research will now focus on deeper insight in aerosol deposition.

Differences in allergic inflammatory responses between urban PM2.5 and fine particle derived from desert-dust in murine lungs

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Miao, E-mail: hemiao@mail.cmu.edu.cn; Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita 870-1201; Ichinose, Takamichi, E-mail: ichinose@oita-nhs.ac.jp

The biological and chemical natures of materials adsorbed onto fine particulate matter (PM2.5) vary by origin and passage routes. The exacerbating effects of the two samples—urban PM2.5 (U-PM2.5) collected during the hazy weather in a Chinese city and fine particles (ASD-PM2.5) collected during Asian sand dust (ASD) storm event days in Japan—on murine lung eosinophilia were compared to clarify the role of toxic materials in PM2.5. The amounts of β-glucan and mineral components were higher in ASD-PM2.5 than in U-PM2.5. On the other hand, organic chemicals, including polycyclic aromatic hydrocarbons (PAHs), were higher in U-PM2.5 than in ASD-PM2.5. When BALB/cmore » mice were intratracheally instilled with U-PM2.5 and ASD-PM2.5 (total 0.4 mg/mouse) with or without ovalbumin (OVA), various biological effects were observed, including enhancement of eosinophil recruitment induced by OVA in the submucosa of the airway, goblet cell proliferation in the bronchial epithelium, synergic increase of OVA-induced eosinophil-relevant cytokines and a chemokine in bronchoalveolar lavage fluid, and increase of serum OVA-specific IgG1 and IgE. Data demonstrate that U-PM2.5 and ASD-PM2.5 induced allergic inflammatory changes and caused lung pathology. U-PM2.5 and ASD-PM2.5 increased F4/80{sup +} CD11b{sup +} cells, indicating that an influx of inflammatory and exudative macrophages in lung tissue had occurred. The ratio of CD206 positive F4/80{sup +} CD11b{sup +} cells (M2 macrophages) in lung tissue was higher in the OVA + ASD-PM2.5 treated mice than in the OVA + U-PM2.5 treated mice. These results suggest that the lung eosinophilia exacerbated by both PM2.5 is due to activation of a Th2-associated immune response along with induced M2 macrophages and the exacerbating effect is greater in microbial element (β-glucan)-rich ASD-PM2.5 than in organic chemical-rich U-PM2.5. - Highlights: • The aggravating effects of urban-PM2.5 and desert-PM2.5 on lung eosinophilia were compared. • Both PM2.5 enhanced Th2-immune response along with induced M2 macrophages. • The effect is greater in desert-PM2.5 than in organic chemical-rich urban-PM2.5. • Desert-PM2.5 may cause greater effects upon human respiratory health than urban-PM2.5.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cordes, L.G.; Brink, E.W.; Checko, P.J.

In a 3-month period, three men who had worked for 5 to 19 years as welders or grinders of steel castings in a foundry acquired pneumonia caused by Acinetobacter calcoaceticus variety anitratus serotype 7J. Two of the men died, and postmortem examination showed mixed-dust pneumoconiosis with iron particles in the lungs. A calcoaceticus variety anitratus serotype 7J was isolated from the air in the foundry but the source was not found. The prevalence of antibody titers of 64 or greater to the 7J strain was significantly higher among foundry workers (15%) than among community controls (2%) (p less than 0.01).more » Sampling showed that the concentrations of total and metallic particles (especially iron) and of free silica in air inhaled by welders and grinders at the foundry frequently exceeded acceptable levels. These findings suggest that chronic exposure to such particles may increase susceptibility to infection by this organism, which rarely affects healthy people.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Jane Y.C., E-mail: jym1@cdc.gov; Young, Shih-Houng; Mercer, Robert R.

Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO{sub 2}) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO{sub 2} on the pulmonary system in a rat model. Specific pathogen-free male Sprague–Dawley rats were exposed to CeO{sub 2} and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO{sub 2} induces a sustained inflammatory response, whereas DEP elicits a switch of themore » pulmonary immune response from Th1 to Th2. Both CeO{sub 2} and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-γ, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO{sub 2}, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP + CeO{sub 2} were significantly larger than CeO{sub 2} or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP + CeO{sub 2} reflects the combination of DEP-exposure plus CeO{sub 2}-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO{sub 2} induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO{sub 2} in the combined exposure. Using CeO{sub 2} as diesel fuel catalyst may cause health concerns. - Highlights: • DEP induced acute lung inflammation and switched immune response from Th1 to Th2. • DEP induced lung granulomas were not affected by the presence of CeO{sub 2}. • CeO{sub 2} induced sustained lung inflammation, phospholipidosis, and fibrosis. • After the combined exposure, CeO{sub 2} and DEP are co-localized in the lung tissues. • CeO{sub 2} + DEP induced lung inflammation, phospholipidosis, granulomas, and fibrosis.« less

Earthicle: The Design of a Conceptually New Type of Particle.

PubMed

Uskoković, Vuk; Pernal, Sebastian; Wu, Victoria M

2017-01-18

The conception and the steps made in the design of a conceptually new type of composite particle, so-called "earthicle", are being described. This particle is meant to roughly mimic the layered structure of the Earth, having zerovalent iron core, silicate mantle, and a thin carbonaceous crust resembling the biosphere and its geological remnants. Particles are made in a stable colloidal form in an aqueous medium, involving chemical precipitation and pyrolysis of citric acid in the solution. The effects of various synthesis parameters were studied, including borohydride and oleate concentrations, APTES/TEOS molar ratio, chemical nature of the carbon precursors, and others. XRD analysis confirmed the predominantly zerovalent iron composition of the core, amorphous silica and crystalline iron silicate/silicide composition of the mesolayer, and the carbonaceous, amorphous graphitic composition of the surface coating. The atomically thin carbon shell was also detected as a distinct shoulder on the broad n-π* absorption resonance and the peak at ∼300 nm, a signature of sp 2 hybridized electronic orbitals and the result of the interband π-π* transition characteristic of graphitic structures. The irregularity of the shape of generally round Fe 0 particles has caused the uniformity of the silica shell to be directly proportional to the particle size. The size of the earthicles ranged from 60 to 500 nm depending on the ionic concentration of the precursors and additives. Silica layer effectively prevented the aggregation of the iron core and increased the biocompatibility of the particles. The point of zero charge first increased from the acidic to the neutral range after coating Fe 0 core with the APTES-functionalized, aminated silica shell and then restored its low value after depositing the carboxylated carbonic crust in a charge-reversal process designed to facilitate the formation of core-multishell structures. Tested on K7M2 osteosarcoma cell line and primary kidney and lung fibroblasts, cytotoxicity was cell-line dependent; however, the trend assessed in both planar and 3D cell culture with respect to the three types of particles, Fe 0 , Fe/SiO 2 , and Fe/SiO 2 /C, was general and independent of the cell line. Thus, the pronounced toxicity of Fe 0 alone became neutralized after the silica layer was coated around Fe 0 . The further addition of the carbonic layer reduced the viability as compared to Fe/SiO 2 , albeit in a statistically significant manner only for K7M2 cell line when compared against the untreated control. Cell response also varied depending on the formulation: while some formulations exhibited lethal effects on kidney fibroblasts, were harmless to lung fibroblasts, and boosted the proliferation of K7M2 osteosarcoma cells, other formulations exhibited the opposite behavior despite being similar in terms of their core/double-shell structure. Compared across three different cancerous cell lines, K7M2 osteosarcoma and U87 and E297 glioblastoma, a similar cell-line dependency in response was observed, yet the viability reduction was consistent for all Fe/SiO 2 /C particles, ranging from 80% to 85% of the untreated control. Carbon surface layer, albeit of graphitic structural nature, was of a markedly more viable character than that of nanosized graphene oxide. The viability of lung fibroblasts incubated with Fe/SiO 2 /C particles was reduced in the presence of the alternating magnetic field of 312.75 A/m and 1 MHz, while the viability reduction caused by Fe/SiO 2 /C particles in kidney fibroblasts and K7M2 cells was converted from statistically insignificant to significant, suggesting that the composite particles could be used for hyperthermia treatments, although their properties should be optimized for a more intense effect. A single-cell immunofluorescent analysis of the interaction of primary kidney fibroblasts and K7M2 osteosarcoma cells with Fe/SiO 2 /C particles demonstrated that the cell uptake and perinuclear localization may be responsible for the necrotic effects. This analysis also showed that composite Fe/SiO 2 /C particles may have the ability to cause the rupture of the cancer cell nucleus while having a harmless effect on the primary cells. Such a promising and selective anticancer activity will be investigated in more detail in future studies.

Measurement Techniques for Respiratory Tract Deposition of Airborne Nanoparticles: A Critical Review

PubMed Central

Möller, Winfried; Pagels, Joakim H.; Kreyling, Wolfgang G.; Swietlicki, Erik; Schmid, Otmar

2014-01-01

Abstract Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their unique properties in inhalation toxicology and medicine. Over the last century, around 50 studies have presented experimental data on lung deposition of nanoparticles (typical diameter≤100 nm, but here≤300 nm). These data show a considerable variability, partly due to differences in the applied methodologies. In this study, we review the experimental techniques for measuring respiratory tract deposition of nano-sized particles, analyze critical experimental design aspects causing measurement uncertainties, and suggest methodologies for future studies. It is shown that, although particle detection techniques have developed with time, the overall methodology in respiratory tract deposition experiments has not seen similar progress. Available experience from previous research has often not been incorporated, and some methodological design aspects that were overlooked in 30–70% of all studies may have biased the experimental data. This has contributed to a significant uncertainty on the absolute value of the lung deposition fraction of nanoparticles. We estimate the impact of the design aspects on obtained data, discuss solutions to minimize errors, and highlight gaps in the available experimental set of data. PMID:24151837

Estimation of inhaled airborne particle number concentration by subway users in Seoul, Korea.

PubMed

Kim, Minhae; Park, Sechan; Namgung, Hyeong-Gyu; Kwon, Soon-Bark

2017-12-01

Exposure to airborne particulate matter (PM) causes several diseases in the human body. The smaller particles, which have relatively large surface areas, are actually more harmful to the human body since they can penetrate deeper parts of the lungs or become secondary pollutants by bonding with other atmospheric pollutants, such as nitrogen oxides. The purpose of this study is to present the number of PM inhaled by subway users as a possible reference material for any analysis of the hazards to the human body arising from the inhalation of such PM. Two transfer stations in Seoul, Korea, which have the greatest number of users, were selected for this study. For 0.3-0.422 μm PM, particle number concentration (PNC) was highest outdoors but decreased as the tester moved deeper underground. On the other hand, the PNC between 1 and 10 μm increased as the tester moved deeper underground and showed a high number concentration inside the subway train as well. An analysis of the particles to which subway users are actually exposed to (inhaled particle number), using particle concentration at each measurement location, the average inhalation rate of an adult, and the average stay time at each location, all showed that particles sized 0.01-0.422 μm are mostly inhaled from the outdoor air whereas particles sized 1-10 μm are inhaled as the passengers move deeper underground. Based on these findings, we expect that the inhaled particle number of subway users can be used as reference data for an evaluation of the hazards to health caused by PM inhalation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of acid functionalization on the cardiopulmonary toxicity of carbon nanotubes and carbon black particles in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tong Haiyan; McGee, John K.; Saxena, Rajiv K.

2009-09-15

Engineered carbon nanotubes are being developed for a wide range of industrial and medical applications. Because of their unique properties, nanotubes can impose potentially toxic effects, particularly if they have been modified to express functionally reactive chemical groups on their surface. The present study was designed to evaluate whether acid functionalization (AF) enhanced the cardiopulmonary toxicity of single-walled carbon nanotubes (SWCNT) as well as control carbon black particles. Mice were exposed by oropharyngeal aspiration to 10 or 40 {mu}g of saline-suspended single-walled carbon nanotubes (SWCNTs), acid-functionalized SWCNTs (AF-SWCNTs), ultrafine carbon black (UFCB), AF-UFCB, or 2 {mu}g LPS. 24 hours later,more » pulmonary inflammatory responses and cardiac effects were assessed by bronchoalveolar lavage and isolated cardiac perfusion respectively, and compared to saline or LPS-instilled animals. Additional mice were assessed for histological changes in lung and heart. Instillation of 40 {mu}g of AF-SWCNTs, UFCB and AF-UFCB increased percentage of pulmonary neutrophils. No significant effects were observed at the lower particle concentration. Sporadic clumps of particles from each treatment group were observed in the small airways and interstitial areas of the lungs according to particle dose. Patches of cellular infiltration and edema in both the small airways and in the interstitium were also observed in the high dose group. Isolated perfused hearts from mice exposed to 40 {mu}g of AF-SWCNTs had significantly lower cardiac functional recovery, greater infarct size, and higher coronary flow rate than other particle-exposed animals and controls, and also exhibited signs of focal cardiac myofiber degeneration. No particles were detected in heart tissue under light microscopy. This study indicates that while acid functionalization increases the pulmonary toxicity of both UFCB and SWCNTs, this treatment caused cardiac effects only with the AF-carbon nanotubes. Further experiments are needed to understand the physico-chemical processes involved in this phenomenon.« less

Efficiency of automotive cabin air filters to reduce acute health effects of diesel exhaust in human subjects

PubMed Central

Rudell, B.; Wass, U.; Horstedt, P.; Levin, J. O.; Lindahl, R.; Rannug, U.; Sunesson, A. L.; Ostberg, Y.; Sandstrom, T.

1999-01-01

OBJECTIVES: To evaluate the efficiency of different automotive cabin air filters to prevent penetration of components of diesel exhaust and thereby reduce biomedical effects in human subjects. Filtered air and unfiltered diluted diesel exhaust (DDE) were used as negative and positive controls, respectively, and were compared with exposure to DDE filtered with four different filter systems. METHODS: 32 Healthy non- smoking subjects (age 21-53) participated in the study. Each subject was exposed six times for 1 hour in a specially designed exposure chamber: once to air, once to unfiltered DDE, and once to DDE filtered with the four different cabin air filters. Particle concentrations during exposure to unfiltered DDE were kept at 300 micrograms/m3. Two of the filters were particle filters. The other two were particle filters combined with active charcoal filters that might reduce certain gaseous components. Subjective symptoms were recorded and nasal airway lavage (NAL), acoustic rhinometry, and lung function measurements were performed. RESULTS: The two particle filters decreased the concentrations of diesel exhaust particles by about half, but did not reduce the intensity of symptoms induced by exhaust. The combination of active charcoal filters and a particle filter significantly reduced the symptoms and discomfort caused by the diesel exhaust. The most noticable differences in efficacy between the filters were found in the reduction of detection of an unpleasant smell from the diesel exhaust. In this respect even the two charcoal filter combinations differed significantly. The efficacy to reduce symptoms may depend on the abilities of the filters investigated to reduce certain hydrocarbons. No acute effects on NAL, rhinometry, and lung function variables were found. CONCLUSIONS: This study has shown that the use of active charcoal filters, and a particle filter, clearly reduced the intensity of symptoms induced by diesel exhaust. Complementary studies on vehicle cabin air filters may result in further diminishing the biomedical effects of diesel exhaust in subjects exposed in traffic and workplaces.   PMID:10450238

Sintered indium-tin oxide particles induce pro-inflammatory responses in vitro, in part through inflammasome activation.

PubMed

Badding, Melissa A; Schwegler-Berry, Diane; Park, Ju-Hyeong; Fix, Natalie R; Cummings, Kristin J; Leonard, Stephen S

2015-01-01

Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1β, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1β release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.

Development of three-dimensional lung multicellular spheroids in air- and liquid-interface culture for the evaluation of anticancer therapeutics.

PubMed

Meenach, Samantha A; Tsoras, Alexandra N; McGarry, Ronald C; Mansour, Heidi M; Hilt, J Zach; Anderson, Kimberly W

2016-04-01

Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions.

Chemical composition of PM10 and its in vitro toxicological impacts on lung cells during the Middle Eastern Dust (MED) storms in Ahvaz, Iran.

PubMed

Naimabadi, Abolfazl; Ghadiri, Ata; Idani, Esmaeil; Babaei, Ali Akbar; Alavi, Nadali; Shirmardi, Mohammad; Khodadadi, Ali; Marzouni, Mohammad Bagherian; Ankali, Kambiz Ahmadi; Rouhizadeh, Ahmad; Goudarzi, Gholamreza

2016-04-01

Reports on the effects of PM10 from dust storm on lung cells are limited. The main purpose of this study was to investigate the chemical composition and in vitro toxicological impacts of PM10 suspensions, its water-soluble fraction, and the solvent-extractable organics extracted from Middle Eastern Dust storms on the human lung epithelial cell (A549). Samples of dust storms and normal days (PM10 < 200 μg m(-3)) were collected from December 2012 until June 2013 in Ahvaz, the capital of Khuzestan Province in Iran. The chemical composition and cytotoxicity were analyzed by ICP- OES and Lactase Dehydrogenase (LDH) reduction assay, respectively. The results showed that PM10 suspensions, their water-soluble fraction and solvent-extractable organics from both dust storm and normal days caused a decrease in the cell viability and an increase in LDH in supernatant in a dose-response manner. Although samples of normal days showed higher cytotoxicity than those of dust storm at the highest treated dosage, T Test showed no significant difference in cytotoxicity between normal days and dust event days (P value > 0.05). These results led to the conclusions that dust storm PM10 as well as normal day PM10 could lead to cytotoxicity, and the organic compounds (PAHs) and the insoluble particle-core might be the main contributors to cytotoxicity. Our results showed that cytotoxicity and the risk of PM10 to human lung may be more severe during dust storm than normal days due to inhalation of a higher mass concentration of airborne particles. Further research on PM dangerous fractions and the most responsible components to make cytotoxicity in exposed cells is recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Pressurized Metered Dose Inhaler Spray Characteristics and Particle Size Distribution on Drug Delivery Efficiency.

PubMed

Yousefi, Morteza; Inthavong, Kiao; Tu, Jiyuan

2017-10-01

A key issue in pulmonary drug delivery is improvement of the delivery device for effective and targeted treatment. Pressurized metered dose inhalers (pMDIs) are the most popular aerosol therapy device for treating lung diseases. This article studies the effect of spray characteristics: injection velocity, spray cone angle, particle size distribution (PSD), and its mass median aerodynamic diameter (MMAD) on drug delivery. An idealized oral airway geometry, extending from mouth to the main bronchus, was connected to a pMDI device. Inhalation flow rates of 15, 30, and 60 L/min were used and drug particle tracking was a one-way coupled Lagrangian model. The results showed that most particles deposited in the pharynx, where the airway has a reduced cross-sectional area. Particle deposition generally decreased with initial spray velocity and with increased spray cone angle for 30 and 60 L/min flow rates. However, for 15 L/min flow rate, the deposition increased slightly with an increase in the spray velocity and cone angle. The effect of spray cone angle was more significant than the initial spray velocity on particle deposition. When the MMAD of a PSD was reduced, the deposition efficiency also reduces, suggesting greater rates of particle entry into the lung. The deposition rate showed negligible change when the MMAD was more than 8 μm. Spray injection angle and velocity change the drug delivery efficacy; however, the efficiency shows more sensitivity to the injection angle. The 30 L/min airflow rate delivers spray particles to the lung more efficiently than 15 and 60 L/min airflow rate, and reducing MMAD can help increase drug delivery to the lung.

Deposition of inhaled particles in the human lung is more peripheral in lunar than in normal gravity.

PubMed

Darquenne, Chantal; Prisk, G Kim

2008-08-01

Lunar dust presents a potential toxic challenge to future explorers of the moon. The extent of the inflammatory response to lunar dust will in part depend on where in the lung particles deposit. To determine the effect of lowered gravity, we measured deposition of 0.5 and 1 microm diameter particles in six subjects on the ground (1G) and during short periods of lunar gravity (1/6G) aboard the NASA Microgravity Research Aircraft. Total deposition was measured during continuous aerosol breathing, and regional deposition by aerosol bolus inhalations at penetration volumes (V (p)) of 200, 500 and 1,200 ml. For both particle sizes (d (p)), deposition was gravity-dependent with the lowest deposition occurring at the lower G-level. Total deposition decreased by 25 and 32% from 1G to 1/6G for 0.5 and 1 microm diameter particles, respectively. In the bolus tests, deposition increased with increasing V (p). However, the penetration volume required to achieve a given deposition level was larger in 1/6G than in 1G. For example, for d (p) = 1 microm (0.5 microm), a level of 25% deposition was reached at V (p) = 260 ml (370 ml) in 1G but not until V (p) = 730 ml (835 ml) in 1/6G. Thus in 1G, deposition in more central airways reduces the transport of fine particles to the lung periphery. In the fractional gravity environment of a lunar outpost, while inhaled fine particle deposition may be lower than on earth, those particles that are deposited will do so in more peripheral regions of the lung.

Co-release of hexabromocyclododecane (HBCD) and Nano- and microparticles from thermal cutting of polystyrene foams.

PubMed

Zhang, Haijun; Kuo, Yu-Ying; Gerecke, Andreas C; Wang, Jing

2012-10-16

Polystyrene foam is a very important insulation material, and hexabromocyclododecane (HBCD) is frequently used as its flame retardant. HBCD is persistent, bioaccumulative, and toxic, and therefore workplace exposure and environmental emission should be avoided. In this study, we investigated the co-release of HBCD and aerosol particles during the thermal cutting of expanded polystyrene foam (EPS) and extruded polystyrene foam (XPS). The generated particles were simultaneously measured by a fast mobility particle sizer (FMPS) and collected by a cascade impactor (NanoMoudi). In the breathing zone of a cutting worker, the number concentration of aerosol particles was above 1 × 10(12) particles m(-3), and the air concentration of HBCD was more than 50 μg m(-3). Most of the released HBCD was partitioned into particles with an aerodynamic diameter at the nanometer scale. The average concentrations of HBCD in these submicrometer particles generated from the thermal cutting of EPS and XPS were 13 times and 15 times higher than the concentrations in raw foams, respectively. An occupational exposure assessment indicated that more than 60% of HBCD and 70% of particles deposited in the lung of cutting worker would be allocated to the alveolar region. The potential subchronic (or chronic) toxicity jointly caused by the particles and HBCD calls for future studies.

Particle deposition in human respiratory system: deposition of concentrated hygroscopic aerosols.

PubMed

Varghese, Suresh K; Gangamma, S

2009-06-01

In the nearly saturated human respiratory tract, the presence of water-soluble substances in the inhaled aerosols can cause change in the size distribution of the particles. This consequently alters the lung deposition profiles of the inhaled airborne particles. Similarly, the presence of high concentration of hygroscopic aerosols also affects the water vapor and temperature profiles in the respiratory tract. A model is presented to analyze these effects in human respiratory system. The model solves simultaneously the heat and mass transfer equations to determine the size evolution of respirable particles and gas-phase properties within human respiratory tract. First, the model predictions for nonhygroscopic aerosols are compared with experimental results. The model results are compared with experimental results of sodium chloride particles. The model reproduces the major features of the experimental data. The water vapor profile is significantly modified only when a high concentration of particles is present. The model is used to study the effect of equilibrium assumptions on particle deposition. Simulations show that an infinite dilution solution assumption to calculate the saturation equilibrium over droplet could induce errors in estimating particle growth. This error is significant in the case of particles of size greater than 1 mum and at number concentrations higher than 10(5)/cm(3).

Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs.

PubMed

Kennedy, T P; Gordon, G B; Paky, A; McShane, A; Adkinson, N F; Peters, S P; Friday, K; Jackman, W; Sciuto, A M; Gurtner, G H

1988-07-01

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.

Local lung deposition of ultrafine particles in healthy adults: experimental results and theoretical predictions.

PubMed

Sturm, Robert

2016-11-01

Ultrafine particles (UFP) of biogenic and anthropogenic origin occur in high numbers in the ambient atmosphere. In addition, aerosols containing ultrafine powders are used for the inhalation therapy of various diseases. All these facts make it necessary to obtain comprehensive knowledge regarding the exact behavior of UFP in the respiratory tract. Theoretical simulations of local UFP deposition are based on previously conducted inhalation experiments, where particles with various sizes (0.04, 0.06, 0.08, and 0.10 µm) were administered to the respiratory tract by application of the aerosol bolus technique. By the sequential change of the lung penetration depth of the inspired bolus, different volumetric lung regions could be generated and particle deposition in these regions could be evaluated. The model presented in this contribution adopted all parameters used in the experiments. Besides the obligatory comparison between practical and theoretical data, also advanced modeling predictions including the effect of varying functional residual capacity (FRC) and respiratory flow rate were conducted. Validation of the UFP deposition model shows that highest deposition fractions occur in those volumetric lung regions corresponding to the small and partly alveolated airways of the tracheobronchial tree. Particle deposition proximal to the trachea is increased in female probands with respect to male subjects. Decrease of both the FRC and the respiratory flow rate results in an enhancement of UFP deposition. The study comes to the conclusion that deposition of UFP taken up via bolus inhalation is influenced by a multitude of factors, among which lung morphometry and breathing conditions play a superior role.

Local lung deposition of ultrafine particles in healthy adults: experimental results and theoretical predictions

PubMed Central

2016-01-01

Background Ultrafine particles (UFP) of biogenic and anthropogenic origin occur in high numbers in the ambient atmosphere. In addition, aerosols containing ultrafine powders are used for the inhalation therapy of various diseases. All these facts make it necessary to obtain comprehensive knowledge regarding the exact behavior of UFP in the respiratory tract. Methods Theoretical simulations of local UFP deposition are based on previously conducted inhalation experiments, where particles with various sizes (0.04, 0.06, 0.08, and 0.10 µm) were administered to the respiratory tract by application of the aerosol bolus technique. By the sequential change of the lung penetration depth of the inspired bolus, different volumetric lung regions could be generated and particle deposition in these regions could be evaluated. The model presented in this contribution adopted all parameters used in the experiments. Besides the obligatory comparison between practical and theoretical data, also advanced modeling predictions including the effect of varying functional residual capacity (FRC) and respiratory flow rate were conducted. Results Validation of the UFP deposition model shows that highest deposition fractions occur in those volumetric lung regions corresponding to the small and partly alveolated airways of the tracheobronchial tree. Particle deposition proximal to the trachea is increased in female probands with respect to male subjects. Decrease of both the FRC and the respiratory flow rate results in an enhancement of UFP deposition. Conclusions The study comes to the conclusion that deposition of UFP taken up via bolus inhalation is influenced by a multitude of factors, among which lung morphometry and breathing conditions play a superior role. PMID:27942511

Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

PubMed Central

Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

2016-01-01

Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

An investigation of fibrogenic and other toxic effects of arc-welding fume particles deposited in the rat lung.

PubMed

Hicks, R; Al-Shamma, K J; Lam, H F; Hewitt, P J

1983-12-01

Lung burdens of deposited particles from fumes generated by arc-welding were established in rats by single inhalation exposures, repeated intermittent exposure or by intratracheal injection. Fumes from manual metal arc-welding using flux-coated mild-steel rods (MMA-MS) were compared with those from metal inert-gas welding with stainless steel wire (MIG-SS). After initial rapid clearance of deposited material from the lungs, persistent residual deposits remained. Such residues resulting from single inhalation were small and confined mainly to peribronchial accumulations in macrophage clusters. Deposits remaining after repeated inhalation were larger and more widespread. Intratracheal administration (50 mg) established massive residual deposits, giving nodular accumulations in peribronchial, subpleural and perivascular sites, with substantial alveolar parenchymal involvement. Deposits from both types of fumes contained predominantly iron. Particles from stainless steel also contained chromium, but concentrations of this element were low in deposits from MMA-MS fumes. MMA-MS deposits contained silica, probably amorphous. Long-term studies (up to 450 days) attempted to detect evidence of fibrosis resulting from particle burdens. Low-grade collagen fibre layers developed at margins of MMA-MS nodules. Diffuse reticulin fibre networks occurred within MIG-SS aggregates. Tissue hydroxyproline levels were increased (doubled) in lungs with intratracheal burdens of MMA-MS particles, but no significant increases resulted from MIG-SS. The major lesions were nodular aggregates of particle-laden macrophages with giant-cell formation, and alveolar epithelial thickening with atelectasis.

TISSUE REMODELING IN THE HUMAN LUNG IN RELATION TO PARTICLE CONCENTRATION AND METAL CONTENT

EPA Science Inventory

TISSUE REMODELING IN THE HUMAN LUNG IN RELATION TO PARTICLE CONCENTRATION AND METAL CONTENT. J Gallagher1, J Inmon1, S Schlaegle2, A Levine2, T Rogers3, J Scott1, F Green4, M Schenker5, K Pinkerton5 1NHEERL, US-EPA, RTP, NC, USA; 2RJ Lee Group Inc, Monroeville, Pa, USA; ...

OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM)

EPA Science Inventory

OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). E S Roberts1, R Jaskot2, J Richards2, and K L Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC a...

Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part II: Dry powder inhaler application.

PubMed

Kolanjiyil, Arun V; Kleinstreuer, Clement; Sadikot, Ruxana T

2017-05-01

Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination. Specific DPI-designs and operations greatly affect drug-aerosol formation and hence local lung deposition. Simulating the fluid-particle dynamics after use of a DPI allows for the assessment of drug-aerosol deposition and can also assist in improving the device configuration and operation. In Part I of this study a first-generation whole lung-airway model (WLAM) was introduced and discussed to analyze particle transport and deposition in a human respiratory tract model. In the present Part II the drug-aerosols are assumed to be injected into the lung airways from a DPI mouth-piece, forming the mouth-inlet. The total as well as regional particle depositions in the WLAM, as inhaled from a DPI, were successfully compared with experimental data sets reported in the open literature. The validated modeling methodology was then employed to study the delivery of curcumin aerosols into lung airways using a commercial DPI. Curcumin has been implicated to possess high therapeutic potential as an antioxidant, anti-inflammatory and anti-cancer agent. However, efficacy of curcumin treatment is limited because of the low bioavailability of curcumin when ingested. Hence, alternative drug administration techniques, e.g., using inhalable curcumin-aerosols, are under investigation. Based on the present results, it can be concluded that use of a DPI leads to low lung deposition efficiencies because large amounts of drugs are deposited in the oral cavity. Hence, the output of a modified DPI has been evaluated to achieve improved drug delivery, especially needed when targeting the smaller lung airways. This study is the first to utilize CF-PD methodology to simulate drug-aerosol transport and deposition under actual breathing conditions in a whole lung model, using a commercial dry-powder inhaler for realistic inlet conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Single particle aerosol mass spectrometry of coal combustion particles associated with high lung cancer rates in Xuanwei and Fuyuan, China.

PubMed

Lu, Senlin; Tan, Zhengying; Liu, Pinwei; Zhao, Hui; Liu, Dingyu; Yu, Shang; Cheng, Ping; Win, Myat Sandar; Hu, Jiwen; Tian, Linwei; Wu, Minghong; Yonemochi, Shinich; Wang, Qingyue

2017-11-01

Coal combustion particles (CCPs) are linked to the high incidence of lung cancer in Xuanwei and in Fuyuan, China, but studies on the chemical composition of the CCPs are still limited. Single particle aerosol mass spectrometry (SPAMS) was recently developed to measure the chemical composition and size of single particles in real-time. In this study, SPAMS was used to measure individual combustion particles emitted from Xuanwei and Fuyuan coal samples and the results were compared with those by ICP-MS and transmission electron microscopy (TEM). The total of 38,372 particles mass-analyzed by SPAMS can be divided into 9 groups based on their chemical composition and their number percentages: carbonaceous, Na-rich, K-rich, Al-rich, Fe-rich, Si-rich, Ca-rich, heavy metal-bearing, and PAH-bearing particles. The carbonaceous and PAH-bearing particles are enriched in the size range below 0.56 μm, Fe-bearing particles range from 0.56 to 1.0 μm in size, and heavy metals such as Ti, V, Cr, Cu, Zn, and Pb have diameters below 1 μm. The TEM results show that the particles from Xuanwei and Fuyuan coal combustion can be classified into soot aggregates, Fe-rich particles, heavy metal containing particles, and mineral particles. Non-volatile particles detected by SPAMS could also be observed with TEM. The number percentages by SPAMS also correlate with the mass concentrations measured by ICP-MS. Our results could provide valuable insight for understanding high lung cancer incidence in the area. Copyright © 2017 Elsevier Ltd. All rights reserved.

A new perspective of carcinogenesis from protracted high-let radiation arises from the two-stage clonal expansion model

NASA Astrophysics Data System (ADS)

Curtis, S. B.; Luebeck, E. G.; Hazelton, W. D.; Moolgavkar, S. H.

When applied to the Colorado Plateau miner population, the two-stage clonal expansion (TSCE) model of radiation carcinogenesis predicts that radiation-induced promotion dominates radiation-induced initiation. Thus, according to the model, at least for alpha-particle radiation from inhaled radon daughters, lung cancer induction over long periods of protracted irradiation appears to be dominated by radiation-induced modification of the proliferation kinetics of already-initiated cells rather than by direct radiation-induced initiation (i.e., mutation) of normal cells. We explore the possible consequences of this result for radiation exposures to space travelers on long missions. Still unknown is the LET dependence of this effect. Speculations of the cause of this phenomenon include the suggestion that modification of cell kinetics is caused by a "bystander" effect, i.e., the traversal of normal cells by alpha particles, followed by the signaling of these cells to nearby initiated cells which then modify their proliferation kinetics.

Alveolar macrophage cytokine response to air pollution particles: oxidant mechanisms.

PubMed

Imrich, Amy; Ning, YaoYu; Lawrence, Joy; Coull, Brent; Gitin, Elena; Knutson, Mitchell; Kobzik, Lester

2007-02-01

Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-l-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 microM) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H(2)O(2) generated by glucose oxidase, 10 microM/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H(2)O(2). The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H(2)O(2) but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H(2)O(2)-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H(2)O(2) released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.

Dissolution and clearance of titanium tritide particles in the lungs of F344/Crl rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Yung-Sung; Snipes, M.B.; Wang, Yansheng

1995-12-01

Metal tritides are compounds in which the radioactive isotope tritium, following adsorption onto the metal, forms a stable chemical compound with the metal. When particles of tritiated metals become airborne, they can be inhaled by workers. Because the particles may be retained in the lung for extended periods, the resulting dose will be greater than doses following exposure to tritium gas or tritium oxide (HTO). Particles of triated metals may be dispersed into the air during routine handling, disruption of contaminated metals, or as a result of spontaneous radioactive decay processes. Unlike metal hydrides and deuterides, tritides are radioactive, andmore » the decay of the tritium atoms affects the metal. Because helium is a product of the decay, helium bubbles form within the metal tritide matrix. The pressure from these bubbles leads to respirable particles breaking off from the tritide surface. Our results show that a substantial amount of titanium tritide remains in the rat lung 10 d after intratracheal instillation, confirming results previously obtain in an in vitro dissolution study.« less

EFFECT OF BODY SIZE ON BREATHING PATTERN AND FINE PARTICLE DEPOSITION IN CHILDREN

EPA Science Inventory

Inter-child variability in breathing patterns may contribute to variability in fine particle, lung deposition and morbidity in children associated with those particles. Fractional deposition (DF) of fine particles (2um monodisperse, carnauba wax particles) was measured in healthy...

Secondhand Smoke Enhances Lung Cancer Risk in Male Smokers: An Interaction.

PubMed

Li, Wentao; Tse, Lap Ah; Au, Joseph S K; Wang, Feng; Qiu, Hong; Yu, Ignatius Tak-Sun

2016-11-01

Previous studies revealed that some indoor air pollutants and fine particle matter can interact with active smoking, enhancing lung cancer risk in smokers. Secondhand smoke (SHS), with remarkable differences from active smoking, contributes significantly to indoor air pollution and generates a considerable amount of fine particle matter, may cause a similar interaction with active smoking. Information on lifetime SHS along with active smoking and other confirmed or suspected risk factors for lung cancer was collected in this case-referent study. Odds ratios and the 95% confidence intervals (95% CIs) of smoking status in different levels of SHS were evaluated. Potential multiplicative and additive interactions were explored. Compared with never-smokers without SHS, current smokers who were exposed to a high level of SHS demonstrated the highest odds ratio (15.13, 95% CI: 8.60, 26.65), almost doubles the effect in the current smokers without SHS. Significant additive interactions between current smoking and high level of SHS were observed for all lung cancers (synergy index = 1.80, 95% CI: 1.02, 3.24) and the squamous carcinoma subgroup. High level of SHS exposure greatly enhanced lung cancer risk among current smokers, consistent with an additive interaction; while this interaction was predominant for the squamous carcinoma. The results provide new evidence to the rationale of promoting global smoking cessation. Some indoor air pollutants can interact with active smoking, yielding a synergistic effect on inducing lung cancer. SHS, with noticeable differences from active smoking, is a major source of indoor air pollution. However, little has been known about the effect of SHS in smokers and whether there is a similar interaction between SHS and active smoking. In this study, we evaluated their separate and joint effects and indeed found a more than additive interaction between them. This finding suggests a potential problem of gathering smoking aggravating by venue restriction policies and re-advocates policy efforts on smoking cessation. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Causes of death of patients with lung cancer.

PubMed

Nichols, Larry; Saunders, Rachel; Knollmann, Friedrich D

2012-12-01

The causes of death for patients with lung cancer are inadequately described. To categorize the immediate and contributing causes of death for patients with lung cancer. The autopsies from 100 patients who died of lung cancer between 1990 and February 2011 were analyzed. Tumor burden was judged the immediate cause of death in 30 cases, including 26 cases of extensive metastases and 4 cases with wholly or primarily lung tumor burden (causing respiratory failure). Infection was the immediate cause of death for 20 patients, including 8 with sepsis and 12 with pneumonia. Complications of metastatic disease were the immediate causes of death in 18 cases, including 6 cases of hemopericardium from pericardial metastases, 3 from myocardial metastases, 3 from liver metastases, and 3 from brain metastases. Other immediate causes of death were pulmonary hemorrhage (12 cases), pulmonary embolism (10 cases, 2 tumor emboli), and pulmonary diffuse alveolar damage (7 cases). From a functional (pathophysiologic) perspective, respiratory failure could be regarded as the immediate cause of death (or mechanism of death) in 38 cases, usually because of a combination of lung conditions, including emphysema, airway obstruction, pneumonia, hemorrhage, embolism, resection, and lung injury in addition to the tumor. For 94 of the 100 patients, there were contributing causes of death, with an average of 2.5 contributing causes and up to 6 contributing causes of death. The numerous and complex ways lung cancer kills patients pose a challenge for efforts to extend and improve their lives.

Identification of stainless steel welding fume particulates in human lung and environmental samples using electron probe microanalysis.

PubMed

Stettler, L E; Groth, D H; MacKay, G R

1977-02-01

Open lung biopsy specimens from two welders and air samples from their workplace environments were examined with the electron probe microanalyzer. X-ray analysis showed that the majority of particles found in the lung tissue from both workers and in the air samples to be composed of varying amounts of iron, chromium, manganese and nickel, the major components of some types of stainless steel. Based upon these analyses, it was concluded that the majority of the particles in both biopsy specimens were a result of the workplace environment.

AIRWAY IDENTIFICATION WITHIN PLANAR GAMMA CAMERA IMAGES USING COMPUTER MODELS OF LUNG MORPHOLOGY

EPA Science Inventory

The quantification of inhaled aerosols could be improved if a more comprehensive assessment of their spatial distribution patterns among lung airways were obtained. A common technique for quantifying particle deposition in human lungs is with planar gamma scintigraphy. However, t...

Influence of polymeric carrier on the disposition and retention of 20(R)-ginsenoside-rg3-loaded swellable microparticles in the lung.

PubMed

Wang, Xiuhua; Zhang, Xiao; Fan, Linlin; He, Huan; Zhang, Xiaofei; Zhang, Yuyang; Mao, Shirui

2018-02-01

The objective of this study was to investigate the influence of differently charged biocompatible polymers, including chitosan (CS), hyaluronic acid (HA), and hydroxypropyl cellulose (HPC), on the disposition and retention of 20(R)-ginsenoside-rg3 (Rg3)-loaded swellable microparticles in the lung. A high-pressure homogenization method combined with spray drying was used to prepare Rg3-loaded microparticles. In vitro aerodynamic performance of different microparticles was characterized by the Next Generation Impactor (NGI). Retention of the swellable microparticles in the rat lung was investigated using bronchoalveolar lavage fluid method. Influence of drug loading, polymer molecular weight, and polymer charge on the properties of the swellable microparticles was investigated. It was found that drug loading had no significant influence on experimental mass median aerodynamic diameter (MMAD e ) and fine particle fraction (FPF). Increasing polymer molecular weight caused no remarkable change in MMAD e value, but the FPF value decreased with the increase of polymer molecular weight. At the same molecular weight level, polymer structure and charge had no statistical influence on the in vitro aerodynamic properties of the microparticles and lung disposition, but it influenced the swelling and bioadhesion behavior and therefore lung retention profile. Desirable phagocytosis escapement and inhibition of A549 cell proliferation were achieved for the developed swellable microparticles. In conclusion, the lung retention of swellable microparticles can be adjusted by selecting polymeric carriers with different structure and charge.

Development of Chitosan-based Dry Powder Inhalation System of Cisplatin for Lung Cancer

PubMed Central

Singh, D. J.; Lohade, A. A.; Parmar, J. J.; Hegde, Darshana D.; Soni, P.; Samad, A.; Menon, Mala D.

2012-01-01

Cisplatin, a platinum compound, exerts its cytotoxic effects by coordinating to DNA where it inhibits both replication and transcription, and induces programmed cell death. It is used in the treatment of non-small cell lung cancer. In the present study, an attempt was made to achieve better treatment of lung cancer by direct lung delivery of cisplatin microparticulate systems, which helps to localize the drug in the lungs, and also provide sustained action. Cisplatin-loaded chitosan microspheres were prepared by emulsification and ionotropic gelation method, and characterized for drug content, particle size, densities, flow properties, moisture content, and surface topography by SEM and in vitro drug release was evaluated in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction (FPF) was determined by using twin stage impinger (TSI). Further stability evaluation of cisplatin-loaded DPI systems was carried out at 25°/60% RH and at 40°/75% RH. PMID:23798777

Epidemiology of Lung Cancer

PubMed Central

Brock, Malcolm V.; Ford, Jean G.; Samet, Jonathan M.; Spivack, Simon D.

2013-01-01

Background: Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. Methods: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. Results: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. Conclusions: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID:23649439

Heterogeneity of Particle Deposition by Pixel Analysis of 2D Gamma Scintigraphy Images

PubMed Central

Xie, Miao; Zeman, Kirby; Hurd, Harry; Donaldson, Scott

2015-01-01

Abstract Background: Heterogeneity of inhaled particle deposition in airways disease may be a sensitive indicator of physiologic changes in the lungs. Using planar gamma scintigraphy, we developed new methods to locate and quantify regions of high (hot) and low (cold) particle deposition in the lungs. Methods: Initial deposition and 24 hour retention images were obtained from healthy (n=31) adult subjects and patients with mild cystic fibrosis lung disease (CF) (n=14) following inhalation of radiolabeled particles (Tc99m-sulfur colloid, 5.4 μm MMAD) under controlled breathing conditions. The initial deposition image of the right lung was normalized to (i.e., same median pixel value), and then divided by, a transmission (Tc99m) image in the same individual to obtain a pixel-by-pixel ratio image. Hot spots were defined where pixel values in the deposition image were greater than 2X those of the transmission, and cold spots as pixels where the deposition image was less than 0.5X of the transmission. The number ratio (NR) of the hot and cold pixels to total lung pixels, and the sum ratio (SR) of total counts in hot pixels to total lung counts were compared between healthy and CF subjects. Other traditional measures of regional particle deposition, nC/P and skew of the pixel count histogram distribution, were also compared. Results: The NR of cold spots was greater in mild CF, 0.221±0.047(CF) vs. 0.186±0.038 (healthy) (p<0.005) and was significantly correlated with FEV1 %pred in the patients (R=−0.70). nC/P (central to peripheral count ratio), skew of the count histogram, and hot NR or SR were not different between the healthy and mild CF patients. Conclusions: These methods may provide more sensitive measures of airway function and localization of deposition that might be useful for assessing treatment efficacy in these patients. PMID:25393109

ATM-activated autotaxin (ATX) propagates inflammation and DNA damage in lung epithelial cells: a new mode of action for silica-induced DNA damage?

PubMed

Zheng, Huiyuan; Högberg, Johan; Stenius, Ulla

2017-12-07

Silica exposure is a common risk factor for lung cancer. It has been claimed that key elements in cancer development are activation of inflammatory cells that indirectly induce DNA damage and proliferative stimuli in respiratory epithelial cells. We studied DNA damage induced by silica particles in respiratory epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). A549 and 16 bronchial epithelial cells (16HBE) lung epithelial cells were exposed to silica particles. Reactive oxygen species (ROS), NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activation, ATX, ataxia telangiectasia mutated (ATM), and DNA damage (γH2AX, pCHK1, pCHK2, comet assay) were end points. Low doses of silica induced NLRP3 activation, DNA damage accumulation, and ATM phosphorylation. A novel finding was that ATM induced ATX generation and secretion. Not only silica but also rotenone, camptothecin and H2O2 activated ATX via ATM, suggesting that ATX is part of a generalized ATM response to double-strand breaks (DSBs). Surprisingly, ATX inhibition mitigated DNA damage accumulation at later time points (6-16 h), and ATX transfection caused NLRP3 activation and DNA damage. Furthermore, the product of ATX enzymatic activity, lysophosphatidic acid, recapitulated the effects of ATX transfection. These data indicate an ATM-ATX-dependent loop that propagates inflammation and DSB accumulation, making low doses of silica effective inducers of DSBs in epithelial cells. We conclude that an ATM-ATX axis interconnects DSBs with silica-induced inflammation and propagates these effects in epithelial cells. Further studies of this adverse outcome pathway may give an accurate assessment of the lowest doses of silica that causes cancer. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evidence for particle transport between alveolar macrophages in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benson, J.M.; Nikula, K.J.; Guilmette, R.A.

1995-12-01

Recent studies at this Institute have focused on determining the role of alveolar macrophages (AMs) in the transport of particles within and form the lung. For those studies, AMs previously labeled using the nuclear stain Hoechst 33342 and polychromatic Fluoresbrite microspheres (1 {mu}m diameter, Polysciences, Inc., Warrington, PA) were instilled into lungs of recipient F344 rats. The fate of the donor particles and the doubly labeled AMs within recipient lungs was followed for 32 d. Within 2-4 d after instillation, the polychromatic microspheres were found in both donor and resident AMs, suggesting that particle transfer occurred between the donor andmore » resident AMs. However, this may also have been an artifact resulting from phagocytosis of the microspheres form dead donor cells or from the fading or degradation of Hoechst 33342 within the donor cells leading to their misidentification as resident AMs. The results support the earlier findings that microspheres in donor AMs can be transferred to resident AMs within 2 d after instillation.« less

Poly(d,l-lactide-co-glycolide)–chitosan composite particles for the treatment of lung cancer

PubMed Central

Arya, Neha; Katti, Dhirendra S

2015-01-01

Tumor heterogeneity makes combination chemotherapy one of the preferred modes of treatment regimens. In this work, sequential exposure of two anticancer agents, paclitaxel (Tx) followed by topotecan (TPT), was shown to have a synergistic effect on non-small cell lung cancer (NSCLC) cell line, NCI-H460. In order to improve patient compliance, the aforementioned concept was translated into a drug delivery system comprising of poly(d,l-lactide-co-glycolide) (PLGA)–chitosan composite particles. TPT-containing chitosan micro-/nanoparticles were prepared by the facile technique of electrospraying and encapsulated within PLGA microparticles using emulsion-solvent evaporation technique for delayed release of TPT. The formulation containing Tx- and TPT-loaded composite particles demonstrated synergism when exposed to NCI-H460 cellular aggregates (tumoroids) generated in vitro. Overall, the results of this study demonstrated the potential of the formulation containing Tx and PLGA–chitosan (TPT-loaded) composite particles for the treatment of lung cancer. PMID:25945047

Alterations in welding process voltage affect the generation of ultrafine particles, fume composition, and pulmonary toxicity.

PubMed

Antonini, James M; Keane, Michael; Chen, Bean T; Stone, Samuel; Roberts, Jenny R; Schwegler-Berry, Diane; Andrews, Ronnee N; Frazer, David G; Sriram, Krishnan

2011-12-01

The goal was to determine if increasing welding voltage changes the physico-chemical properties of the fume and influences lung responses. Rats inhaled 40 mg/m³ (3 h/day × 3 days) of stainless steel (SS) welding fume generated at a standard voltage setting of 25 V (regular SS) or at a higher voltage (high voltage SS) of 30 V. Particle morphology, size and composition were characterized. Bronchoalveolar lavage was performed at different times after exposures to assess lung injury. Fumes collected from either of the welding conditions appeared as chain-like agglomerates of nanometer-sized primary particles. High voltage SS welding produced a greater number of ultrafine-sized particles. Fume generated by high voltage SS welding was higher in manganese. Pulmonary toxicity was more substantial and persisted longer after exposure to the regular SS fume. In summary, a modest raise in welding voltage affected fume size and elemental composition and altered the temporal lung toxicity profile.

Pneumoconiosis after sericite inhalation.

PubMed

Algranti, E; Handar, A M; Dumortier, P; Mendonça, E M C; Rodrigues, G L; Santos, A M A; Mauad, T; Dolhnikoff, M; De Vuyst, P; Saldiva, P H N; Bussacos, M A

2005-03-01

Between 1997 and 1999 three sericite plant workers in Parana, Brazil, were diagnosed with pneumoconiosis. To investigate and describe the radiological, clinical, and pathological changes in miners and millers exposed to sericite dust with mineralogical characteristics of inhaled dust. The working premises were visited to examine the sericite processing and to classify the jobs according to make qualitative evaluation. Respirable dust was collected and the amount of crystalline silica and particle size distribution were measured. Forty four workers were examined by a standard questionnaire for respiratory symptoms, spirometry, and chest x ray. Material from an open lung biopsy was reviewed for histopathological and mineralogical analysis, together with sericite samples from the work site to compare the mineral characteristics in lung lesions and work area. Respirable dust contained 4.5-10.0% crystalline silica. Particle size distribution showed a heavy burden of very fine particles (23-55%) with a mean diameter of <0.5 microm. Mean age of sericite miners was 41.0 (11.9) and mean number of years of exposure was 13.5 (10.1). In 52.3% of workers (23/44), chest radiographs presented a median category of 1/0 or above, and 18.2% (8/44) had a reduced FEV1. There was a significant association between exposure indices and x ray category. Histological studies of the lung biopsy showed lesions compatible with mixed dust fibrosis with no silicotic nodules. x Ray diffraction analysis of the lung dust residue and the bulk samples collected from work area showed similar mineralogical characteristics. Muscovite and kaolinite were the major mineral particle inclusions in the lung. Exposure to fine sericite particles is associated with the development of functional and radiological changes in workers inducing mixed dust lesions, which are distinct histologically from silicosis.

Decreased Dissolution of ZnO by Iron Doping Yields Nanoparticles with Reduced Toxicity in the Rodent Lung and Zebrafish Embryos

PubMed Central

Xia, Tian; Zhao, Yan; Sager, Tina; George, Saji; Pokhrel, Suman; Li, Ning; Schoenfeld, David; Meng, Huan; Lin, Sijie; Wang, Xiang; Wang, Meiying; Ji, Zhaoxia; Zink, Jeffrey I.; Mädler, Lutz; Castranova, Vincent; Lin, Shuo; Nel, Andre E.

2014-01-01

We have recently shown that the dissolution of ZnO nanoparticles and Zn2+ shedding leads to a series of sub-lethal and lethal toxicological responses at cellular level that can be alleviated by iron-doping. Iron-doping changes the particle matrix and slows the rate of particle dissolution. To determine whether iron doping of ZnO also leads to lesser toxic effects in vivo, toxicity studies were performed in rodent and zebrafish models. First, we synthesized a fresh batch of ZnO nanoparticles doped with 1–10 wt % of Fe. These particles were extensively characterized to confirm their doping status, reduced rate of dissolution in an exposure medium and reduced toxicity in a cellular screen. Subsequent studies compared the effects of undoped to doped particles in the rat lung, mouse lung and the zebrafish embryo. The zebrafish studies looked at embryo hatching and mortality rates as well as the generation of morphological defects, while the endpoints in the rodent lung included an assessment of inflammatory cell infiltrates, LDH release and cytokine levels in the bronchoalveolar lavage fluid. Iron doping, similar to the effect of the metal chelator, DTPA, interfered in the inhibitory effects of Zn2+ on zebrafish hatching. In the oropharyngeal aspiration model in the mouse, iron doping was associated with decreased polymorphonuclear cell counts and IL-6 mRNA production. Doped particles also elicited decreased heme oxygenase 1 expression in the murine lung. In the intratracheal instillation studies in the rat, Fe-doping was associated with decreased polymorphonuclear cell counts, LDH and albumin levels. All considered, the above data show that Fe-doping is a possible safe design strategy for preventing ZnO toxicity in animals and the environment. PMID:21250651

METHODS OF CALCULATINAG LUNG DELIVERY AND DEPOSITION OF AEROSOL PARTICLES

EPA Science Inventory

Lung deposition of aerosol is measured by a variety of methods. Total lung deposition can be measured by monitoring inhaled and exhaled aerosols in situ by laser photometry or by collecting the aerosols on filters. The measurements can be performed accurately for stable monod...

Phospholipid lung surfactant and nanoparticle surface toxicity: Lessons from diesel soots and silicate dusts

NASA Astrophysics Data System (ADS)

Wallace, William E.; Keane, Michael J.; Murray, David K.; Chisholm, William P.; Maynard, Andrew D.; Ong, Tong-man

2007-01-01

Because of their small size, the specific surface areas of nanoparticulate materials (NP), described as particles having at least one dimension smaller than 100 nm, can be large compared with micrometer-sized respirable particles. This high specific surface area or nanostructural surface properties may affect NP toxicity in comparison with micrometer-sized respirable particles of the same overall composition. Respirable particles depositing on the deep lung surfaces of the respiratory bronchioles or alveoli will contact pulmonary surfactants in the surface hypophase. Diesel exhaust ultrafine particles and respirable silicate micrometer-sized insoluble particles can adsorb components of that surfactant onto the particle surfaces, conditioning the particles surfaces and affecting their in vitro expression of cytotoxicity or genotoxicity. Those effects can be particle surface composition-specific. Effects of particle surface conditioning by a primary component of phospholipid pulmonary surfactant, diacyl phosphatidyl choline, are reviewed for in vitro expression of genotoxicity by diesel exhaust particles and of cytotoxicity by respirable quartz and aluminosilicate kaolin clay particles. Those effects suggest methods and cautions for assaying and interpreting NP properties and biological activities.

Adverse effects of inhaled sand dust particles on the respiratory organs of sheep and goats exposed to severe sand storms in Mongolia.

PubMed

Kobayashi, Yoshimi; Shimada, Akinori; Nemoto, Mai; Morita, Takehito; Adilbish, Altanchimeg; Bayasgalan, Mungun-Ochir

2014-01-01

Sand storms in Mongolia have increased in frequency and scale, resulting in increased exposure of the inhabitants of Asian countries, including Japan and Korea, to Asian sand dust (ASD), which results in adverse effects on the respiratory system. However, there is no information on the health risks of severe sand storms in domestic animals in Mongolia. The aim of the study was to investigate the effects of sand dust particles on the respiratory organs, including the lungs and tracheobronchial lymph nodes, of sheep and goats exposed to severe sand storms in Mongolia. Seven adult sheep and 4 adult goats that had been exposed to sand storms and 3 sheep with no history of exposure were included in this study. Lung tissues and tracheobronchial lymph nodes were subjected to histopathological and immunohistochemical examination. The mineralogical contents of the lungs and lymph nodes were determined using inductively coupled plasma atomic emission spectroscopy. Fibrosis and granulomatous lesions comprising macrophages containing fine sand dust particles were observed exclusively in the lungs of sheep and goats exposed to sand storms. The activity of macrophages was also demonstrated by the presence of IL-6, TNF, and lysozyme. In addition, silicon, which is the major element of ASD (kosa aerosol), was detected exclusively in the lung tissues of the exposed animals. Our findings suggest that exposure to sand dust particles may affect the respiratory systems of domestic animals during their relatively short life span.

A Proposed In Vitro Method to Assess Effects of Inhaled Particles on Lung Surfactant Function.

PubMed

Sørli, Jorid B; Da Silva, Emilie; Bäckman, Per; Levin, Marcus; Thomsen, Birthe L; Koponen, Ismo K; Larsen, Søren T

2016-03-01

The lung surfactant (LS) lining is a thin liquid film covering the air-liquid interface of the respiratory tract. LS reduces surface tension, enabling lung surface expansion and contraction with minimal work during respiration. Disruption of surface tension is believed to play a key role in severe lung conditions. Inhalation of aerosols that interfere with the LS may induce a toxic response and, as a part of the safety assessment of chemicals and inhaled medicines, it may be relevant to study their impact on LS function. Here, we present a novel in vitro method, based on the constrained drop surfactometer, to study LS functionality after aerosol exposure. The applicability of the method was investigated using three inhaled asthma medicines, micronized lactose, a pharmaceutical excipient used in inhaled medication, and micronized albumin, a known inhibitor of surfactant function. The surfactometer was modified to allow particles mixed in air to flow through the chamber holding the surfactant drop. The deposited dose was measured with a custom-built quartz crystal microbalance. The alterations allowed the study of continuously increasing quantified doses of particles, allowing determination of the dose of particles that affects the LS function. The tested pharmaceuticals did not inhibit the function of a model LS even at extreme doses--neither did lactose. Micronized albumin, however, impaired surfactant function. The method can discriminate between safe inhaled aerosols--as exemplified by the approved inhaled medicines and the pharmaceutical excipient lactose--and albumin known to impair lung functionality by inhibiting LS function.

Combination of icotinib, surgery, and internal-radiotherapy of a patient with lung cancer severely metastasized to the vertebrae bones with EGFR mutation: a case report.

PubMed

Qu, Li-Li; Qin, Hai-Feng; Gao, Hong-Jun; Liu, Xiao-Qing

2015-01-01

A 48-year-old Chinese female was referred to us regarding EGFR-mutated advanced non-small cell lung cancer, and metastasis to left scapula and vertebrae bones which caused pathological fracture at T8 and T10 thoracic vertebrae. An aggressive combined therapy with icotinib, vertebrae operation, and radioactive particle implantation and immunotherapy was proposed to prevent paraplegia, relieve pain, and control the overall and local tumor lesions. No postoperative symptoms were seen after surgery, and the pain was significantly relieved. Icotinib merited a 31-month partial response with grade 1 diarrhea as its drug-related adverse event. High dose of icotinib was administered after pelvis lesion progression for 3 months with good tolerance. Combination therapy of icotinib, surgery, and internal radiation for metastases of the vertebrae bones from non-small cell lung cancer seems to be a very promising technique both for sufficient pain relief and for local control of the tumor, vertebrae operation can be an encouraging option for patients with EFGR positive mutation and good prognosis indicator.

Direct and indirect air particle cytotoxicity in human alveolar epithelial cells.

PubMed

Orona, N S; Astort, F; Maglione, G A; Saldiva, P H N; Yakisich, J S; Tasat, D R

2014-08-01

Air particulate matter has been associated with adverse impact on the respiratory system leading to cytotoxic and proinflammatory effects. The biological mechanisms behind these associations may be initiated by inhaled small size particles, particle components (soluble fraction) and/or mediators released by particle-exposed cells (conditioned media). The effect of Urban Air Particles from Buenos Aires (UAP-BA) and Residual Oil Fly Ash (ROFA) a surrogate of ambient air pollution, their Soluble Fractions (SF) and Conditioned Media (CM) on A549 lung epithelial cells was examined. After 24 h exposure to TP (10 and 100 μg/ml), SF or CM, several biological parameters were assayed on cultured A549 cells. We tested cell viability by MTT, superoxide anion (O₂(-)) generation by NBT and proinflammatory cytokine (TNFα, IL-6 and IL-8) production by ELISA. UAP-BA particles or its SF (direct effect) did not modify cell viability and generation of O₂(-) for any of the doses tested. On the contrary, UAP-BA CM (indirect effect) reduced cell viability and increased both generation of O₂(-) and IL-8 production. Exposure to ROFA particles, SF or ROFA CM reduced proliferation and O₂(-) but, stimulated IL-8. It is worth to note that UAP-BA and ROFA depicted distinct effects on particle-exposed A549 cells implicating morphochemical dependence. These in vitro findings support the hypothesis that particle-induced lung inflammation and disease may involve lung-derived mediators. Copyright © 2014 Elsevier Ltd. All rights reserved.

In vitro evaluation of pulmonary deposition of airborne volcanic ash

NASA Astrophysics Data System (ADS)

Lähde, Anna; Sæunn Gudmundsdottir, Sigurbjörg; Joutsensaari, Jorma; Tapper, Unto; Ruusunen, Jarno; Ihalainen, Mika; Karhunen, Tommi; Torvela, Tiina; Jokiniemi, Jorma; Järvinen, Kristiina; Gíslason, Sigurður Reynir; Briem, Haraldur; Gizurarson, Sveinbjörn

2013-05-01

There has been an increasing interest in the effects of volcanic eruption on the environment, climate, and health following two recent volcanic eruptions in Iceland. Although health issues are mainly focused on subjects living close to the eruption due to the high concentration of airborne ash and gasses in close vicinity to the volcanoes, the ash may also reach high altitude and get distributed thousands of kilometers away from the volcano. Ash particles used in the studies were collected at the Eyjafjallajökull and Grímsvötn eruption sites. The composition, size, density and morphology of the particles were analyzed and the effect of particle properties on the re-dispersion and lung deposition were studied. The aerodynamic size and morphology of the particles were consistent with field measurement results obtained during the eruptions. Due to their size and structure, the ash particles can be re-suspended and transported into the lungs. The total surface area of submicron ash particles deposited into the alveolar and tracheobronchial regions of the lungs were 3-9% and 1-2%, respectively. Although the main fraction of the surface area is deposited in the head airways region, a significant amount of particles can deposit into the alveolar and tracheobronchial regions. The results indicate that a substantial increase in the concentration of respirable airborne ash particles and associated health hazard can take place if the deposited ash particles are re-suspended under dry, windy conditions or by outdoor human activity.

Effect of radon on the immune system: alterations in the cellularity and functions of T cells in lymphoid organs of mouse.

PubMed

Nagarkatti, M; Nagarkatti, P S; Brooks, A

1996-04-19

Exposure to radon and its progeny induces significant damage to the cells of the respiratory tract and causes lung cancer. Whether a similar exposure to radon would alter the functions of the immune system has not been previously investigated. In the current study, we investigated the effect of exposure of C57BL/6 mice to 1000 or 2500 working-level months (WLM) of radon and its progeny by inhalation, on the number and function of T lymphocytes in lymphoid organs. The control mice received uranium ore dust carrier aerosol by inhalation. Exposure to radon induced marked decrease in the total cellularity of most lymphoid organs such as thymus, peripheral lymph nodes (PLN), and lung-associated lymph nodes (LALN), when compared to the controls. The percentage of T cells increased, while that of non-T cells decreased, in all peripheral lymphoid organs at both the doses of radon. In the thymus, particularly at 2500 WLM of radon exposure, there was a marked decrease in CD4+CD8+ T cells and an increase in the immature CD4-CD8- T cells. Such alterations in both the numbers and percentages of lymphocytes and macrophages in radon-exposed mice may have resulted from the cell killing by the alpha particles as the immune cells were migrating through the lungs, or it may have been caused by altered migration of cells, inasmuch as expression of CD44, a molecule involved in migration and homing of immune cells, was significantly altered on cells found in different lymphoid organs. In the LALN, where one would predict the largest number of damaged cells to be present, there was a significant decrease in the T-cell responsiveness to mitogens while the B-cell response was not affected. Such alterations may have resulted from the direct effect of alpha-particle exposure on the migrating lymphocytes, altered percentage of lymphocytes as seen in secondary lymphoid organs, or altered expression of adhesion molecules involved in cell activation such as CD44 and CD3. Interestingly, radon exposure caused and increase in the T- and B-cell responsiveness to mitogens in the spleen and PLN. Since there is little evidence of direct radiation dose from radon in lymphoid organs, our studies demonstrating immunological alterations suggest an indirect effect of radon exposure that may have significant repercussions on the development of hypersensitivity and increased susceptibility to infections and cancer in the lung.

EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

EPA Science Inventory

ABSTRACT

Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

A NOVEL TECHNIQUE FOR QUANTITATIVE ESTIMATION OF UPTAKE OF DIESEL EXHAUST PARTICLES BY LUNG CELLS

EPA Science Inventory

While airborne particulates like diesel exhaust particulates (DEP) exert significant toxicological effects on lungs, quantitative estimation of accumulation of DEP inside lung cells has not been reported due to a lack of an accurate and quantitative technique for this purpose. I...

Formulation of Biologically-Inspired Silk-Based Drug Carriers for Pulmonary Delivery Targeted for Lung Cancer

PubMed Central

Kim, Sally Yunsun; Naskar, Deboki; Kundu, Subhas C.; Bishop, David P.; Doble, Philip A.; Boddy, Alan V.; Chan, Hak-Kim; Wall, Ivan B.; Chrzanowski, Wojciech

2015-01-01

The benefits of using silk fibroin, a major protein in silk, are widely established in many biomedical applications including tissue regeneration, bioactive coating and in vitro tissue models. The properties of silk such as biocompatibility and controlled degradation are utilized in this study to formulate for the first time as carriers for pulmonary drug delivery. Silk fibroin particles are spray dried or spray-freeze-dried to enable the delivery to the airways via dry powder inhalers. The addition of excipients such as mannitol is optimized for both the stabilization of protein during the spray-freezing process as well as for efficient dispersion using an in vitro aerosolisation impactor. Cisplatin is incorporated into the silk-based formulations with or without cross-linking, which show different release profiles. The particles show high aerosolisation performance through the measurement of in vitro lung deposition, which is at the level of commercially available dry powder inhalers. The silk-based particles are shown to be cytocompatible with A549 human lung epithelial cell line. The cytotoxicity of cisplatin is demonstrated to be enhanced when delivered using the cross-linked silk-based particles. These novel inhalable silk-based drug carriers have the potential to be used as anti-cancer drug delivery systems targeted for the lungs. PMID:26234773

Lung burden and deposition distribution of inhaled atmospheric urban ultrafine particles as the first step in their health risk assessment

NASA Astrophysics Data System (ADS)

Salma, Imre; Füri, Péter; Németh, Zoltán; Balásházy, Imre; Hofmann, Werner; Farkas, Árpád

2015-03-01

Realistic median particle number size distributions were derived by a differential mobility particle sizer in a diameter range of 6-1000 nm for near-city background, city centre, street canyon and road tunnel environments in Budapest. Deposition of inhaled particles within airway generations of an adult woman was determined by a stochastic lung deposition model for sleeping, sitting, light and heavy exercise breathing conditions. Deposition fractions in the respiratory tract were considerable and constant for all physical activities with a mean of 56%. Mean deposition fraction in the extra-thoracic region averaged for the urban environments was decreasing monotonically from 26% for sleeping to 9.4% for heavy exercise. The mean deposition fractions in the tracheobronchial region were constant for the physical activities and urban environments with an overall mean of 12.5%, while the mean deposition fraction in the acinar region averaged for the urban locations increased monotonically with physical activity from 14.7% for sleeping to 34% for heavy exercise. The largest contribution of the acinar deposition to the lung deposition was 75%. The deposition rates in the lung were larger than in the extra-thoracic region, and the deposition rate in the lung was increasingly realised in the AC region by physical activity. It was the extra-thoracic region that received the largest surface density deposition rates; its loading was higher by 3 orders of magnitude than for the lung. Deposition fractions in the airway generations exhibited a distinct peak in the acinar region. The maximum of the curves was shifted to peripheral airway generations with physical activity. The shapes of the surface density deposition rate curves were completely different from those for the deposition rates, indicating that the first few airway generations received the highest surface loading in the lung.

Comparison of deposited surface area of airborne ultrafine particles generated from two welding processes.

PubMed

Gomes, J F; Albuquerque, P C; Miranda, Rosa M; Santos, Telmo G; Vieira, M T

2012-09-01

This article describes work performed on the assessment of the levels of airborne ultrafine particles emitted in two welding processes metal-active gas (MAG) of carbon steel and friction-stir welding (FSW) of aluminium in terms of deposited area in alveolar tract of the lung using a nanoparticle surface area monitor analyser. The obtained results showed the dependence from process parameters on emitted ultrafine particles and clearly demonstrated the presence of ultrafine particles, when compared with background levels. The obtained results showed that the process that results on the lower levels of alveolar-deposited surface area is FSW, unlike MAG. Nevertheless, all the tested processes resulted in important doses of ultrafine particles that are to be deposited in the human lung of exposed workers.

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

NASA Astrophysics Data System (ADS)

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-06-01

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

PubMed Central

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-01-01

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831

Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia.

PubMed

Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S H; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

2015-06-29

Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

Solubility of indium-tin oxide in simulated lung and gastric fluids: Pathways for human intake.

PubMed

Andersen, Jens Christian Østergård; Cropp, Alastair; Paradise, Diane Caroline

2017-02-01

From being a metal with very limited natural distribution, indium (In) has recently become disseminated throughout the human society. Little is known of how In compounds behave in the natural environment, but recent medical studies link exposure to In compounds to elevated risk of respiratory disorders. Animal tests suggest that exposure may lead to more widespread damage in the body, notably the liver, kidneys and spleen. In this paper, we investigate the solubility of the most widely used In compound, indium-tin oxide (ITO) in simulated lung and gastric fluids in order to better understand the potential pathways for metals to be introduced into the bloodstream. Our results show significant potential for release of In and tin (Sn) in the deep parts of the lungs (artificial lysosomal fluid) and digestive tract, while the solubility in the upper parts of the lungs (the respiratory tract or tracheobronchial tree) is very low. Our study confirms that ITO is likely to remain as solid particles in the upper parts of the lungs, but that particles are likely to slowly dissolve in the deep lungs. Considering the prolonged residence time of inhaled particles in the deep lung, this environment is likely to provide the major route for uptake of In and Sn from inhaled ITO nano- and microparticles. Although dissolution through digestion may also lead to some uptake, the much shorter residence time is likely to lead to much lower risk of uptake. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Leah J.; Holmes, Amie L.; Maine Center for Environmental Toxicology and Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300

Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in human lung cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobaltmore » ion levels. Based on intracellular cobalt ion levels, we found that soluble cobalt was more cytotoxic than particulate cobalt while particulate and soluble cobalt induced similar levels of genotoxicity. However, soluble cobalt induced cell cycle arrest indicated by the lack of metaphases at much lower intracellular cobalt concentrations compared to cobalt oxide. Accordingly, we investigated the role of particle internalization in cobalt oxide-induced toxicity and found that particle-cell contact was necessary to induce cytotoxicity and genotoxicity after cobalt exposure. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung fibroblasts, and solubility plays a key role in cobalt-induced lung toxicity. - Highlights: • Particulate and soluble cobalt are cytotoxic and genotoxic to human lung cells. • Soluble cobalt induces more cytotoxicity compared to particulate cobalt. • Soluble and particulate cobalt induce similar levels of genotoxicity. • Particle-cell contact is required for particulate cobalt-induced toxicity.« less

Transient right-to-left shunt in massive pulmonary embolism.

PubMed

Panoutsopoulos, G; Ilias, L; Christakopoulou, I

2000-06-01

A 56-yr-old man, two months after an operation for an acoustic neurinoma, gradually developed dyspnea. Massive pulmonary embolism (MPE), with a significant right-to-left (R-L) shunt, was seen in a perfusion scan of the lungs with Tc-99m MAA. Radioactivity was noted in the thyroid, spleen, kidneys and brain. A cardiac ultrasound study did not reveal intracardiac shunting. A few days later, when the patient's condition improved, another perfusion scan of the lungs did not show the shunt, whereas a subsequent digital subtraction angiographic study confirmed the diagnosis of MPE but failed to reveal the cause of the shunt. In the absence of any possible pathophysiological mechanism, to explain the observed R-L shunt, we deduce that the particles of Tc-99m MAA might have passed through the precapillary pulmonary arteriovenous anastomoses and/or through dilated pulmonary capillaries, as a result of highly increased pulmonary vascular pressure due to MPE.

Pulmonary epithelial response in the rat lung to instilled Montserrat respirable dusts and their major mineral components.

PubMed

Housley, D G; Bérubé, K A; Jones, T P; Anderson, S; Pooley, F D; Richards, R J

2002-07-01

The Soufriere Hills, a stratovolcano on Montserrat, started erupting in July 1995, producing volcanic ash, both from dome collapse pyroclastic flows and phreatic explosions. The eruptions/ash resuspension result in high concentrations of suspended particulate matter in the atmosphere, which includes cristobalite, a mineral implicated in respiratory disorders. To conduct toxicological studies on characterised samples of ash, together with major components of the dust mixture (anorthite, cristobalite), and a bioreactive mineral control (DQ12 quartz). Rats were challenged with a single mass (1 mg) dose of particles via intratracheal instillation and groups sacrificed at one, three, and nine weeks. Acute bioreactivity of the particles was assessed by increases in lung permeability and inflammation, changes in epithelial cell markers, and increase in the size of bronchothoracic lymph nodes. Data indicated that respirable ash derived from pyroclastic flows (20.1% cristobalite) or phreatic explosion (8.6% cristobalite) had minimal bioreactivity in the lung. Anorthite showed low bioreactivity, in contrast to pure cristobalite, which showed progressive increases in lung damage. Results suggests that either the percentage mass of cristobalite particles present in Montserrat ash was not sufficient as a catalyst in the lung environment, or its surface reactivity was masked by the non-reactive volcanic glass components during the process of ash formation.

Pulmonary toxicity study in rats with PM 10 and PM 2.5: Differential responses related to scale and composition

NASA Astrophysics Data System (ADS)

Zhang, Wei; Lei, Tian; Lin, Zhi-Qing; Zhang, Hua-Shan; Yang, Dan-Feng; Xi, Zhu-Ge; Chen, Jian-Hua; Wang, Wei

2011-02-01

ObjectionTo study the pollution of atmospheric particles at winter in Beijing and compare the lung toxicity which induced by particle samples from different sampling sites. MethodWe collected samples from two sampling points during the winter for toxicity testing and chemical analysis. Wistar rats were administered with particles by intratracheal instillation. After exposure, biochemically index, esimmunity indexes, histopathology and DNA damage were detected in rat pulmonary cells. ResultThe elements with enrichment factors (EF) larger than 10 were As, Cd, Cu, Zn, S and Pb in the four experiment groups. The priority control of the total concentration of polycyclic aromatic hydrocarbons (PAHs) in PM 10 and PM 2.5 of Near-traffic source was much higher than that of Far-traffic source, it demonstrated that near the traffic source of PAHs pollution was heavier than that of Far-traffic source, as it was close to main roads Beiyuan Road, motor vehicle emissions were much higher. The pathology of lung showed that the degree of inflammation was increased with the particle diameter minished, it was the same as the detection of biochemical parameters such as lactate dehydrogenase (LDH), Total antioxidant status(T-AOC) and total protein (TP) in BALF and inflammation cytokine(interleukin-1, interleukin-6 and tumor necrosis factor-alpha) in lung homogenate. The indexes of DNA damage including the content of DNA and Olive empennage of PM 2.5 were significant higher than that of PM 10 at the same surveillance point ( P < 0.05), near-traffic particles were higher than the far-traffic particles at the same diameter, ( P < 0.05). ConclusionNear-traffic area particles had certain pollution at winter in Beijing. Meanwhile, atmospheric particulate matters on lung toxicity were related to the particles size and distance related sites which were exposed: smaller size, more toxicity; nearer from traffic, more toxicity.

Air pollution particles and iron homeostasis

EPA Science Inventory

Background: The mechanism underlying biological effects of particles deposited in the lung has not been defined. Major Conclusions: A disruption in iron homeostasis follows exposure of cells to all particulate matter including air pollution particles. Following endocytosis, fun...

Particle exposures and infections

EPA Science Inventory

Particle exposures increase the risk for human infections. Particles can deposit in the nose, pharynx, larynx, trachea, bronchi, and distal lung and, accordingly, the respiratory tract is the system most frequently infected after such exposure; however, meningitis also occurs. Ci...

Experimental investigation of particle deposition mechanisms in the lung acinus using microfluidic models.

NASA Astrophysics Data System (ADS)

Fishler, Rami; Mulligan, Molly; Dubowski, Yael; Sznitman, Josue; Sznitman Lab-department of Biomedical Engineering Team; Dubowski Lab-faculty of Civil; Environmental Engineering Team

2014-11-01

In order to experimentally investigate particle deposition mechanisms in the deep alveolated regions of the lungs, we have developed a novel microfluidic device mimicking breathing acinar flow conditions directly at the physiological scale. The model features an anatomically-inspired acinar geometry with five dichotomously branching airway generations lined with periodically expanding and contracting alveoli. Deposition patterns of airborne polystyrene microspheres (spanning 0.1 μm to 2 μm in diameter) inside the airway tree network compare well with CFD simulations and reveal the roles of gravity and Brownian motion on particle deposition sites. Furthermore, measured trajectories of incense particles (0.1-1 μm) inside the breathing device show a critical role for Brownian diffusion in determining the fate of inhaled sub-micron particles by enabling particles to cross from the acinar ducts into alveolar cavities, especially during the short time lag between inhalation and exhalation phases.

Biokinetics and internal dosimetry of inhaled metal tritide particles

NASA Astrophysics Data System (ADS)

Wang, Yansheng

1998-12-01

Metal tritides (MT), stable chemical compounds of tritium, are widely used in nuclear engineering facilities. MT particles can be released as aerosols. Inhaling MT particles is a potential occupational radiation hazard. Little information is available on their dissolution behavior, biokinetics, and dosimetry. The objectives of present dissertation are to estimate dissolution rates, to develop biokinetic models, to improve internal dosimetric considerations, and to classify MT materials. This study consisted of three phases: In vitro dissolution in a simulated lung fluid, In vivo rat experiments on retention and clearance, and biokinetic modeling and dosimetric evaluation. There was a supporting study on self- absorption of tritium beta in MT particles. MT materials used in this study were titanium (Ti) and zirconium (Zr) tritides. Results shows considerable self-absorption of beta particles and their energy, even for respirable MT particles smaller than 5 μm. The self-absorption factors should be required for counting MT particle samples and for estimating absorbed dose to tissues. In vitro and in vivo dissolution data indicate that Ti and Zr tritides are poorly soluble materials. Ti tritide belongs to the W class or M type while Zr tritide can be classified as Y class or S type. Due to long retention time of the MT particles, tritium betas directly from the particles contribute over 90% of the absorbed dose to lung. The lung dose contributes most of the effective dose to the whole body. Dissolved tritium including tritiated water (HTO) and organically bound tritium (OBT) has less effect on the lung dose and effective dose. Results on the annual limit on intake (ALI) indicate that the current radiation protection guideline based on HTO is not adequate for inhalation exposure to MT particles and needs to be modified. The biokinetic models developed in this study have predictive powers to estimate the consequences of a human inhalation exposure to MT aerosols. The animal excretory patterns found from in vivo rat studies may provide useful information for nuclear engineering facilities to setup bioassay program in workplace. The applications of the results from this research are limited in their scopes.

Causes of death in long-term survivors of non-small cell lung cancer: A regional Surveillance, Epidemiology, and End Results study.

PubMed

Kanitkar, Amaraja A; Schwartz, Ann G; George, Julie; Soubani, Ayman O

2018-01-01

Survival from lung cancer is improving. There are limited data on the causes of death in 5-year survivors of lung cancer. The aim of this study is to explore the causes of death in long-term survivors of non-small cell lung cancer (NSCLC) and describe the odds of dying from causes other than lung cancer in this patient population. An analysis of 5-year survivors of newly diagnosed NSCLC from 1996 to 2007, in Metropolitan Detroit included in Surveillance, Epidemiology, and End Results program, was done. Of 23,059 patients identified, 3789 (16.43%) patients were alive at 5-year period (long-term survivors) and 1897 (50.06%) patients died in the later follow-up period (median 88 months; range 1-219 months). The causes of death besides lung cancer were observed in 55.2% of these patients. The most common causes of death were cardiovascular diseases (CVDs) (16%), chronic obstructive pulmonary diseases (11%), and other malignancies (8%). Patients older than 65 years, males, and those who underwent surgery for treatment of lung cancer faced a greater likelihood of death by other causes as compared to lung cancer (OR: 1.45, 95% confidence interval [CI]: 1.18-1.77; OR: 1.24, 95% CI: 1.02-1.51; and OR: 1.39, 95% CI: 1.06-1.82, respectively). Five-year survivors of NSCLC more commonly die from causes such as CVDs, lung diseases, and other malignancies. Aggressive preventive and therapeutic measures of these diseases may further improve the outcome in this patient population.

Lung-clearance classification of radionuclides in calcined phosphate rock dust

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalkwarf, D.R.; Jackson, P.O.

1984-08-01

Lung-clearance classifications for /sup 210/Pb and /sup 210/Po in airborne dust from elemental phosphorus plants were estimated for use with the lung clearance model proposed by the ICRP Task Group on Lung Dynamics. Estimates were based on measurements of dissolution rates for these radionuclides from sized dust samples into simulated lung fluid at 37/sup 0/C. The estimates were expressed in the classification terms of the model, i.e., D, W and Y, indicating lung clearance half-times of 0 to 10 days, 11 to 100 days and more than 100 days. Dust samples were obtained from two plants in the western Unitedmore » States, and dissolution trials were conducted on fractions containing particles with aerodynamic equivalent diameters (AED) of 0 to 3 ..mu..m and of 3 to 10 ..mu..m. The /sup 210/Pb and /sup 210/Po in each of these fractions were classified 100% Class Y. The specific activities of both radionuclides increased with decreasing AED of the particles. 11 references, 1 figure, 4 tables.« less

Space radiation-associated lung injury in a murine model.

PubMed

Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia; Schweitzer, Kelly S; Berdyshev, Evgeny V; McCarthy, Maureen; Corbitt, Astrid; Alwood, Joshua S; Yu, Yongjia; Globus, Ruth K; Solomides, Charalambos C; Ullrich, Robert L; Petrache, Irina

2015-03-01

Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions. Copyright © 2015 the American Physiological Society.

Health Effects of Ozone and Particle Pollution

MedlinePlus

... policy . Skip to main content ABOUT US OUR INITIATIVES LUNG HEALTH & DISEASES SUPPORT & COMMUNITY STOP SMOKING GET ... Supporters Careers Contact Us Corporate Ethics Reporting OUR INITIATIVES LUNG FORCE Saved By The Scan Research Healthy ...

Measurement of Flow Patterns and Dispersion in the Human Airways

NASA Astrophysics Data System (ADS)

Fresconi, Frank E.; Prasad, Ajay K.

2006-03-01

A detailed knowledge of the flow and dispersion within the human respiratory tract is desirable for numerous reasons. Both risk assessments of exposure to toxic particles in the environment and the design of medical delivery systems targeting both lung-specific conditions (asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD)) and system-wide ailments (diabetes, cancer, hormone replacement) would profit from such an understanding. The present work features experimental efforts aimed at elucidating the fluid mechanics of the lung. Particle image velocimetry (PIV) and laser induced fluorescence (LIF) measurements of oscillatory flows were undertaken in anatomically accurate models (single and multi-generational) of the conductive region of the lung. PIV results captured primary and secondary velocity fields. LIF was used to determine the amount of convective dispersion across an individual generation of the lung.

Preparation and properties of inhalable nanocomposite particles: effects of the temperature at a spray-dryer inlet upon the properties of particles.

PubMed

Tomoda, Keishiro; Ohkoshi, Takumi; Kawai, Yusaku; Nishiwaki, Motoko; Nakajima, Takehisa; Makino, Kimiko

2008-02-15

To overcome the disadvantages both of microparticles and nanoparticles for inhalation, we have prepared nanocomposite particles as drug carriers targeting lungs. The nanocomposite particles having sizes about 2.5 microm composed of sugar and drug-loaded PLGA nanoparticles can reach deep in the lungs, and they are decomposed into drug-loaded PLGA nanoparticles in the alveoli. Sugar was used as a binder of PLGA nanoparticles to be nanocomposite particles and is soluble in alveolar lining fluid. The primary nanoparticles containing bioactive materials were prepared by using a probe sonicator. And then they were spray dried with carrier materials, such as trehalose and lactose. The effects of inlet temperature of spray dryer were studied between 60 and 120 degrees C and the kind of sugars upon properties of nanocomposite particles. When the inlet temperatures were 80 and 90 degrees C, nanocomposite particles with average diameters of about 2.5 microm are obtained and they are decomposed into primary nanoparticles in water, in both sugars are used as a binder. But, those prepared above 100 degrees C are not decomposed into nanoparticles in water, while the average diameter was almost 2.5 microm. On the other hand, nanocomposite particles prepared at lower inlet temperatures have larger sizes but better redispersion efficiency in water. By the measurements of aerodynamic diameters of the nanocomposite particles prepared with trehalose at 70, 80, and 90 degrees C, it was shown that the particles prepared at 80 degrees C have the highest fine particle fraction (FPF) value and the particles are suitable for pulmonary delivery of bioactive materials deep in the lungs. Meanwhile the case with lactose, the particles prepared at 90 degrees C have near the best FPF value but they have many particles larger than 11 microm.

Toxicity of Paraquat and Diquat Aerosols Generated by a Size-selective Cyclone: Effect of Particle Size Distribution

PubMed Central

Gage, J. C.

1968-01-01

The toxicity of paraquat and diquat aerosols to several species has been investigated. In order to obtain an atmosphere of `respirable' particles, an atomizer has been constructed with an upper cut-off of size by a cyclone separator, and with a calibrated reservoir to enable the concentration output to be estimated by inspection. Paraquat has an irritant action on the lungs, and at lethal concentrations death is delayed and is associated with pulmonary haemorrhage and oedema. After single exposures the LC50 appears to be a function of the duration and of the concentration; in the rat the lethal concentration-time product (CT) is about 6 μg./l.hr. Guinea-pigs and male mice are about as sensitive as rats. Female mice and rabbits are less sensitive. The dog can tolerate a CT product of 25 μg./l. hr without ill-effects. The toxicity is a complex function of particle size. In the rat it appears that the most effective size is in the region of 3 μ, as larger particles do not reach the alveolar regions and finer particles are probably not retained there. Repeated daily 6-hr exposures of rats to paraquat aerosols over a three-week period produce signs of lung irritation but no deaths at 0·4 μg./l., and the no-effect level is about 0·1 μg./litre. Paraquat appears to be poorly absorbed from the lungs. After single exposures death is associated with a paraquat content of about 6 μg. in the lungs. Paraquat is subsequently cleared from the lung with a half-life of about 36 hr. Diquat is much less irritant to the lungs than is paraquat; the no-effect levels on single and repeated exposure are at least five times larger. It is concluded that paraquat and diquat do not present an inhalation hazard under normal conditions of application, but with paraquat under abnormal conditions it may be desirable to provide respiratory protection. Images PMID:5723352

[The respiratory system--its self-cleaning system. General mechanisms of clearance].

PubMed

Mustajbegović, J; Zuskin, E

1998-01-01

The behaviour of particles and deposition in different parts of respiratory system are described. Listed are factors which contribute to the deposition of particles in the lungs and upper areas of the respiratory system. The general mechanisms of lung clearance and their action such as cough, mucociliary transport, alveolar clearance and immunological system are reported. Particularly is stressed the necessity of coordination of all defense mechanisms in order to maintain normal respiratory function.

Clinical perspectives on pulmonary systemic and macromolecular delivery.

PubMed

Scheuch, Gerhard; Kohlhaeufl, Martin J; Brand, Peter; Siekmeier, Ruediger

2006-10-31

The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of drugs for treatment of systemic disorders. However, the deposition behaviour of aerosol particles in the respiratory tract depends on a number of physical (e.g. properties of the particle), chemical (e.g. properties of the drug) and physiological (e.g. breathing pattern, pulmonary diseases) factors. If these are not considered, it will not be possible to deposit a reproducible and sufficient amount of drug in a predefined lung region by means of aerosol inhalation. The lack of consideration of such issues led to many problems in inhalation drug therapy for many years mainly because physiological background of aerosol inhalation was not fully understood. However, over the last 20 years, there has been considerable progress in aerosol research and in the understanding of the underlying mechanisms of particle inhalation and pulmonary particle deposition. As a consequence, an increasing number of studies have been performed for the lung administration of drugs using a variety of different inhalation techniques. This review describes the physical and in part some of the physiological requirements that need to be considered for the optimization of pulmonary drug delivery to target certain lung regions.

Pulmonary sustained release of insulin from microparticles composed of polyelectrolyte layer-by-layer assembly.

PubMed

Amancha, Kiran Prakash; Balkundi, Shantanu; Lvov, Yuri; Hussain, Alamdar

2014-05-15

The present study tests the hypothesis that layer-by-layer (LbL) nanoassembly of thin polyelectrolyte films on insulin particles provides sustained release of the drug after pulmonary delivery. LbL insulin microparticles were formulated using cationic and anionic polyelectrolytes. The microparticles were characterized for particle size, particle morphology, zeta potential and in vitro release. The pharmacokinetics and pharmacodynamics of drug were assessed by measuring serum insulin and glucose levels after intrapulmonary administration in rats. Bronchoalveolar lavage (BAL) and evans blue (EB) extravasation studies were performed to investigate the cellular or biochemical changes in the lungs caused by formulation administration. The mass median aerodynamic diameter (MMAD) of the insulin microparticles was 2.7 μm. Confocal image of the formulation particles confirmed the polyelectrolyte deposition around the insulin particles. Zeta potential measurements showed that there was charge reversal after each layering. Pulmonary administered LbL insulin formulation resulted in sustained serum insulin levels and concomitant decrease in serum glucose levels. The BAL and EB extravasation studies showed that the LbL insulin formulation did not elicit significant increase in marker enzymes activities compared to control group. These results demonstrate that the sustained release of insulin could be achieved using LbL nanoassembly around the insulin particles. Copyright © 2014 Elsevier B.V. All rights reserved.

Health risk of chrysotile revisited

PubMed Central

Dunnigan, Jacques; Hesterberg, Thomas; Brown, Robert; Velasco, Juan Antonio Legaspi; Barrera, Raúl; Hoskins, John; Gibbs, Allen

2013-01-01

This review provides a basis for substantiating both kinetically and pathologically the differences between chrysotile and amphibole asbestos. Chrysotile, which is rapidly attacked by the acid environment of the macrophage, falls apart in the lung into short fibers and particles, while the amphibole asbestos persist creating a response to the fibrous structure of this mineral. Inhalation toxicity studies of chrysotile at non-lung overload conditions demonstrate that the long (>20 µm) fibers are rapidly cleared from the lung, are not translocated to the pleural cavity and do not initiate fibrogenic response. In contrast, long amphibole asbestos fibers persist, are quickly (within 7 d) translocated to the pleural cavity and result in interstitial fibrosis and pleural inflammation. Quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type and have also differentiated between these two minerals. These studies have been reviewed in light of the frequent use of amphibole asbestos. As with other respirable particulates, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The importance of the present and other similar reviews is that the studies they report show that low exposures to chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low with even high exposures experienced over a short duration. PMID:23346982

Emerging mechanistic targets in lung injury induced by combustion-generated particles.

EPA Science Inventory

ABSTRACT The mechanism for biological effect following pulmonary exposure to combustion-generated particles is incompletely defined. Transient receptor potential (TRP) cation channels were identified as “particle sensors” in that their activation was coupled with the initiation ...

LIGHT MICROSCOPY DETECTION OF NANOSCALE PARTICLE INTERNALIZATION BY HUMAN LUNG CELLS

EPA Science Inventory

RATIONALE. Ultrafine particulate matter (PM) is reported to be more strongly correlated with adverse health effects relative to larger particle size fractions. These epidemiological findings are supported by toxicological studies suggesting that particle size is inversely associa...

Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomono, Takumi; Kajita, Masahiro; Yano, Kentaro

P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNAmore » expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment. -- Highlights: •Adenovirus vector infection induced P-gp mRNA expression in three NSCLC cell lines. •Adenovirus vector infection enhanced P-gp-mediated doxorubicin efflux from the cells. •The increase of P-gp was not mediated by nuclear receptors (PXR, CAR) or COX-2.« less

A computer model for the simulation of nanoparticle deposition in the alveolar structures of the human lungs.

PubMed

Sturm, Robert

2015-11-01

According to epidemiological and experimental studies, inhalation of nanoparticles is commonly believed as a main trigger for several pulmonary dysfunctions and lung diseases. Concerning the transport and deposition of such nano-scale particles in the different structures of the human lungs, some essential questions are still in need of a clarification. Therefore, main objective of the study was the simulation of nanoparticle deposition in the alveolar region of the human respiratory tract (HRT). Respective factors describing the aerodynamic behavior of spherical and non-spherical particles in the inhaled air stream (i.e., Cunningham slip correction factors, dynamic shape factors, equivalent-volume diameters, aerodynamic diameters) were computed. Alveolar deposition of diverse nanomaterials according to several known mechanisms, among which Brownian diffusion and sedimentation play a superior role, was approximated by the use of empirical and analytical formulae. Deposition calculations were conducted with a currently developed program, termed NANODEP, which allows the variation of numerous input parameters with regard to particle geometry, lung morphometry, and aerosol inhalation. Generally, alveolar deposition of nanoparticles concerned for this study varies between 0.1% and 12.4% during sitting breathing and between 2.0% and 20.1% during heavy-exercise breathing. Prolate particles (e.g., nanotubes) exhibit a significant increase in deposition, when their aspect ratio is enhanced. In contrast, deposition of oblate particles (e.g., nanoplatelets) is remarkably declined with any reduction of the aspect ratio. The study clearly demonstrates that alveolar deposition of nanoparticles represents a topic certainly being of superior interest for physicists and respiratory physicians in future.

CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease.

PubMed

Fernandez Fernandez, Elena; de Santi, Chiara; De Rose, Virginia; Greene, Catherine M

2018-05-11

Obstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are causes of high morbidity and mortality worldwide. CF is a multiorgan genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by progressive chronic obstructive lung disease. Most cases of COPD are a result of noxious particles, mainly cigarette smoke but also other environmental pollutants. Areas covered: Although the pathogenesis and pathophysiology of CF and COPD differ, they do share key phenotypic features and because of these similarities there is great interest in exploring common mechanisms and/or factors affected by CFTR mutations and environmental insults involved in COPD. Various molecular, cellular and clinical studies have confirmed that CFTR protein dysfunction is common in both the CF and COPD airways. This review provides an update of our understanding of the role of dysfunctional CFTR in both respiratory diseases. Expert Commentary: Drugs developed for people with CF to improve mutant CFTR function and enhance CFTR ion channel activity might also be beneficial in patients with COPD. A move toward personalized therapy using, for example, microRNA modulators in conjunction with CFTR potentiators or correctors, could enhance treatment of both diseases.

Environmental tobacco smoke particles in multizone indoor environments

NASA Astrophysics Data System (ADS)

Miller, S. L.; Nazaroff, W. W.

Environmental tobacco smoke (ETS) is a major source of human exposure to airborne particles. To better understand the factors that affect exposure, and to investigate the potential effectiveness of technical control measures, a series of experiments was conducted in a two-room test facility. Particle concentrations, size distributions, and airflow rates were measured during and after combustion of a cigarette. Experiments were varied to obtain information about the effects on exposure of smoker segregation, ventilation modification, and air filtration. The experimental data were used to test the performance of an analytical model of the two-zone environment and a numerical multizone aerosol dynamics model. A respiratory tract particle deposition model was also applied to the results to estimate the mass of ETS particles that would be deposited in the lungs of a nonsmoker exposed in either the smoking or nonsmoking room. Comparisons between the experimental data and model predictions showed good agreement. For time-averaged particle mass concentration, the average bias between model and experiments was less than 10%. The average absolute error was typically 35%, probably because of variability in particle emission rates from cigarettes. For the conditions tested, the use of a portable air filtration unit yielded 65-90% reductions in predicted lung deposition relative to the baseline scenario. The use of exhaust ventilation in the smoking room reduced predicted lung deposition in the nonsmoking room by more than 80%, as did segregating the smoker from nonsmokers with a closed door.

¹¹¹Indium-labeled ultrafine carbon particles; a novel aerosol for pulmonary deposition and retention studies.

PubMed

Sanchez-Crespo, Alejandro; Klepczynska-Nyström, Anna; Lundin, Anders; Larsson, Britt Marie; Svartengren, Magnus

2011-02-01

Continuous environmental or occupational exposure to airborne particulate pollution is believed to be a major hazard for human health. A technique to characterize their deposition and clearance from the lungs is fundamental to understand the underlying mechanisms behind their negative health effects. In this work, we describe a method for production and follow up of ultrafine carbon particles labeled with radioactive ¹¹¹Indium (¹¹¹In). The physicochemical and biological properties of the aerosol are described in terms of particle size and concentration, agglomeration rate, chemical bonding stability, and human lung deposition and retention. Preliminary in vivo data from a healthy human pilot exposure and 1-week follow up of the aerosol is presented. More than 98% of the generated aerosol was labeled with Indium and with particle sizes log normally distributed around 79  nm count median diameter. The aerosol showed good generation reproducibility and chemical stability, about 5% leaching 7 days after generation. During human inhalation, the particles were deposited in the alveolar space, with no central airways involvement. Seven days after exposure, the cumulative activity retention was 95.3%. Activity leaching tests from blood and urine samples confirmed that the observed clearance was explained by unbound activity, suggesting that there was no significant elimination of ultrafine particles. Compared to previously presented methods based on Technegas, ¹¹¹In-labelled ultrafine carbon particles allow for extended follow-up assessments of particulate pollution retention in healthy and diseased lungs.

Human Lung Cancer Risks from Radon – Part I - Influence from Bystander Effects - A Microdose Analysis

PubMed Central

Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

2010-01-01

Since the publication of the BEIR VI report in 1999 on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, at low domestic and workplace radon levels, in particular the Bystander Effect (BE) and the Adaptive Response radio-protection (AR). We analyzed the microbeam and broadbeam alpha particle data of Miller et al. (1995, 1999), Zhou et al. (2001, 2003, 2004), Nagasawa and Little (1999, 2002), Hei et al. (1999), Sawant et al. (2001a) and found that the shape of the cellular response to alphas is relatively independent of cell species and LET of the alphas. The same alpha particle traversal dose response behavior should be true for human lung tissue exposure to radon progeny alpha particles. In the Bystander Damage Region of the alpha particle response, there is a variation of RBE from about 10 to 35. There is a transition region between the Bystander Damage Region and Direct Damage Region of between one and two microdose alpha particle traversals indicating that perhaps two alpha particle “hits” are necessary to produce the direct damage. Extrapolation of underground miners lung cancer risks to human risks at domestic and workplace levels may not be valid. PMID:21731539

Bronchoscopy in the investigation of outpatients with hemoptysis at a lung cancer clinic.

PubMed

Arooj, Parniya; Bredin, Emily; Henry, Michael T; Khan, Kashif A; Plant, Barry J; Murphy, Desmond M; Kennedy, Marcus P

2018-06-01

In the investigation of lung cancer, current practice in many healthcare systems would support bronchoscopy regardless of CT findings in patients with hemoptysis. We sought to identify the cause, the diagnostic yield of CT and bronchoscopy and the requirement for bronchoscopy in at risk patients with hemoptysis with a normal CT scan through our rapid access lung cancer clinic (RALC). Initially, a chart review was performed on all patients with hemoptysis (2011-2012) and thereafter a prospective analysis was performed (2013-2016). Our analysis represents the largest study to date in outpatients with hemoptysis. In our retrospective study, 155 patients reported hemoptysis. Causes were lower respiratory tract infections (RTIs) (47%) and lung cancer (16%). Our prospective study included 182 patients. The causes of hemoptysis were RTIs (50%) and lung cancer (18%). There were no false negative CT-scans for lung cancer. 47/57 present with lung cancer underwent bronchoscopy and 43/47 were positive for lung cancer (92%). Patients with hemoptysis and lung cancer have a higher stage of malignancy with a predominance of squamous cell lung carcinoma. Smoking status, the duration of hemoptysis or description of hemoptysis were not predictive of lung cancer however lung cancer was not identified in patients age <50. One sixth of patients presenting with hemoptysis to our lung cancer clinic had lung cancer. No patient identified with cancer related haemoptysis had a CT negative for lung cancer and a combination of bronchoscopy plus endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) in those patients with a CT suspicious of lung cancer is 92% sensitive for lung cancer causing hemoptysis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Coal dust alters β-naphthoflavone-induced aryl hydrocarbon receptor nuclear translocation in alveolar type II cells

PubMed Central

Ghanem, Mohamed M; Battelli, Lori A; Law, Brandon F; Castranova, Vincent; Kashon, Michael L; Nath, Joginder; Hubbs, Ann F

2009-01-01

Background Many polycyclic aromatic hydrocarbons (PAHs) can cause DNA adducts and initiate carcinogenesis. Mixed exposures to coal dust (CD) and PAHs are common in occupational settings. In the CD and PAH-exposed lung, CD increases apoptosis and causes alveolar type II (AT-II) cell hyperplasia but reduces CYP1A1 induction. Inflammation, but not apoptosis, appears etiologically associated with reduced CYP1A1 induction in this mixed exposure model. Many AT-II cells in the CD-exposed lungs have no detectable CYP1A1 induction after PAH exposure. Although AT-II cells are a small subfraction of lung cells, they are believed to be a potential progenitor cell for some lung cancers. Because CYP1A1 is induced via ligand-mediated nuclear translocation of the aryl hydrocarbon receptor (AhR), we investigated the effect of CD on PAH-induced nuclear translocation of AhR in AT-II cells isolated from in vivo-exposed rats. Rats received CD or vehicle (saline) by intratracheal (IT) instillation. Three days before sacrifice, half of the rats in each group started daily intraperitoneal injections of the PAH, β-naphthoflavone (BNF). Results Fourteen days after IT CD exposure and 1 day after the last intraperitoneal BNF injection, AhR immunofluorescence indicated that proportional AhR nuclear expression and the percentage of cells with nuclear AhR were significantly increased in rats receiving IT saline and BNF injections compared to vehicle controls. However, in CD-exposed rats, BNF did not significantly alter the nuclear localization or cytosolic expression of AhR compared to rats receiving CD and oil. Conclusion Our findings suggest that during particle and PAH mixed exposures, CD alters the BNF-induced nuclear translocation of AhR in AT-II cells. This provides an explanation for the modification of CYP1A1 induction in these cells. Thus, this study suggests that mechanisms for reduced PAH-induced CYP1A1 activity in the CD exposed lung include not only the effects of inflammation on the lung as a whole, but also reduced PAH-associated nuclear translocation of AhR in an expanded population of AT-II cells. PMID:19650907

Ultrafine particle transport and deposition in a large scale 17-generation lung model.

PubMed

Islam, Mohammad S; Saha, Suvash C; Sauret, Emilie; Gemci, Tevfik; Yang, Ian A; Gu, Y T

2017-11-07

To understand how to assess optimally the risks of inhaled particles on respiratory health, it is necessary to comprehend the uptake of ultrafine particulate matter by inhalation during the complex transport process through a non-dichotomously bifurcating network of conduit airways. It is evident that the highly toxic ultrafine particles damage the respiratory epithelium in the terminal bronchioles. The wide range of in silico available and the limited realistic model for the extrathoracic region of the lung have improved understanding of the ultrafine particle transport and deposition (TD) in the upper airways. However, comprehensive ultrafine particle TD data for the real and entire lung model are still unavailable in the literature. Therefore, this study is aimed to provide an understanding of the ultrafine particle TD in the terminal bronchioles for the development of future therapeutics. The Euler-Lagrange (E-L) approach and ANSYS fluent (17.2) solver were used to investigate ultrafine particle TD. The physical conditions of sleeping, resting, and light activity were considered in this modelling study. A comprehensive pressure-drop along five selected path lines in different lobes was calculated. The non-linear behaviour of pressure-drops is observed, which could aid the health risk assessment system for patients with respiratory diseases. Numerical results also showed that ultrafine particle-deposition efficiency (DE) in different lobes is different for various physical activities. Moreover, the numerical results showed hot spots in various locations among the different lobes for different flow rates, which could be helpful for targeted therapeutical aerosol transport to terminal bronchioles and the alveolar region. Copyright © 2017 Elsevier Ltd. All rights reserved.

Particulate matter from both heavy fuel oil and diesel fuel shipping emissions show strong biological effects on human lung cells at realistic and comparable in vitro exposure conditions.

PubMed

Oeder, Sebastian; Kanashova, Tamara; Sippula, Olli; Sapcariu, Sean C; Streibel, Thorsten; Arteaga-Salas, Jose Manuel; Passig, Johannes; Dilger, Marco; Paur, Hanns-Rudolf; Schlager, Christoph; Mülhopt, Sonja; Diabaté, Silvia; Weiss, Carsten; Stengel, Benjamin; Rabe, Rom; Harndorf, Horst; Torvela, Tiina; Jokiniemi, Jorma K; Hirvonen, Maija-Riitta; Schmidt-Weber, Carsten; Traidl-Hoffmann, Claudia; BéruBé, Kelly A; Wlodarczyk, Anna J; Prytherch, Zoë; Michalke, Bernhard; Krebs, Tobias; Prévôt, André S H; Kelbg, Michael; Tiggesbäumker, Josef; Karg, Erwin; Jakobi, Gert; Scholtes, Sorana; Schnelle-Kreis, Jürgen; Lintelmann, Jutta; Matuschek, Georg; Sklorz, Martin; Klingbeil, Sophie; Orasche, Jürgen; Richthammer, Patrick; Müller, Laarnie; Elsasser, Michael; Reda, Ahmed; Gröger, Thomas; Weggler, Benedikt; Schwemer, Theo; Czech, Hendryk; Rüger, Christopher P; Abbaszade, Gülcin; Radischat, Christian; Hiller, Karsten; Buters, Jeroen T M; Dittmar, Gunnar; Zimmermann, Ralf

2015-01-01

Ship engine emissions are important with regard to lung and cardiovascular diseases especially in coastal regions worldwide. Known cellular responses to combustion particles include oxidative stress and inflammatory signalling. To provide a molecular link between the chemical and physical characteristics of ship emission particles and the cellular responses they elicit and to identify potentially harmful fractions in shipping emission aerosols. Through an air-liquid interface exposure system, we exposed human lung cells under realistic in vitro conditions to exhaust fumes from a ship engine running on either common heavy fuel oil (HFO) or cleaner-burning diesel fuel (DF). Advanced chemical analyses of the exhaust aerosols were combined with transcriptional, proteomic and metabolomic profiling including isotope labelling methods to characterise the lung cell responses. The HFO emissions contained high concentrations of toxic compounds such as metals and polycyclic aromatic hydrocarbon, and were higher in particle mass. These compounds were lower in DF emissions, which in turn had higher concentrations of elemental carbon ("soot"). Common cellular reactions included cellular stress responses and endocytosis. Reactions to HFO emissions were dominated by oxidative stress and inflammatory responses, whereas DF emissions induced generally a broader biological response than HFO emissions and affected essential cellular pathways such as energy metabolism, protein synthesis, and chromatin modification. Despite a lower content of known toxic compounds, combustion particles from the clean shipping fuel DF influenced several essential pathways of lung cell metabolism more strongly than particles from the unrefined fuel HFO. This might be attributable to a higher soot content in DF. Thus the role of diesel soot, which is a known carcinogen in acute air pollution-induced health effects should be further investigated. For the use of HFO and DF we recommend a reduction of carbonaceous soot in the ship emissions by implementation of filtration devices.

Particulate Matter from Both Heavy Fuel Oil and Diesel Fuel Shipping Emissions Show Strong Biological Effects on Human Lung Cells at Realistic and Comparable In Vitro Exposure Conditions

PubMed Central

Dilger, Marco; Paur, Hanns-Rudolf; Schlager, Christoph; Mülhopt, Sonja; Diabaté, Silvia; Weiss, Carsten; Stengel, Benjamin; Rabe, Rom; Harndorf, Horst; Torvela, Tiina; Jokiniemi, Jorma K.; Hirvonen, Maija-Riitta; Schmidt-Weber, Carsten; Traidl-Hoffmann, Claudia; BéruBé, Kelly A.; Wlodarczyk, Anna J.; Prytherch, Zoë; Michalke, Bernhard; Krebs, Tobias; Prévôt, André S. H.; Kelbg, Michael; Tiggesbäumker, Josef; Karg, Erwin; Jakobi, Gert; Scholtes, Sorana; Schnelle-Kreis, Jürgen; Lintelmann, Jutta; Matuschek, Georg; Sklorz, Martin; Klingbeil, Sophie; Orasche, Jürgen; Richthammer, Patrick; Müller, Laarnie; Elsasser, Michael; Reda, Ahmed; Gröger, Thomas; Weggler, Benedikt; Schwemer, Theo; Czech, Hendryk; Rüger, Christopher P.; Abbaszade, Gülcin; Radischat, Christian; Hiller, Karsten; Buters, Jeroen T. M.; Dittmar, Gunnar; Zimmermann, Ralf

2015-01-01

Background Ship engine emissions are important with regard to lung and cardiovascular diseases especially in coastal regions worldwide. Known cellular responses to combustion particles include oxidative stress and inflammatory signalling. Objectives To provide a molecular link between the chemical and physical characteristics of ship emission particles and the cellular responses they elicit and to identify potentially harmful fractions in shipping emission aerosols. Methods Through an air-liquid interface exposure system, we exposed human lung cells under realistic in vitro conditions to exhaust fumes from a ship engine running on either common heavy fuel oil (HFO) or cleaner-burning diesel fuel (DF). Advanced chemical analyses of the exhaust aerosols were combined with transcriptional, proteomic and metabolomic profiling including isotope labelling methods to characterise the lung cell responses. Results The HFO emissions contained high concentrations of toxic compounds such as metals and polycyclic aromatic hydrocarbon, and were higher in particle mass. These compounds were lower in DF emissions, which in turn had higher concentrations of elemental carbon (“soot”). Common cellular reactions included cellular stress responses and endocytosis. Reactions to HFO emissions were dominated by oxidative stress and inflammatory responses, whereas DF emissions induced generally a broader biological response than HFO emissions and affected essential cellular pathways such as energy metabolism, protein synthesis, and chromatin modification. Conclusions Despite a lower content of known toxic compounds, combustion particles from the clean shipping fuel DF influenced several essential pathways of lung cell metabolism more strongly than particles from the unrefined fuel HFO. This might be attributable to a higher soot content in DF. Thus the role of diesel soot, which is a known carcinogen in acute air pollution-induced health effects should be further investigated. For the use of HFO and DF we recommend a reduction of carbonaceous soot in the ship emissions by implementation of filtration devices. PMID:26039251

Pulmonary epithelial response in the rat lung to instilled Montserrat respirable dusts and their major mineral components

PubMed Central

Housley, D; Berube, K; Jones, T; Anderson, S; Pooley, F; Richards, R

2002-01-01

Background: The Soufriere Hills, a stratovolcano on Montserrat, started erupting in July 1995, producing volcanic ash, both from dome collapse pyroclastic flows and phreatic explosions. The eruptions/ash resuspension result in high concentrations of suspended particulate matter in the atmosphere, which includes cristobalite, a mineral implicated in respiratory disorders. Aims: To conduct toxicological studies on characterised samples of ash, together with major components of the dust mixture (anorthite, cristobalite), and a bioreactive mineral control (DQ12 quartz). Methods: Rats were challenged with a single mass (1 mg) dose of particles via intratracheal instillation and groups sacrificed at one, three, and nine weeks. Acute bioreactivity of the particles was assessed by increases in lung permeability and inflammation, changes in epithelial cell markers, and increase in the size of bronchothoracic lymph nodes. Results: Data indicated that respirable ash derived from pyroclastic flows (20.1% cristobalite) or phreatic explosion (8.6% cristobalite) had minimal bioreactivity in the lung. Anorthite showed low bioreactivity, in contrast to pure cristobalite, which showed progressive increases in lung damage. Conclusion: Results suggests that either the percentage mass of cristobalite particles present in Montserrat ash was not sufficient as a catalyst in the lung environment, or its surface reactivity was masked by the non-reactive volcanic glass components during the process of ash formation. PMID:12107295

Case Report: Analytical Electron Microscopy of Lung Granulomas Associated with Exposure to Coating Materials Carried by Glass Wool Fibers

PubMed Central

Ferreira, Angela S.; Moreira, Valéria B.; Castro, Marcos César S.; Soares, Porfírio J.; Algranti, Eduardo; Andrade, Leonardo R.

2010-01-01

Context Man-made vitreous fibers (MMVFs) are noncrystalline inorganic fibrous material used for thermal and acoustical insulation (e.g., rock wool, glass wool, glass microfibers, and refractory ceramic fibers). Neither epidemiologic studies of human exposure nor animal studies have shown a noticeable hazardous effect of glass wools on health. However, MMVFs have been anecdotally associated with granulomatous lung disease in several case reports. Case presentation Here, we describe the case of a patient with multiple bilateral nodular opacities who was exposed to glass wool fibers and coating materials for 7 years. Bronchoalveolar lavage fluid revealed an increased total cell count (predominantly macrophages) with numerous cytoplasmic particles. Lung biopsy showed peribronchiolar infiltration of lymphoid cells and many foreign-body–type granulomas. Alveolar macrophages had numerous round and elongated platelike particles inside the cytoplasm. X-ray microanalysis of these particles detected mainly oxygen/aluminum/silicon and oxygen/magnesium/silicon, compatible with kaolinite and talc, respectively. No elemental evidence for glass fibers was found in lung biopsy. Discussion The contribution of analytical electron microscopy applied in the lung biopsy was imperative to confirm the diagnosis of pneumoconiosis associated with a complex occupational exposure that included both MMVFs and coating materials. Relevance to clinical or professional practice This case study points out the possible participation of other components (coating materials), beyond MMVFs, in the etiology of pneumoconiosis. PMID:20123612

Secondary flow measurements and passive tracer dispersion in multi-generational models of conducting airways of the lung

NASA Astrophysics Data System (ADS)

Fresconi, Frank; Prasad, Ajay

2006-11-01

A detailed knowledge of the flow and dispersion within the human respiratory tract is desirable for numerous reasons. Both risk assessments of exposure to toxic particles in the environment and the design of medical delivery systems targeting both lung-specific conditions (asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD)) and system-wide ailments (diabetes, cancer, hormone replacement) would profit from such an understanding. The present work features experimental efforts aimed at elucidating the fluid mechanics of the lung. Particle image velocimetry (PIV) and laser induced fluorescence (LIF) measurements of steady and oscillatory flows were undertaken in anatomically accurate models (single and multi-generational) of the conductive region of the lung. PIV results captured primary and secondary velocity fields. LIF allowed visualization of the time-dependent deformation of a passive tracer and also quantified convective dispersion through the usage of a transport profile.

Impacts of antioxidants on hydroxyl radical production from individual and mixed transition metals in a surrogate lung fluid

NASA Astrophysics Data System (ADS)

Charrier, Jessica G.; Anastasio, Cort

2011-12-01

Inhalation of ambient particulate matter causes morbidity and mortality in humans. One hypothesized mechanism of toxicity is the particle-induced formation of reactive oxygen species (ROS) - including the highly damaging hydroxyl radical ( rad OH) - followed by inflammation and a variety of diseases. While past studies have found correlations between ROS formation and a variety of metals, there are no quantitative measurements of rad OH formation from transition metals at concentrations relevant to 24-hour ambient particulate exposure. This research reports specific and quantitative measurements of rad OH formation from 10 individual transition metals (and several mixtures) in a cell-free surrogate lung fluid (SLF) with four antioxidants: ascorbate, citrate, glutathione, and uric acid. We find that Fe and Cu can produce rad OH under all antioxidant conditions as long as ascorbate is present and that mixtures of the two metals synergistically increase rad OH production. Manganese and vanadium can also produce rad OH under some conditions, but given that their ambient levels are typically very low, these metals are not likely to chemically produce significant levels of rad OH in the lung fluid. Cobalt, chromium, nickel, zinc, lead, and cadmium do not produce rad OH under any of our experimental conditions. The antioxidant composition of our SLF significantly affects rad OH production from Fe and Cu: ascorbate is required for rad OH formation, citrate increases rad OH production from Fe, and both citrate and glutathione suppress rad OH production from Cu. MINTEQ ligand speciation modeling indicates that citrate and glutathione affect rad OH production by changing metal speciation, altering the reactivity of the metals. In the most realistic SLF (i.e., with all four antioxidants), Fe generates approximately six times more rad OH than does the equivalent amount of Cu. Since levels of soluble Fe in PM are typically higher than those of Cu, our results suggest that Fe dominates the chemical generation of rad OH from deposited particles in the lungs.

Differential regulation of the lung endothelin system by urban particulate matter and ozone.

PubMed

Thomson, Errol; Kumarathasan, Prem; Goegan, Patrick; Aubin, Rémy A; Vincent, Renaud

2005-11-01

Periodic elevation of ambient particulate matter and ozone levels is linked to acute cardiac morbidity and mortality. Increased plasma levels of the potent vasoconstrictor endothelin (ET)-1, a prognostic indicator of cardiac mortality, have been detected in both animal models and humans after exposure to air pollutants. The lungs are the primary source of circulating ET-1, but the direct effects of individual air pollutants and their interaction in modulating the pulmonary endothelin system are unknown. Fischer-344 rats were exposed to particles (0, 5, 50 mg/m3 EHC-93), ozone (0, 0.4, 0.8 ppm), or combinations of particles and ozone for 4 h. Changes in gene expression were measured using real-time reverse transcription polymerase chain reaction immediately after exposure and following 24 h recovery in clean air. Both pollutants individually increased preproET-1, endothelin converting enzyme-1, and endothelial nitric oxide synthase mRNA levels in the lungs shortly after exposure, consistent with the concomitant increase in plasma of the 21 amino acid ET-1[1-21] peptide measured by HPLC-fluorescence. PreproET-1 mRNA remained elevated 24 h after exposure to particles but not after ozone, in line with previously documented changes of the peptide in plasma. Both pollutants transiently increased endothelin-B receptor mRNA expression, while ozone decreased endothelin-A receptor mRNA levels. Coexposure to particles plus ozone increased lung preproET-1 mRNA but not plasma ET-1[1-21], suggesting alternative processing or degradation of endothelins. This coincided with an increase in the lungs of matrix metalloproteinase-2 (MMP-2), an enzyme that cleaves bigET-1 to ET-1[1-32]. Taken together, our data indicate that ozone and particulate matter independently regulate the expression of lung endothelin system genes, but show complex toxicological interaction with respect to plasma ET-1.

Cluster-guided imaging-based CFD analysis of airflow and particle deposition in asthmatic human lungs

NASA Astrophysics Data System (ADS)

Choi, Jiwoong; Leblanc, Lawrence; Choi, Sanghun; Haghighi, Babak; Hoffman, Eric; Lin, Ching-Long

2017-11-01

The goal of this study is to assess inter-subject variability in delivery of orally inhaled drug products to small airways in asthmatic lungs. A recent multiscale imaging-based cluster analysis (MICA) of computed tomography (CT) lung images in an asthmatic cohort identified four clusters with statistically distinct structural and functional phenotypes associating with unique clinical biomarkers. Thus, we aimed to address inter-subject variability via inter-cluster variability. We selected a representative subject from each of the 4 asthma clusters as well as 1 male and 1 female healthy controls, and performed computational fluid and particle simulations on CT-based airway models of these subjects. The results from one severe and one non-severe asthmatic cluster subjects characterized by segmental airway constriction had increased particle deposition efficiency, as compared with the other two cluster subjects (one non-severe and one severe asthmatics) without airway constriction. Constriction-induced jets impinging on distal bifurcations led to excessive particle deposition. The results emphasize the impact of airway constriction on regional particle deposition rather than disease severity, demonstrating the potential of using cluster membership to tailor drug delivery. NIH Grants U01HL114494 and S10-RR022421, and FDA Grant U01FD005837. XSEDE.

Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs.

PubMed

Nambiar, Madhusoodana P; Wright, Benjamin S; Rezk, Peter E; Smith, Kelvin B; Gordon, Richard K; Moran, Theodore S; Richards, Shannon M; Sciuto, Alfred M

2006-01-01

Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.

Differences in allergic inflammatory responses between urban PM2.5 and fine particle derived from desert-dust in murine lungs.

PubMed

He, Miao; Ichinose, Takamichi; Kobayashi, Makoto; Arashidani, Keiichi; Yoshida, Seiichi; Nishikawa, Masataka; Takano, Hirohisa; Sun, Guifan; Shibamoto, Takayuki

2016-04-15

The biological and chemical natures of materials adsorbed onto fine particulate matter (PM2.5) vary by origin and passage routes. The exacerbating effects of the two samples-urban PM2.5 (U-PM2.5) collected during the hazy weather in a Chinese city and fine particles (ASD-PM2.5) collected during Asian sand dust (ASD) storm event days in Japan-on murine lung eosinophilia were compared to clarify the role of toxic materials in PM2.5. The amounts of β-glucan and mineral components were higher in ASD-PM2.5 than in U-PM2.5. On the other hand, organic chemicals, including polycyclic aromatic hydrocarbons (PAHs), were higher in U-PM2.5 than in ASD-PM2.5. When BALB/c mice were intratracheally instilled with U-PM2.5 and ASD-PM2.5 (total 0.4 mg/mouse) with or without ovalbumin (OVA), various biological effects were observed, including enhancement of eosinophil recruitment induced by OVA in the submucosa of the airway, goblet cell proliferation in the bronchial epithelium, synergic increase of OVA-induced eosinophil-relevant cytokines and a chemokine in bronchoalveolar lavage fluid, and increase of serum OVA-specific IgG1 and IgE. Data demonstrate that U-PM2.5 and ASD-PM2.5 induced allergic inflammatory changes and caused lung pathology. U-PM2.5 and ASD-PM2.5 increased F4/80(+) CD11b(+) cells, indicating that an influx of inflammatory and exudative macrophages in lung tissue had occurred. The ratio of CD206 positive F4/80(+) CD11b(+) cells (M2 macrophages) in lung tissue was higher in the OVA+ASD-PM2.5 treated mice than in the OVA+U-PM2.5 treated mice. These results suggest that the lung eosinophilia exacerbated by both PM2.5 is due to activation of a Th2-associated immune response along with induced M2 macrophages and the exacerbating effect is greater in microbial element (β-glucan)-rich ASD-PM2.5 than in organic chemical-rich U-PM2.5. Copyright © 2016 Elsevier Inc. All rights reserved.

A systems-based approach to analyse the host response in murine lung macrophages challenged with respiratory syncytial virus

PubMed Central

2013-01-01

Background Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection in young children. The degree of disease severity is determined by the host response to infection. Lung macrophages play an important early role in the host response to infection and we have used a systems-based approach to examine the host response in RSV-infected lung-derived macrophage cells. Results Lung macrophage cells could be efficiently infected (>95%) with RSV in vitro, and the expression of several virus structural proteins could be detected. Although we failed to detect significant levels of virus particle production, virus antigen could be detected up until 96 hours post-infection (hpi). Microarray analysis indicated that 20,086 annotated genes were expressed in the macrophage cells, and RSV infection induced an 8.9% and 11.3% change in the global gene transcriptome at 4 hpi and 24 hpi respectively. Genes showing up-regulated expression were more numerous and exhibited higher changes in expression compared to genes showing down-regulated expression. Based on gene ontology, genes with cytokine, antiviral, cell death, and signal transduction functions showed the highest increases in expression, while signalling transduction, RNA binding and protein kinase genes showed the greatest reduction in expression levels. Analysis of the global gene expression profile using pathway enrichment analysis confirmed that up-regulated expression of pathways related to pathogen recognition, interferon signalling and antigen presentation occurred in the lung macrophage cells challenged with RSV. Conclusion Our data provided a comprehensive analysis of RSV-induced gene expression changes in lung macrophages. Although virus gene expression was detected, our data was consistent with an abortive infection and this correlated with the activation of several antivirus signalling pathways such as interferon type I signalling and cell death signalling. RSV infection induced a relatively large increase in pro-inflammatory cytokine expression, however the maintenance of this pro-inflammatory response was not dependent on the production of infectious virus particles. The sustained pro-inflammatory response even in the absence of a productive infection suggests that drugs that control the pro-inflammatory response may be useful in the treatment of patients with severe RSV infection. PMID:23506210

Augmenting regional and targeted delivery in the pulmonary acinus using magnetic particles

PubMed Central

Ostrovski, Yan; Hofemeier, Philipp; Sznitman, Josué

2016-01-01

Background It has been hypothesized that by coupling magnetic particles to inhaled therapeutics, the ability to target specific lung regions (eg, only acinar deposition), or even more so specific points in the lung (eg, tumor targeting), can be substantially improved. Although this method has been proven feasible in seminal in vivo studies, there is still a wide gap in our basic understanding of the transport phenomena of magnetic particles in the pulmonary acinar regions of the lungs, including particle dynamics and deposition characteristics. Methods Here, we present computational fluid dynamics-discrete element method simulations of magnetically loaded microdroplet carriers in an anatomically inspired, space-filling, multi-generation acinar airway tree. Breathing motion is modeled by kinematic sinusoidal displacements of the acinar walls, during which droplets are inhaled and exhaled. Particle dynamics are governed by viscous drag, gravity, and Brownian motion as well as the external magnetic force. In particular, we examined the roles of droplet diameter and volume fraction of magnetic material within the droplets under two different breathing maneuvers. Results and discussion Our results indicate that by using magnetic-loaded droplets, 100% of the particles that enter are deposited in the acinar region. This is consistent across all particle sizes investigated (ie, 0.5–3.0 µm). This is best achieved through a deep inhalation maneuver combined with a breath-hold. Particles are found to penetrate deep into the acinus and disperse well, while the required amount of magnetic material is maintained low (<2.5%). Although particles in the size range of ~90–500 nm typically show the lowest deposition fractions, our results suggest that this feature could be leveraged to augment targeted delivery. PMID:27547034

Pneumotoxicity and pulmonary clearance of different welding fumes after intratracheal instillation in the rat.

PubMed

Antonini, J M; Krishna Murthy, G G; Rogers, R A; Albert, R; Ulrich, G D; Brain, J D

1996-09-01

The objectives of this study were to compare different welding fumes in regard to their potential to elicit lung inflammation or injury and to examine possible mechanisms whereby welding fumes may damage the lungs. Fume was collected on filters from conventional spray [mild steel (MS-SPRAY) or stainless steel (SS-SPRAY) electrode wire] or pulsed current [mild steel (MS-PULSE) electrode wire] gas-shielded metal arc welding. Rats were given one of the three welding fume samples by intratracheal instillation (1.0 mg/100 g body wt). Other rats received a relatively inert dust (iron oxide), a pneumotoxic dust (crystalline silica), or a vehicle control (saline). Bronchoalveolar lavage (BAL) was performed 1, 7, 14, and 35 days postinstillation, and indicators of pulmonary damage [cellular differential, albumin, as well as, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), lactate dehydrogenase, and beta-n-acetyl glucosaminidase release] were assessed. One day postinstillation, some evidence of lung inflammation (more neutrophils) was observed for all particle groups, while increased BAL TNF-alpha and IL-1 beta were observed only in the SS-SPRAY and silica groups. By 14 days, lungs appeared normal among the MS-SPRAY, MS-PULSE, and iron oxide groups. At 14 and 35 days postinstillation, elevated pulmonary responses persisted for the animals exposed to silica and the SS-SPRAY welding fume. By 35 days, however, the SS-SPRAY group approached control levels, while the injury induced by silica increased. Using magnetometric estimates of welding fumes, we observed that MS-SPRAY fume was cleared from the lungs at a faster rate than the SS-SPRAY particles. We have demonstrated that the SS-SPRAY fume has more pneumotoxicity than MS fumes. This difference may reflect a greater retention of the SS-SPRAY particles in the lungs and different elemental composition of the fume. The SS-SPRAY fume also had enhanced release of TNF-alpha and IL-1 beta from lung cells soon after fume instillation. In contrast, we saw no influence of the power supply on particle size, composition, or toxicity.

Translational toxicology in setting occupational exposure limits for dusts and hazard classification - a critical evaluation of a recent approach to translate dust overload findings from rats to humans.

PubMed

Morfeld, Peter; Bruch, Joachim; Levy, Len; Ngiewih, Yufanyi; Chaudhuri, Ishrat; Muranko, Henry J; Myerson, Ross; McCunney, Robert J

2015-04-23

We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of "granular biopersistent particles without known specific toxicity" (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK's human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.

Relaxation of ferromagnetic nanoparticles in macrophages: In vitro and in vivo studies

NASA Astrophysics Data System (ADS)

Möller, Winfried; Takenaka, Shinji; Buske, Norbert; Felten, Kathrin; Heyder, Joachim

2005-05-01

The relaxation characteristics of magnetic nanoparticles (CoFe 2O 4) were investigated in J774A.1 macrophages and after voluntary inhalation. In dry form 25% of the particles showed Néel relaxation. Relaxation in macrophages occurred within minutes and could be inhibited by fixation, showing Brownian relaxation and intracellular transport processes. Relaxation in the lung happened similarly, but was dependent on the time after deposition. The particles were cleared from the lung within 2 weeks.

Formation of PAH-DNA adducts after in vivo and vitro exposure of rats and lung cells to different commercial carbon blacks.

PubMed

Borm, Paul J A; Cakmak, Gonca; Jermann, Erich; Weishaupt, Christel; Kempers, Pascal; van Schooten, Frederik Jan; Oberdörster, Günter; Schins, Roel P F

2005-06-01

The current study was designed to test the possible release and bioavailability of polycyclic aromatic hydrocarbons (PAHs) from a set of commercial carbon blacks (CBs) as well as the ability of these PAHs to form bulky DNA adducts. In four commercial CBs (Printex 90, Sterling V, N330, Lampblack 101), leaching of PAH was examined through (1) release of parent PAHs in saline with or without surfactant, and (2) PAH adducts in lung epithelial cells (A549) or in rat lungs after exposure to two CBs (Printex 90, Sterling V) for 13 weeks (50 mg/m(3)). In vitro experiments were done with original and extracted particles, as well as organic extracts of CB in DMSO. As positive controls, B[a]P (0.03 microM) and a mixture of 16 PAHs (0.1 microM) were used. No leaching of PAHs was measured in saline or surfactant-containing saline. In vitro incubations with CB particles (30-300 microg/cm(2)) revealed no adduct spots except for Sterling V. However, the spot was not concentration dependent and remains unidentified. Lung DNA from rats after inhalation of Printex 90 or Sterling V showed no spots related to PAH-DNA adduct formation compared to sham-exposed rats. The results suggest that PAHs are very tightly bound to these CBs. Only using organic extracts or particles of low-surface Sterling V, with high PAH content, PAHs may become available to form PAH-DNA adducts. However, the in vitro conditions showing this effect will not be encountered in vivo and renders this mechanism in particle-induced lung cancer at in vivo exposures highly unlikely.

Wood combustion particles induce adverse effects to normal and diseased airway epithelia.

PubMed

Krapf, Manuel; Künzi, Lisa; Allenbach, Sandrine; Bruns, Emily A; Gavarini, Ilaria; El-Haddad, Imad; Slowik, Jay G; Prévôt, André S H; Drinovec, Luka; Močnik, Griša; Dümbgen, Lutz; Salathe, Matthias; Baumlin, Nathalie; Sioutas, Constantinos; Baltensperger, Urs; Dommen, Josef; Geiser, Marianne

2017-04-19

Residential wood burning is a major source of poorly characterized, deleterious particulate matter, whose composition and toxicity may vary with wood type, burning condition and photochemical age. The causative link between ambient wood particle constituents and observed adverse health effects is currently lacking. Here we investigate the relationship between chemical properties of primary and atmospherically aged wood combustion particles and acute toxicity in human airway epithelial cells. Emissions from a log wood burner were diluted and injected into a smog chamber for photochemical aging. After concentration-enrichment and removal of oxidizing gases, directly emitted and atmospherically aged particles were deposited on cell cultures at the air-liquid interface for 2 hours in an aerosol deposition chamber mimicking physiological conditions in lungs. Cell models were fully differentiated normal and diseased (cystic fibrosis and asthma) human bronchial epithelia (HBE) and the bronchial epithelial cell line BEAS-2B. Cell responses were assessed at 24 hours after aerosol exposure. Atmospherically relevant doses of wood combustion particles significantly increased cell death in all but the asthma cell model. Expression of oxidative stress markers increased in HBE from all donors. Increased cell death and inflammatory responses could not be assigned to a single chemical fraction of the particles. Exposure to primary and aged wood combustion particles caused adverse effects to airway epithelia, apparently induced by several interacting components.

Do nanoparticles provide a new opportunity for diagnosis of distal airspace disease?

PubMed Central

Löndahl, Jakob; Jakobsson, Jonas KF; Broday, David M; Aaltonen, H Laura; Wollmer, Per

2017-01-01

There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4–1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic resonance imaging with hyperpolarized gases, an aerosol-based method is likely to be less time consuming, considerably cheaper, simpler to use, and easier to interpret (providing a single value rather than an image that has to be analyzed). Compared to diagnosis by carbon monoxide (DL,CO), the uptake of nanoparticles in the lung is not affected by blood flow, hemoglobin concentration or alterations of the alveolar membranes, but relies only on lung morphology. PMID:28053522

Do nanoparticles provide a new opportunity for diagnosis of distal airspace disease?

PubMed

Löndahl, Jakob; Jakobsson, Jonas Kf; Broday, David M; Aaltonen, H Laura; Wollmer, Per

There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4-1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic resonance imaging with hyperpolarized gases, an aerosol-based method is likely to be less time consuming, considerably cheaper, simpler to use, and easier to interpret (providing a single value rather than an image that has to be analyzed). Compared to diagnosis by carbon monoxide ( D L,CO ), the uptake of nanoparticles in the lung is not affected by blood flow, hemoglobin concentration or alterations of the alveolar membranes, but relies only on lung morphology.

Lung Cancer

MedlinePlus

Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

PubMed

Jain, Sumeet V; Kollisch-Singule, Michaela; Satalin, Joshua; Searles, Quinn; Dombert, Luke; Abdel-Razek, Osama; Yepuri, Natesh; Leonard, Antony; Gruessner, Angelika; Andrews, Penny; Fazal, Fabeha; Meng, Qinghe; Wang, Guirong; Gatto, Louis A; Habashi, Nader M; Nieman, Gary F

2017-12-01

Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH 2 O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H DS , n = 6) and (2) over-distension + low dynamic strain (OD + L DS , n = 6). OD was caused by setting the inspiratory pressure at 40 cmH 2 O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. In normal tissue (N T ), OD + L DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H DS . In acutely injured tissue (ALI T ), OD + L DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H DS . Both N T and ALI T are resistant to VILI caused by OD alone, but when combined with a H DS , significant tissue injury develops.

Thoracoscopic decortication for the management of trapped lung caused by 14-year pneumothorax: A case report.

PubMed

Tian, Yan; Zheng, Wenqi; Zha, Nashunbayaer; Wang, Yufei; Huang, Shaojun; Guo, Zhanlin

2018-05-26

Trapped lung is defined by the lung's inability to expand and fill the thoracic cavity because of a restricting "peel" caused by benign or malignant pleural disease. However, trapped lung secondary to pneumothorax is rarely reported. We present a case of trapped lung caused by a pneumothorax that occurred some 14 years before the patient presented to our hospital with a complaint of incapacitating dyspnea. Computed tomography (CT) scans revealed trapping of the right lung with abnormal thickening of the visceral pleura. In view of the patient's history of pneumothorax, we concluded that his dyspnea was attributable mainly to the trapping of his lung by the earlier pneumothorax. We therefore scheduled thoracoscopic decortication, which was successfully completed. The patient's recovery after the operation was uneventful, and seven weeks after surgery the right lung had re-expanded well. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Late-occurring pulmonary pathologies following inhalation of mixed oxide (uranium + plutonium oxide) aerosol in the rat.

PubMed

Griffiths, N M; Van der Meeren, A; Fritsch, P; Abram, M-C; Bernaudin, J-F; Poncy, J L

2010-09-01

Accidental exposure by inhalation to alpha-emitting particles from mixed oxide (MOX: uranium and plutonium oxide) fuels is a potential long-term health risk to workers in nuclear fuel fabrication plants. For MOX fuels, the risk of lung cancer development may be different from that assigned to individual components (plutonium, uranium) given different physico-chemical characteristics. The objective of this study was to investigate late effects in rat lungs following inhalation of MOX aerosols of similar particle size containing 2.5 or 7.1% plutonium. Conscious rats were exposed to MOX aerosols and kept for their entire lifespan. Different initial lung burdens (ILBs) were obtained using different amounts of MOX. Lung total alpha activity was determined by external counting and at autopsy for total lung dose calculation. Fixed lung tissue was used for anatomopathological, autoradiographical, and immunohistochemical analyses. Inhalation of MOX at ILBs ranging from 1-20 kBq resulted in lung pathologies (90% of rats) including fibrosis (70%) and malignant lung tumors (45%). High ILBs (4-20 kBq) resulted in reduced survival time (N = 102; p < 0.05) frequently associated with lung fibrosis. Malignant tumor incidence increased linearly with dose (up to 60 Gy) with a risk of 1-1.6% Gy for MOX, similar to results for industrial plutonium oxide alone (1.9% Gy). Staining with antibodies against Surfactant Protein-C, Thyroid Transcription Factor-1, or Oct-4 showed differential labeling of tumor types. In conclusion, late effects following MOX inhalation result in similar risk for development of lung tumors as compared with industrial plutonium oxide.

Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk.

PubMed

Hesterberg, Thomas W; Long, Christopher M; Bunn, William B; Lapin, Charles A; McClellan, Roger O; Valberg, Peter A

2012-06-01

The mutagenicity of organic solvent extracts from diesel exhaust particulate (DEP), first noted more than 55 years ago, initiated an avalanche of diesel exhaust (DE) health effects research that now totals more than 6000 published studies. Despite an extensive body of results, scientific debate continues regarding the nature of the lung cancer risk posed by inhalation of occupational and environmental DE, with much of the debate focused on DEP. Decades of scientific scrutiny and increasingly stringent regulation have resulted in major advances in diesel engine technologies. The changed particulate matter (PM) emissions in "New Technology Diesel Exhaust (NTDE)" from today's modern low-emission, advanced-technology on-road heavy-duty diesel engines now resemble the PM emissions in contemporary gasoline engine exhaust (GEE) and compressed natural gas engine exhaust more than those in the "traditional diesel exhaust" (TDE) characteristic of older diesel engines. Even with the continued publication of epidemiologic analyses of TDE-exposed populations, this database remains characterized by findings of small increased lung cancer risks and inconsistent evidence of exposure-response trends, both within occupational cohorts and across occupational groups considered to have markedly different exposures (e.g. truckers versus railroad shopworkers versus underground miners). The recently published National Institute for Occupational Safety and Health (NIOSH)-National Cancer Institute (NCI) epidemiologic studies of miners provide some of the strongest findings to date regarding a DE-lung cancer association, but some inconsistent exposure-response findings and possible effects of bias and exposure misclassification raise questions regarding their interpretation. Laboratory animal studies are negative for lung tumors in all species, except for rats under lifetime TDE-exposure conditions with durations and concentrations that lead to "lung overload." The species specificity of the rat lung response to overload, and its occurrence with other particle types, is now well-understood. It is thus generally accepted that the rat bioassay for inhaled particles under conditions of lung overload is not predictive of human lung cancer hazard. Overall, despite an abundance of epidemiologic and experimental data, there remain questions as to whether TDE exposure causes increased lung cancers in humans. An abundance of emissions characterization data, as well as preliminary toxicological data, support NTDE as being toxicologically distinct from TDE. Currently, neither epidemiologic data nor animal bioassay data yet exist that directly bear on NTDE carcinogenic potential. A chronic bioassay of NTDE currently in progress will provide data on whether NTDE poses a carcinogenic hazard, but based on the significant reductions in PM mass emissions and the major changes in PM composition, it has been hypothesized that NTDE has a low carcinogenic potential. When the International Agency for Research on Cancer (IARC) reevaluates DE (along with GEE and nitroarenes) in June 2012, it will be the first authoritative body to assess DE carcinogenic health hazards since the emergence of NTDE and the accumulation of data differentiating NTDE from TDE.

Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk

PubMed Central

Hesterberg, Thomas W.; Long, Christopher M.; Bunn, William B.; Lapin, Charles A.; McClellan, Roger O.; Valberg, Peter A.

2012-01-01

The mutagenicity of organic solvent extracts from diesel exhaust particulate (DEP), first noted more than 55 years ago, initiated an avalanche of diesel exhaust (DE) health effects research that now totals more than 6000 published studies. Despite an extensive body of results, scientific debate continues regarding the nature of the lung cancer risk posed by inhalation of occupational and environmental DE, with much of the debate focused on DEP. Decades of scientific scrutiny and increasingly stringent regulation have resulted in major advances in diesel engine technologies. The changed particulate matter (PM) emissions in “New Technology Diesel Exhaust (NTDE)” from today's modern low-emission, advanced-technology on-road heavy-duty diesel engines now resemble the PM emissions in contemporary gasoline engine exhaust (GEE) and compressed natural gas engine exhaust more than those in the “traditional diesel exhaust” (TDE) characteristic of older diesel engines. Even with the continued publication of epidemiologic analyses of TDE-exposed populations, this database remains characterized by findings of small increased lung cancer risks and inconsistent evidence of exposure-response trends, both within occupational cohorts and across occupational groups considered to have markedly different exposures (e.g. truckers versus railroad shopworkers versus underground miners). The recently published National Institute for Occupational Safety and Health (NIOSH)-National Cancer Institute (NCI) epidemiologic studies of miners provide some of the strongest findings to date regarding a DE-lung cancer association, but some inconsistent exposure-response findings and possible effects of bias and exposure misclassification raise questions regarding their interpretation. Laboratory animal studies are negative for lung tumors in all species, except for rats under lifetime TDE-exposure conditions with durations and concentrations that lead to'lung overload."The species specificity of the rat lung response to overload, and its occurrence with other particle types, is now well-understood. It is thus generally accepted that the rat bioassay for inhaled particles under conditions of lung overload is not predictive of human lung cancer hazard. Overall, despite an abundance of epidemiologic and experimental data, there remain questions as to whether TDE exposure causes increased lung cancers in humans. An abundance of emissions characterization data, as well as preliminary toxicological data, support NTDE as being toxicologically distinct from TDE. Currently, neither epidemiologic data nor animal bioassay data yet exist that directly bear on NTDE carcinogenic potential. A chronic bioassay of NTDE currently in progress will provide data on whether NTDE poses a carcinogenic hazard, but based on the significant reductions in PM mass emissions and the major changes in PM composition, it has been hypothesized that NTDE has a low carcinogenic potential. When the International Agency for Research on Cancer (IARC) reevaluates DE (along with GEE and nitroarenes) in June 2012, it will be the first authoritative body to assess DE carcinogenic health hazards since the emergence of NTDE and the accumulation of data differentiating NTDE from TDE. PMID:22663144

Diesel and biodiesel exhaust particle effects on rat alveolar macrophages with in vitro exposure

PubMed Central

Bhavaraju, Laya; Shannahan, Jonathan; William, Aaron; McCormick, Robert; McGee, John; Kodavanti, Urmila; Madden, Michael

2014-01-01

Combustion emissions from diesel engines emit particulate matter which deposits within the lungs. Alveolar macrophages (AM) encounter the particles and attempt to engulf the particles. Emissions particles from diesel combustion engines have been found to contain diverse biologically active components including metals and polyaromatic hydrocarbons which cause adverse health effects. However little is known about AM response to particles from the incorporation of biodiesel. The objective of this study was to examine the toxicity in Wistar Kyoto rat AM of biodiesel blend (B20) and low sulfur petroleum diesel (PDEP) exhaust particles. Particles were independently suspended in media at a range of 1–500µg/mL. Results indicated B20 and PDEP initiated a dose dependent increase of inflammatory signals from AM after exposure. After 24hr exposure to B20 and PDEP gene expression of cyclooxygenase-2 (COX-2) and macrophage inflammatory protein 2 (MIP-2) increased. B20 exposure resulted in elevated prostaglandin E2 (PGE2) release at lower particle concentrations compared to PDEP. B20 and PDEP demonstrated similar affinity for sequesteration of PGE2 at high concentrations, suggesting detection is not imparied. Our data suggests PGE2 release from AM is dependent on the chemical composition of the particles. Particle analysis including measurments of metals and ions indicate B20 contains more of select metals than PDEP. Other particle components generally reduced by 20% with 20% incoporation of biodiesel into original diesel. This study shows AM exposure to B20 results in increased production of PGE2 in vitro relative to diesel. PMID:24268344

The preparation of <100 particles per trial having the same mole fraction of 12 inorganic compounds at diameters of 6.8, 3.8, or 2.6 [mu]m followed by their deposition onto human lung cells (A549) with measurement of the relative downstream differential expression of ICAM-1

NASA Astrophysics Data System (ADS)

Eleghasim, Ndukauba M.; Haddrell, Allen E.; van Eeden, Stephen; Agnes, George R.

2006-12-01

The characterization of particulate matter suspended in the troposphere (PM10) based on size is an important basis for assessing the extent of their adverse effects on human health. The relevance of such assessments is anticipated to be significantly improved through the continued development of tools that can identify the chemical components within individual ambient particles, and the injury that they cause. We use recently reported methodology to create mimics of ambient particle types of known size and chemical composition that are levitated within an ac trap. The ac trap uses electric fields to levitate the particles that have a given mass and net elementary charge, and as such the ac trap is a mass-to-charge filter. The ac trap was used to levitate populations of particles where the size of particles in any given population could be altered. The levitated particles are delivered direct from the ac trap to human lung cells (A549), in vitro, with downstream measurement of differential expression of intercellular adhesion molecule (ICAM)-1 and counting of the number of particles actually delivered to the culture using an optical microscope. In this study, the chemical composition of the ambient particle mimics was restricted to inorganic compounds whose relative abundance was purposely designed to mimic the average abundance in Environmental Health Center-93 (EHC-93) particles. The sizes of the multilelement particle types prepared were 6.8 +/- 0.5, 3.8 +/- 0.3, 2.6 +/- 0.2 (mean +/- S.D.). Particles of either elemental carbon, or elemental carbon containing glycerol were used as control particle types. In any given experiment, a known number of particles, but always <100, of a given size, were deposited onto a small region of an A549 cell culture. Following an 18-h incubation period and anti-body labeling of ICAM-1, the fluorescence emission from a 1.07 mm2 area of the cell culture centered at the site of particle deposition was acquired. The relative differential expression of ICAM-1 was greatest for multielement particle types having diameters of 2.6 +/- 0.2 [mu]m for which as few as ~15 particles deposited onto the culture resulted in maximal ICAM-1 expression, whereas with multielement particle types having diameters of 6.8 +/- 0.5 [mu]m, it was necessary to deposit >50 particles in order to effect comparable ICAM-1 expression. This data set indicates that for multi-element particle types comprised of the same mole fraction of inorganic compounds and of sizes within the course fraction of PM10, the 2.6 [mu]m particle type was the most potent with respect to effecting differential expression of ICAM-1.

Novel Polymeric Nanoparticles for Pulmonary Gene Delivery

NASA Astrophysics Data System (ADS)

Fields, Rachel Jennifer

The lung is an important target for gene and drug therapy of many diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), tubuerculosis (TB) and lung cancer. In fact, the pulmonary route has been employed as a means of delivering drugs for centuries, dating back 4000 years to India where inhaled vapors were used for medicinal purpose. Currently, pulmonary administration of small, hydrophobic drugs leads to rapid local and systemic absorption. However, delivery of large biomacromolecules, such as therapeutic genes, has not yet been accomplished. Here, I test the hypothesis that a rationally engineered nanoparticle (NP) vector can improve delivery of large biomacromolecules. . In this dissertation I tested this hypothesis using a hybrid NP delivery system consisting of a blend of poly(lactic-co-glycolic acid) (PLGA) and a poly(beta-amino ester) (PBAE), a cationic polymer that is particularly useful for delivery of nucleic acids.. PBAE/PLGA nanoparticles (15% PBAE) loaded with plasmid DNA were surface modified with cell-penetrating peptides (CPPs) via a PEGylated phospholipid linker. This optimized NP formulation was able to induce substantial intracellular uptake and transfect lung epithelial cells in vitro while imparting minimal cellular toxicity. In order to determine the most effective method to deliver these NPs to the lung I used fluorescently labeled particles to study the biodistribution of particles after administration to the lung of mice via various administration routes. I determined that the intranasal route was most effective. I further investigated this route and determined that an average of 37.1 +/- 15.1 % of lung cells had NP association after 4hrs. I also investigated the association of particles with different lung cell types like macrophages and alveolar epithelial cells and determined that our best particle formulations associated with approximately 80% of both of these cell types. To demonstrate the ability of the NPs to deliver difficult to gene therapy reagents, such as PNAs, to cells within the lung, I loaded NPs with PNA and DNA and administered them via the intranasal route. Triplex forming peptide nucleic acids (PNAs) are gene therapy reagents that can mediate site-specific homologous recombination with genomic DNA when successfully delivered to the nucleus of cells in combination with donor DNA oligos. Delivery of NPs resulted in EGFP expression in transgenic mice with an aberrant EGFP gene that could be corrected and effectively expressed with nuclear delivery of a PNA/DNA. This work represents the first successful use of PNA/DNA mediated homologous recombination to target cells of the lung.

Inhalational system for Etoposide liposomes: formulation development and in vitro deposition.

PubMed

Parmar, J J; Singh, D J; Lohade, A A; Hegde, Darshana D; Soni, P S; Samad, A; Menon, Mala D

2011-11-01

Etoposide is a semisynthetic compound, widely used in treatment of non small cell lung cancer. However, frequent dosing and adverse effects remain a major concern in the use of etoposide. Liposomal systems for pulmonary drug delivery have been particularly attractive because of their compatibility with lung surfactant components. In the present investigation, pulmonary liposomal delivery system of etoposide was prepared by film hydration method. Various parameters were optimized with respect to entrapment efficiency as well as particle size of etoposide liposomes. For better shelf life of etoposide liposomes, freeze drying using trehalose as cryoprotectant was carried out. The liposomes were characterized for entrapment efficiency, particle size, surface topography, and in vitro drug release was carried out in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction was determined by using twin stage impinger. The stability study of freeze dried as well as aqueous liposomal systems was carried out at 2-8° and at ambient temperature (28±4°). The freeze dried liposomes showed better fine particle fraction and drug content over the period of six months at ambient as well as at 2-8° storage condition compared to aqueous dispersion of liposomes.

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

PubMed

Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

2014-12-01

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

[Evaluation of the fibrogenic effect of coke dust on the lungs and internal organs of experimental animals].

PubMed

Zyłka-Włoszczyk, M; Ociepiński, M; Szaflarska-Stojko, E

1991-01-01

Based on the data collected by the Provincial Regional Administration Unit for Control of Epidemics and Hygiene in Katowice, dust concentration at the MAKOSZOWY Coking Plant in Zabrze at 18 work-places exceeded the TLV's. The purpose of this study was to determine changes within the respiratory systems of experimental animals exposed to intratracheal administration of MAKOSZOWY Coking Plant dust, sampled at the charging larry 3-4 operating stand and at the battery roof. After pulverization the dusts contained 98.1% and 99.6% respirable particles, and 6.5% and 6.0% of SiO2, respectively, determined with the Polezhajev method. They also contained aluminum and iron compounds. Hydroxyproline content in the lungs of the animals following the intratracheal administration of 50 mg of the dusts investigated 3-6 months after the experiment was determined. Determination of Hypro contend within the animals' lungs was pursued with the Stegemann method as modified by Hurych and Chvapil. The biochemical investigation results obtained were statistically analyzed with the t-Student's Test. Single intratracheal administration of dust from the battery roof work stand of the MAKOSZOWY Coking Plant caused within 6 months a statistically significant increase in the lung Hydroxyproline level in experimental animals (t = 13.10). An almost triole Hypro increase with respect to the control group was observed. No analogy between lung Hypro level increase (12.833 mg) and histological change was noted. Such a significant lung Hydroxyproline level increase could have been due to the SiO2 content of dust (6%), as well as to the presence of iron compounds in it (4.98%).(ABSTRACT TRUNCATED AT 250 WORDS)

DEPOSITION DISTRIBUTION OF NANO AND ULTRAFINE PARTICLES IN HUMAN LUNGS DURING CONTROLLED MOUTH BREATHING

EPA Science Inventory

Nano and ultrafine particles are abundant in the atmosphere and the level of human exposure to these tiny particles is expected to increase markedly as industrial activities increase manufacturing nano-sized materials. Exposure-dose relationships and site-specific internal dose a...

Predictive model of early mortality following acute inhalation of PuO/sub 2/ aerosols. [Extrapolation of beagle data to man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raabe, O.G.; Goldman, M.

Since data on the pulmonary toxicity of plutonium in people are not available, estimates must be based upon available experimental animal data. For this purpose, inhalation studies with beagle dogs exposed to aerosols of /sup 238/PuO/sub 2/ and /sup 239/PuO/sub 2/ were analyzed and a simple model has been proposed to describe apparent dose-response relationships. It was found that for each aerosol and radionuclide form, the cumulative absorbed lung dose that leads to death from lung damage up to 1000 days could be assumed to have a log-normal distribution of values that was independent of time to death. The datamore » was satisfactorily fit to a model in which the time of death postexposure is given by: t = (K/D), with the time to death, the cumulative dose to lung tissue (the killing dose), and anti D the average dose rate to lung tissue from time of exposure to death. The ratios of median K values, normalized to the value for /sup 90/Sr--Y FAP, indicate a relative biological effectiveness (RBE) of 14 for /sup 239/PuO/sub 2/ particles and 5 for /sup 238/PuO/sub 2/ particles. This demonstrates an effect of particle specific activity on relative biological effectiveness for early mortality, since an increase in specific activity of particles leads to a lower apparent RBE.« less

Airflow and particle deposition simulations in health and emphysema: from in vivo to in silico animal experiments.

PubMed

Oakes, Jessica M; Marsden, Alison L; Grandmont, Celine; Shadden, Shawn C; Darquenne, Chantal; Vignon-Clementel, Irene E

2014-04-01

Image-based in silico modeling tools provide detailed velocity and particle deposition data. However, care must be taken when prescribing boundary conditions to model lung physiology in health or disease, such as in emphysema. In this study, the respiratory resistance and compliance were obtained by solving an inverse problem; a 0D global model based on healthy and emphysematous rat experimental data. Multi-scale CFD simulations were performed by solving the 3D Navier-Stokes equations in an MRI-derived rat geometry coupled to a 0D model. Particles with 0.95 μm diameter were tracked and their distribution in the lung was assessed. Seven 3D-0D simulations were performed: healthy, homogeneous, and five heterogeneous emphysema cases. Compliance (C) was significantly higher (p = 0.04) in the emphysematous rats (C = 0.37 ± 0.14 cm(3)/cmH2O) compared to the healthy rats (C = 0.25 ± 0.04 cm(3)/cmH2O), while the resistance remained unchanged (p = 0.83). There were increases in airflow, particle deposition in the 3D model, and particle delivery to the diseased regions for the heterogeneous cases compared to the homogeneous cases. The results highlight the importance of multi-scale numerical simulations to study airflow and particle distribution in healthy and diseased lungs. The effect of particle size and gravity were studied. Once available, these in silico predictions may be compared to experimental deposition data.

Comparison of radiography and ultrasonography in the detection of lung and liver cysts in cattle and buffaloes

PubMed Central

Kumar, Ashwani; Saini, Narinder Singh; Mohindroo, Jitender; Singh, Balbir Bagicha; Sangwan, Vandana; Sood, Naresh Kumar

2016-01-01

Aim: Echinococcosis is the major cause of lung and liver cysts in ruminants. This study compared usefulness of radiography and ultrasonography (USG) in the detection of lung and/or liver cysts in sick bovine animals. The study also worked out cooccurrence of lung and liver cysts, and whether these cysts were primary cause of sickness or not. Materials and Methods: This study was conducted on 45 sick bovine (37 buffaloes and 8 cattle) suffering from lung and liver cysts. A complete history of illness and clinical examination was carried out. Lateral radiographs of chest and reticular region were taken. In radiographically positive or suspected cases of cysts, USG of the lung and liver region was done. Depending on the location of cyst and clinical manifestations of the animal, the cysts were categorized as primary or secondary causes of sickness. Results: Using either imaging technique, it was observed that 46.7% of the animals had both lung and liver cysts, whereas 33.3% had only lung and 20% had only liver cyst. Cysts were identified as primary cause of sickness in 31.1% animals only. For diagnosing lung cysts, radiography (71.1%) and USG (62.2%) had similar diagnostic utility. However, for detecting liver cysts, USG was the only imaging tool. Conclusion: The lung and liver cysts, depending on their number and size may be a primary cause of sickness in bovine. Radiography and USG are recommended, in combination, as screening tools to rule out echinococcosis. PMID:27847421

Bioavailability, Intracellular Mobilization of Nickel, and HIF-1α Activation in Human Lung Epithelial Cells Exposed to Metallic Nickel and Nickel Oxide Nanoparticles

PubMed Central

Liu, Xinyuan; Smith, Ashley; McNeil, Kevin; Weston, Paula; Zhitkovich, Anatoly; Hurt, Robert; Kane, Agnes B.

2011-01-01

Micron-sized particles of poorly soluble nickel compounds, but not metallic nickel, are established human and rodent carcinogens. In contrast, little is known about the toxic effects of a growing number of Ni-containing materials in the nano-sized range. Here, we performed physicochemical characterization of NiO and metallic Ni nanoparticles and examined their metal ion bioavailability and toxicological properties in human lung epithelial cells. Cellular uptake of metallic Ni and NiO nanoparticles, but not metallic Ni microparticles, was associated with the release of Ni(II) ions after 24–48 h as determined by Newport Green fluorescence. Similar to soluble NiCl2, NiO nanoparticles induced stabilization and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) transcription factor followed by upregulation of its target NRDG1 (Cap43). In contrast to no response to metallic Ni microparticles, nickel nanoparticles caused a rapid and prolonged activation of the HIF-1α pathway that was stronger than that induced by soluble Ni (II). Soluble NiCl2 and NiO nanoparticles were equally toxic to H460 human lung epithelial cells and primary human bronchial epithelial cells; metallic Ni nanoparticles showed lower toxicity and Ni microparticles were nontoxic. Cytotoxicity induced by all forms of Ni occurred concomitant with activation of an apoptotic response, as determined by dose- and time-dependent cleavage of caspases and poly (ADP-ribose) polymerase. Our results show that metallic Ni nanoparticles, in contrast to micron-sized Ni particles, activate a toxicity pathway characteristic of carcinogenic Ni compounds. Moderate cytotoxicity and sustained activation of the HIF-1α pathway by metallic Ni nanoparticles could promote cell transformation and tumor progression. PMID:21828359

μ-PIV/Shadowgraphy measurements to elucidate dynamic physicochemical interactions in a multiphase model of pulmonary airway reopening

NASA Astrophysics Data System (ADS)

Yamaguchi, Eiichiro

2010-10-01

We employ micro-particle image velocimetry (μ-PIV) and shadowgraphy to measure the ensemble-averaged fluid-phase velocity field and interfacial geometry during pulsatile bubble propagation that includes a reverse-flow phase under influence of exogenous lung surfactant (Infasurf). Disease states such as respiratory distress syndrome (RDS) are characterized by insufficient pulmonary surfactant concentrations that enhance airway occlusion and collapse. Subsequent airway reopening, driven by mechanical ventilation, may generate damaging stresses that cause ventilator-induced lung injury (VILI). It is hypothesized that reverse flow may enhance surfactant uptake and protect the lung from VILI. The microscale observations conducted in this study will provide us with a significant understanding of dynamic physicochemical interactions that can be manipulated to reduce the magnitude of this damaging mechanical stimulus during airway reopening. Bubble propagation through a liquid-occluded fused glass capillary tube is controlled by linear-motor-driven syringe pumps that provide mean and sinusoidal velocity components. A translating microscope stage mechanically subtracts the mean velocity of the bubble tip in order to hold the progressing bubble tip in the microscope field of view. To optimize the signal-to-noise ratio near the bubble tip, μ-PIV and shadow images are recorded in separate trials then combined during post-processing with help of a custom-designed micro scale marker. Non-specific binding of Infasurf proteins to the channel wall is controlled by oxidation and chemical treatment of the glass surface. The colloidal stability and dynamic/static surface properties of the Infasurf-PIV particle solution are carefully adjusted based on Langmuir trough measurements. The Finite Time Lyapunov Exponent (FTLE) is computed to provide a Lagrangian perspective for comparison with our boundary element predictions.

Poorly soluble particulates: searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation.

PubMed

Pauluhn, Jürgen

2011-01-11

Under the new European chemicals regulation, REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) a Derived No-Effect Level (DNEL), i.e., the level of exposure above which humans should not be exposed, is defined. The focus of this paper is to develop a weight-of-evidence-based DNEL-approach for inhaled poorly soluble particles. Despite the common mode of action of inhaled insoluble, spherical particulate matter (PM), a unifying, most appropriate metric conferring pulmonary biopersistence and toxicity has yet not been demonstrated. Nonetheless, there is compelling evidence from repeated rat inhalation exposure studies suggesting that the particle displacement volume is the most prominent unifying denominator linking the pulmonary retained dose with toxicity. Procedures were developed to analyze and model the pulmonary toxicokinetics from short-term to long-term exposure. Six different types of poorly soluble nano- to submicron PMs were compared: ultrafine and pigmentary TiO₂, synthetic iron oxide (Fe₃O₄, magnetite), two aluminum oxyhydroxides (AlOOH, Boehmite) with primary isometric particles approximately of either 10 or 40 nm, and MWCNT. The specific agglomerate densities of these materials ranged from 0.1 g/cm³ (MWCNT) to 5 g/cm³ (Fe₃O₄). Along with all PM, due to their long retention half-times and associated biopersistence in the lung, even short-term inhalation studies may require postexposure periods of at least 3 months to reveal PM-specific dispositional and toxicological characteristics. This analysis provides strong evidence that pulmonary toxicity (sustained inflammation) is dependent on the volume-based cumulative lung exposure dose. Lung toxicity, evidenced by PMN in BAL occurred at lung doses exceeding 10-times the overload threshold. Furthermore, the conclusion is supported that repeated inhalation studies on rats should utilize an experimental window of cumulative volume loads of respirable PM in the range of 1 μl/lung (no-adverse-effect range); however, not exceeding ≈10 μl/lung that would lead to retention half-times increasing 1 year. This can be targeted best by computational toxicology, i.e., the modeling of particle deposition and lung retention biokinetics during the exposure and recovery periods. Inhalation studies exceeding that threshold volume may lead to meaningless findings difficult to extrapolate to any real-life scenario. In summary, this analysis supports a volume-based generic mass concentration of 0.5 μl PM(respirable)/m³ x agglomerate density, independent on nano- or submicron-sized properties, as a generic no-adverse effect level in both rats and humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Mica dust and pneumoconiosis: example of a pure occupational exposure in a muscovite milling unit.

PubMed

Hulo, Sébastien; Cherot-kornobis, Nathalie; Edme, Jean-Louis; de Broucker, Virginie; Falgayrac, Guillaume; Penel, Guillaume; Legrand-Cattan, Karinne; Remy, Jacques; Sobaszek, Annie

2013-12-01

We present pulmonary disorders of four employees who were exposed to high concentration of pure mica dust in a muscovite milling unit. All cases underwent traditional examinations with a dual-energy chest computed tomographic scan. An analysis of exhaled breath condensate by Raman microspectrometry and of mineralogical content of a lung biopsy was performed for one case. All cases showed bilateral micronodular ground glass opacities and mediastinal and hilar hyperdense lymph nodes consistent with the nodal sequestration of mineral particles. Histological analysis showed giant cell granulomas without typical silicotic nodule with high concentration of birefringent particles consistent with mica. Mica particles found in the exhaled breath condensate were identical to particles in ambient air at the company. Occupational exposure to mica dust is responsible for diffuse infiltrative lung disease by overload processes.

Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells

PubMed Central

2014-01-01

Background The mechanisms of toxicity of metal oxide particles towards lung cells are far from being understood. In particular, the relative contribution of intracellular particulate versus solubilized fractions is rarely considered as it is very challenging to assess, especially for low-solubility particles such as cobalt oxide (Co3O4). Methods This study was possible owing to two highly sensitive, independent, analytical techniques, based on single-cell analysis, using ion beam microanalysis, and on bulk analysis of cell lysates, using mass spectrometry. Results Our study shows that cobalt oxide particles, of very low solubility in the culture medium, are readily incorporated by BEAS-2B human lung cells through endocytosis via the clathrin-dependent pathway. They are partially solubilized at low pH within lysosomes, leading to cobalt ions release. Solubilized cobalt was detected within the cytoplasm and the nucleus. As expected from these low-solubility particles, the intracellular solubilized cobalt content is small compared with the intracellular particulate cobalt content, in the parts-per-thousand range or below. However, we were able to demonstrate that this minute fraction of intracellular solubilized cobalt is responsible for the overall toxicity. Conclusions Cobalt oxide particles are readily internalized by pulmonary cells via the endo-lysosomal pathway and can lead, through a Trojan-horse mechanism, to intracellular release of toxic metal ions over long periods of time, involving specific toxicity. PMID:24669904

Aerodynamics and deposition effects of inhaled submicron drug aerosol in airway diseases.

PubMed

Faiyazuddin, Md; Mujahid, Md; Hussain, Talib; Siddiqui, Hefazat H; Bhatnagar, Aseem; Khar, Roop K; Ahmad, Farhan J

2013-01-01

Particle engineering is the prime focus to improve pulmonary drug targeting with the splendor of nanomedicines. In recent years, submicron particles have emerged as prettyful candidate for improved fludisation and deposition. For effective deposition, the particle size must be in the range of 0.5-5 μm. Inhalers design for the purpose of efficient delivery of powders to lungs is again a crucial task for pulmonary scientists. A huge number of DPI devices exist in the market, a significant number are awaiting FDA approval, some are under development and a large number have been patented or applied for patent. Even with superior design, the delivery competence is still deprived, mostly due to fluidisation problems which cause poor aerosol generation and deposition. Because of the cohesive nature and poor flow characteristics, they are difficult to redisperse upon aerosolization with breath. These problems are illustrious in aerosol research, much of which is vastly pertinent to pulmonary therapeutics. A technical review is presented here of advances that have been utilized in production of submicron drug particles, their in vitro/in vivo evaluations, aerosol effects and pulmonary fate of inhaled submicron powders.

MECHANISMS OF ACTION OF INHALED FIBERS, PARTICLES AND NANOPARTICLES IN LUNG AND CARDIOVASCULAR DISEASES

EPA Science Inventory

ABSTRACT: A symposium on the mechanisms of action of inhaled airborne particulate matter (PM),pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28,
...

FE2O3 PARTICLE-INDUCED PROSTAGLANDIN E2 (PGE2) SYNTHESIS IN ALVEOLAR MACROPHAGES (AM) DETERMINES PARTICULATE INFLAMMATORY POTENTIAL

EPA Science Inventory

As shown by epidemiologic studies, acute exposure to ambient particles is associated with exacerbation of pulmonary and cardiovascular diseases. Metals associated with particles are able to mediate lung injury via oxidant-catalyzed reactions. However, the underlying mechanism i...

Particles, particles everywhere: What is in the air we breathe?

USDA-ARS?s Scientific Manuscript database

Particulate matter (PM) air pollution consists of extremely small particles, some so small that they can directly enter the bloodstream through the lungs. PM is of prime concern from both health and environmental perspectives. Current research is focused on understanding how PM forms in the atmosphe...

ANALYSIS OF TOTAL RESPIRATORY DEPOSITION OF INHALED ULTRAFINE PARTICLES IN ADULT SUBJECTS AT VARIOUS BREATHING PATTERNS

EPA Science Inventory

Ultrafine particles are ubiquitous in the ambient air and their unique physicochemical characteristics may pose a potential health hazard. Accurate lung dose information is essential to assess a potential health risk to exposure to these particles. In the present study, we measur...

EFFECTS OF FORMALDEHYDE AND PARTICLE-BOUND FORMALDEHYDE ON LUNG MACROPHAGE FUNCTIONS

EPA Science Inventory

Dr. George Jakab and associates exposed mice to varying levels (ranging from 0.5 to 15 parts per million [ppm]) of formaldehyde alone or to formaldehyde (5 and 2.5 ppm) mixed with carbon black particles. Carbon black particles were chosen because of their similarity to comb...

Association of particulate air pollution and acute mortality: involvement of ultrafine particles?

NASA Technical Reports Server (NTRS)

Oberdorster, G.; Gelein, R. M.; Ferin, J.; Weiss, B.; Clarkson, T. W. (Principal Investigator)

1995-01-01

Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.

Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation.

PubMed

Abdulnour, R E; Sham, H P; Douda, D N; Colas, R A; Dalli, J; Bai, Y; Ai, X; Serhan, C N; Levy, B D

2016-09-01

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.

Lung injury following thoracoscopic talc insufflation: experience of a single North American center.

PubMed

Gonzalez, Anne V; Bezwada, Vishnu; Beamis, John F; Villanueva, Andrew G

2010-06-01

Thoracoscopic talc insufflation (TTI) has been used to obliterate the pleural space and prevent recurrent pleural effusions or pneumothorax. Reports of acute pneumonitis and ARDS after the use of talc raised concern about its safety. Differences in particle size of various talc preparations may explain the variable occurrence of pneumonitis. We sought to determine the incidence of lung injury after TTI over a 13-year period at our institution. Patients who underwent TTI between January 1994 and July 2007 were identified from a prospectively maintained logbook. The talc used was commercially available sterile talc (Sclerosol). The hospital course was reviewed in detail, and all cases of respiratory insufficiency were examined with regard to onset, suspected cause, and outcome. Talc-related lung injury was defined as the presence of new infiltrates on chest radiograph and increased oxygen requirements, with no other identifiable trigger than talc exposure. A total of 138 patients underwent 142 TTIs for recurrent pleural effusions or spontaneous pneumothorax. TTI was performed most frequently for malignant pleural effusions (75.5% of effusions). The median dose of talc was 6 g (range, 2-8 g). Dyspnea with increased oxygen requirements developed within 72 h postprocedure for 12 patients. Four patients (2.8%) had talc-related lung injury, and talc exposure may have contributed to the respiratory deterioration in four additional patients. We report the occurrence of lung injury after TTI using the only talc approved by the US Food and Drug Administration. These results reinforce previous concerns regarding the talc used for pleurodesis in North America.

Human exposure to polyhexamethylene guanidine phosphate from humidifiers in residential settings: Cause of serious lung disease.

PubMed

Lee, Ji Hyun; Yu, Il Je

2017-11-01

Exposure to the humidifier disinfectant, polyhexamethylene guanidine phosphate (PHMG), in mists generated from ultrasonic humidifiers was studied in a simulation chamber and apartment rooms. PHMG is suspected as a causative agent of lung disease in Korea residences. In the simulation-chamber study, the amount of disinfectant discharged from three different ultrasonic humidifiers was measured. Mists generated at 1, 2, and 4 times the recommended amount of disinfectant were sampled with an impinger, and the effect of relative humidity (RH) on airborne disinfectant concentration was studied by changing RH from 60%-70% to 90%-100%. In addition, particle size distribution (PSD) in mists was measured by scanning mobility particle sizer (SMPS), aerodynamic particle sizer (APS), and Mastersizer. In the apartment study, mists generated from ultrasonic humidifiers were sampled for 6 h in small and large rooms during fall ( n = 10) and winter ( n = 15). In the simulation study, the humidifiers discharged 205 ± 24.6 ml/h of mist at maximum capacity. Concentrations of airborne disinfectant increased with increasing concentration of disinfectant. RH affected airborne disinfectant concentration in the chamber, with increasing concentration with increasing RH. Below RH 70%, no airborne PHMG was detected. PHMG-containing mists generated from ultrasonic humidifier showed various sizes ranging from 149-157 nm to 690-740 nm to larger than 5.4 µm by SMPS, APS, and Mastersizer, respectively. Surface area mean diameter measured by Mastersizer ranged from 5.39 µm to 5.72 µm. In the apartment study conducted during the fall, the geometric mean (GM) and geometric standard deviation (GSD) and arithmetic mean (AM) and standard deviation (SD) of airborne PHMG concentration were 3.22 + 5.13 µg/m 3 and 8.26 ± 12.18 µg/m 3 , respectively. In the winter, GM + GSD and AM ± SD of airborne PHMG concentration were 0.21 + 2.11 µg/m 3 and 0.35 ± 0.62 µg/m 3 , respectively. RH and temperature in the apartment rooms for fall and winter were 22.5 ± 1.7°C, 74.5 ± 15.6% and 22.0 ± 2°C, 51.1 ± 12.9%, respectively. Different RHs in the fall and winter resulted in very different airborne concentrations of disinfectant in the apartment rooms. Exposure levels and PSD of mists generated from ultrasonic humidifiers in apartments are not sufficient to conclude that PHMG causes lung disease in Korean residences.

Cadmium-enriched cigarette smoke-induced cytological and biochemical alterations in rat lungs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gairola, C.G.

Male Sprague-Dawley rats were exposed daily for 52 wk in a nose-only exposure system to smoke from the University of Kentucky 2R1 reference cigarettes (SM) or from cigarettes made of cadmium-enriched tobacco (Cd-SM). At sacrifice, the animals were evaluated by bronchoalveolar lavage (BAL) for inflammatory cell response in the lungs, and the cells so obtained were analyzed for phagocytosis of particles (latex and IgG-coated SRBCs) and for their ability to release oxidants upon phagocytic challenge. Additionally, lung tissues were analyzed for Cd levels and lung homogenate fractions were assayed for aryl hydrocarbon hydroxylase (AHH) as well as total and selenium-dependentmore » glutathione peroxidase (GSH-Px) activities. BAL cell counts showed a significant influx of inflammatory cells into the lungs of the Cd-SM group but not the SM group. The proportion of neutrophils in the BAL cells of the Cd-Sm group was elevated to 40 {plus minus} 9%, compared with less than 2% in the SM group. Phagocytosis of both types of particles by macrophages from SM and Cd-SM groups was similar to that of the control groups, except that a greater uptake of latex particles was seen is Cd-SM macrophages. The release of oxidants (superoxides and hydrogen peroxide) by the BAL cells was severely impaired in the Cd-SM group, whereas a slight stimulation was seen in the SM gropu. Pulmonary GSH-Px activity was the same in all groups. A significant induction of the pulmonary AHH activity was observed in the SM group only. The Cd levels in the lungs were approximately 8- and 200-fold greater than controls in SM and Cd-SM groups, respectively. These observation suggest a significant influence of tabacco Cd on the toxicity of cigarette smoke.« less

Symposium Entitled: Particle Lung Interactions: ’Overload’ Related Phenomena. A Journal of Aerosol Medicine - Deposition, Clearance, and Effects in the Lung. Volume 3, Supplement 1

DTIC Science & Technology

1991-04-01

week and two years (subchronic GMRL studies versus chronic ITRI and Fh-ITA studies ); exposure concentrations were changed by a factor of 40 (Fh-ITA...a forum for the publication of studies involving inhalation of particles and gases in the respiratory tract, covering the use of aerosols as tools to... study basic physiologic phenomena, their use as selective delivery systems for medication, and the toxic effects of inhaled agents. JOURNAL OF AEROSOL

PM 2.5 Airborne Particulates Near Frac Sand Operations.

PubMed

Walters, Kristin; Jacobson, Jeron; Kroening, Zachary; Pierce, Crispin

2015-11-01

The rapid growth of hydraulic fracturing for oil and gas extraction in the U.S. has led to 135 active "frac" sand mines, processing plants, and rail transfer stations in Wisconsin. Potential environmental health risks include increased truck traffic, noise, ecosystem loss, and groundwater, light, and air pollution. Emitted air contaminants include fine particulate matter (PM2.5) and respirable crystalline silica. Inhalation of fine dust particles causes increased mortality, cardiovascular disease, lung disease, and lung cancer. In the authors' pilot study, use of a filter-based ambient particulate monitor found PM2.5 levels of 5.82-50.8 µg/m3 in six 24-hour samples around frac sand mines and processing sites. Enforcement of the existing U.S. Environmental Protection Agency annual PM2.5 standard of 12 µg/m3 is likely to protect the public from silica exposure risks as well. PM2.5 monitoring around frac sand sites is needed to ensure regulatory compliance, inform nearby communities, and protect public health.

Multifunctional superparamagnetic nanocrystals for imaging and targeted drug delivery to the lung

NASA Astrophysics Data System (ADS)

Armijo, Leisha M.; Brandt, Yekaterina I.; Withers, Nathan J.; Plumley, John B.; Cook, Nathaniel C.; Rivera, Antonio C.; Yadav, Surabhi; Smolyakov, Gennady A.; Monson, Todd; Huber, Dale L.; Smyth, Hugh D. C.; Osiński, Marek

2012-03-01

Iron oxide colloidal nanocrystals (ferrofluids) are investigated for application in the treatment of cystic fibrosis lung infections, the leading cause of mortality in cystic fibrosis patients. We investigate the use of iron oxide nanocrystals to increase the effectiveness of inhalation aerosol antibiotics therapy through two mechanisms: directed particle movement in the presence of a static external magnetic field and magnetic hyperthermia. Magnetic hyperthermia is an effective method for decreasing the viscosity of the mucus and biofilm thereby increasing drug, immune cell, and antibody penetration to the affected area. Iron oxide nanocrystals of various sizes and morphologies were synthesized and tested for specific losses (heating power) using frequencies of 111.1 kHz and 629.2 kHz, and corresponding magnetic field strengths of 9 and 25 mT. Nanocrystals in the superparamagnetic to ferromagnetic size range exhibited excellent heating power. Additionally, iron oxide-zinc selenide core-shell nanoparticles were prepared in parallel in order to allow imaging of the iron oxide nanoparticles.

Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

PubMed

Bhargava, Rhea; Janssen, William; Altmann, Christopher; Andrés-Hernando, Ana; Okamura, Kayo; Vandivier, R William; Ahuja, Nilesh; Faubel, Sarah

2013-01-01

Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation. Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment. Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin. IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.

Fine and ultrafine particle doses in the respiratory tract from digital printing operations.

PubMed

Voliotis, Aristeidis; Karali, Irene; Kouras, Athanasios; Samara, Constantini

2017-01-01

In this study, we report for the first time particle number doses in different parts of the human respiratory tract and real-time deposition rates for particles in the 10 nm to 10 μm size range emitted by digital printing operations. Particle number concentrations (PNCs) and size distribution were measured in a typical small-sized printing house using a NanoScan scanning mobility particle sizer and an optical particle sizer. Particle doses in human lung were estimated applying a multiple-path particle dosimetry model under two different breathing scenarios. PNC was dominated by the ultrafine particle fractions (UFPs, i.e., particles smaller than 100 nm) exhibiting almost nine times higher levels in comparison to the background values. The average deposition rate fοr each scenario in the whole lung was estimated at 2.0 and 2.9 × 10 7 particles min -1 , while the respective highest particle dose in the tracheobronchial tree (2.0 and 2.9 × 10 9 particles) was found for diameter of 50 nm. The majority of particles appeared to deposit in the acinar region and most of them were in the UFP size range. For both scenarios, the maximum deposition density (9.5 × 10 7 and 1.5 × 10 8 particles cm -2 ) was observed at the lobar bronchi. Overall, the differences in the estimated particle doses between the two scenarios were 30-40% for both size ranges.

The effect of device resistance and inhalation flow rate on the lung deposition of orally inhaled mannitol dry powder.

PubMed

Yang, Michael Y; Verschuer, Jordan; Shi, Yuyu; Song, Yang; Katsifis, Andrew; Eberl, Stefan; Wong, Keith; Brannan, John D; Cai, Weidong; Finlay, Warren H; Chan, Hak-Kim

2016-11-20

The present study investigates the effect of DPI resistance and inhalation flow rates on the lung deposition of orally inhaled mannitol dry powder. Mannitol powder radiolabeled with 99m Tc-DTPA was inhaled from an Osmohaler™ by healthy human volunteers at 50-70L/min peak inhalation flow rate (PIFR) using both a low and high resistance Osmohaler™, and 110-130L/min PIFR using the low resistance Osmohaler™ (n=9). At 50-70L/min PIFR, the resistance of the Osmohaler™ did not significantly affect the total and peripheral lung deposition of inhaled mannitol [for low resistance Osmohaler™, 20% total lung deposition (TLD), 0.3 penetration index (PI); for high resistance Osmohaler™, 17% TLD, 0.23 PI]. Increasing the PIFR 50-70L/min to 110-130L/min (low resistance Osmohaler™) significantly reduced the total lung deposition (10% TLD) and the peripheral lung deposition (PI 0.21). The total lung deposition showed dependency on the in vitro FPF (R 2 =1.0). On the other hand, the PI had a stronger association with the MMAD (R 2 =1.0) than the FPF (R 2 =0.7). In conclusion the resistance of Osmohaler™ did not significantly affect the total and regional lung deposition at 50-70L/min PIFR. Instead, the total and regional lung depositions are dependent on the particle size of the aerosol and inhalation flow rate, the latter itself affecting the particle size distribution. Copyright © 2016 Elsevier B.V. All rights reserved.

Ultrafine Particles from Traffic Emissions and Children's Health (UPTECH) in Brisbane, Queensland (Australia): study design and implementation.

PubMed

Ezz, Wafaa Nabil; Mazaheri, Mandana; Robinson, Paul; Johnson, Graham R; Clifford, Samuel; He, Congrong; Morawska, Lidia; Marks, Guy B

2015-02-02

Ultrafine particles are particles that are less than 0.1 micrometres (µm) in diameter. Due to their very small size they can penetrate deep into the lungs, and potentially cause more damage than larger particles. The Ultrafine Particles from Traffic Emissions and Children's Health (UPTECH) study is the first Australian epidemiological study to assess the health effects of ultrafine particles on children's health in general and peripheral airways in particular. The study is being conducted in Brisbane, Australia. Continuous indoor and outdoor air pollution monitoring was conducted within each of the twenty five participating school campuses to measure particulate matter, including in the ultrafine size range, and gases. Respiratory health effects were evaluated by conducting the following tests on participating children at each school: spirometry, forced oscillation technique (FOT) and multiple breath nitrogen washout test (MBNW) (to assess airway function), fraction of exhaled nitric oxide (FeNO, to assess airway inflammation), blood cotinine levels (to assess exposure to second-hand tobacco smoke), and serum C-reactive protein (CRP) levels (to measure systemic inflammation). A pilot study was conducted prior to commencing the main study to assess the feasibility and reliably of measurement of some of the clinical tests that have been proposed for the main study. Air pollutant exposure measurements were not included in the pilot study.

Ultrafine Particles from Traffic Emissions and Children’s Health (UPTECH) in Brisbane, Queensland (Australia): Study Design and Implementation

PubMed Central

Ezz, Wafaa Nabil; Mazaheri, Mandana; Robinson, Paul; Johnson, Graham R.; Clifford, Samuel; He, Congrong; Morawska, Lidia; Marks, Guy B.

2015-01-01

Ultrafine particles are particles that are less than 0.1 micrometres (µm) in diameter. Due to their very small size they can penetrate deep into the lungs, and potentially cause more damage than larger particles. The Ultrafine Particles from Traffic Emissions and Children’s Health (UPTECH) study is the first Australian epidemiological study to assess the health effects of ultrafine particles on children’s health in general and peripheral airways in particular. The study is being conducted in Brisbane, Australia. Continuous indoor and outdoor air pollution monitoring was conducted within each of the twenty five participating school campuses to measure particulate matter, including in the ultrafine size range, and gases. Respiratory health effects were evaluated by conducting the following tests on participating children at each school: spirometry, forced oscillation technique (FOT) and multiple breath nitrogen washout test (MBNW) (to assess airway function), fraction of exhaled nitric oxide (FeNO, to assess airway inflammation), blood cotinine levels (to assess exposure to second-hand tobacco smoke), and serum C-reactive protein (CRP) levels (to measure systemic inflammation). A pilot study was conducted prior to commencing the main study to assess the feasibility and reliably of measurement of some of the clinical tests that have been proposed for the main study. Air pollutant exposure measurements were not included in the pilot study. PMID:25648226

Lung lavage therapy to lessen the biological effects of inhaled sup 144 Ce in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muggenburg, B.A.; Boecker, B.B.; Hahn, F.F.

1990-11-01

To evaluate the therapeutic effects of removal of an internally deposited radionuclide on long-term biological effects, lung lavage was used to treat dogs that had inhaled 144Ce in a relatively insoluble form, in fused aluminosilicate particles. Either 10 lung lavages were performed between Days 2 and 56 after exposure or 20 lung lavages were performed between Days 2 and 84 after exposure. Approximately one-half of the 144Ce was removed by the lavages, resulting in a corresponding reduction in the total absorbed beta dose to lung. The mean survival time of the treated dogs was 1270 days compared to 370 daysmore » for untreated dogs whose initial pulmonary burdens of 144Ce were similar. Treated dogs died late from cancers of the lung or liver, whereas the untreated dogs died at much earlier times from radiation pneumonitis. Dogs treated with lung lavage but not exposed to 144Ce had a mean survival of 4770 days. We concluded that removal of 144Ce from the lung by lavage resulted in increased survival time and in a change in the biological effects from inhaled 144Ce from early-occurring inflammatory disease to late-occurring effects, principally cancer. In addition, the biological effects occurring in the treated dogs could be better predicted from the total absorbed beta dose in the lung and the dose rate after treatment rather than from the original dose rate to the lung. Therefore, we concluded that prompt treatment to remove radioactive materials could be of significant benefit to persons accidentally exposed to high levels of airborne, relatively insoluble, radioactive particles.« less

The association between lung cancer incidence and ambient air pollution in China: A spatiotemporal analysis.

PubMed

Guo, Yuming; Zeng, Hongmei; Zheng, Rongshou; Li, Shanshan; Barnett, Adrian G; Zhang, Siwei; Zou, Xiaonong; Huxley, Rachel; Chen, Wanqing; Williams, Gail

2016-01-01

China is experiencing more and more days of serious air pollution recently, and has the highest lung cancer burden in the world. To examine the associations between lung cancer incidence and fine particles (PM2.5) and ozone in China. We used 75 communities' data of lung cancer incidence from the National Cancer Registration of China from 1990 to 2009. The annual concentrations of fine particles (PM2.5) and ozone at 0.1°×0.1° spatial resolution were generated by combing remote sensing, global chemical transport models, and improvements in coverage of surface measurements. A spatial age-period-cohort model was used to examine the relative risks of lung cancer incidence associated with the air pollutants, after adjusting for impacts of age, period, and birth cohort, sex, and community type (rural and urban) as well as the spatial variation on lung cancer incidence. The relative risks of lung cancer incidence related to a 10 µg/m(3) increase in 2-year average PM2.5 were 1.055 (95% confidence interval (CI): 1.038, 1.072) for men, 1.149 (1.120, 1.178) for women, 1.060 (1.044, 1.075) for an urban communities, 1.037 (0.998, 1.078) for a rural population, 1.074 (1.052, 1.096) for people aged 30-65 years, and 1.111 (1.077, 1.146) for those aged over 75 years. Ozone also had a significant association with lung cancer incidence. The increased risks of lung cancer incidence were associated with PM2.5 and ozone air pollution. Control measures to reduce air pollution would likely lower the future incidence of lung cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

RESPONSES OF LUNG CELLS TO METALS IN MANUFACTURED NANOPARTICLES

EPA Science Inventory

DIMINISHED INJURY IN HYPOTRANSFERENEMIC MICE AFTER EXPOSURE TO A METAL-RICH PARTICLE

EPA Science Inventory

Using the hypotransferrinemic (Hp) mouse model, we studied the effect of altered iron homeostasis on the lung?s defense against catalytically active metal. The homozygotic (hpx/hpx) Hp mice had greatly diminished concentrations of both serum and lavage transferrin relative to ...

Impact of Diesel Exhaust Particles on Th2 Response in the Lung in Asthmatic Mice

PubMed Central

Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

2008-01-01

Although it has been accepted that pulmonary exposure to diesel exhaust particles (DEP), representative constituents in particulate matter of mass median aerodynamic diameter < or 2.5 µm (PM2.5), exacerbates murine allergic asthma, the in vivo effects of DEP on their cellular events in the context of allergen-specific Th response have never been examined. The aim of this study is to elucidate whether in vivo repetitive exposure to DEP combined with allergen (ovalbumin) facilitate allergen-specific Th response in the lung using a simple ex vivo assay system. As a result, repetitive pulmonary exposure to DEP in vivo, if combined with allergen, amplifies ex vivo allergen-specific Th2 response in the lung compared to that to allergen alone, characterized by high levels of interleukin (IL)-4 and IL-5. The result suggests that in asthmatic subjects, DEP promote Th2-prone milieu in the lung, which additively/synergistically augment asthma pathophysiology in vivo. PMID:19015755

Anacardic Acids from Cashew Nuts Ameliorate Lung Damage Induced by Exposure to Diesel Exhaust Particles in Mice

PubMed Central

Carvalho, Ana Laura Nicoletti; Annoni, Raquel; Torres, Larissa Helena Lobo; Durão, Ana Carolina Cardoso Santos; Shimada, Ana Lucia Borges; Almeida, Francine Maria; Hebeda, Cristina Bichels; Lopes, Fernanda Degobbi Tenorio Quirino Santos; Dolhnikoff, Marisa; Martins, Milton Arruda; Silva, Luiz Fernando Ferraz; Farsky, Sandra Helena Poliselli; Saldiva, Paulo Hilário Nascimento; Ulrich, Cornelia M.; Owen, Robert W.; Marcourakis, Tania; Trevisan, Maria Teresa Salles; Mauad, Thais

2013-01-01

Anacardic acids from cashew nut shell liquid, a Brazilian natural substance, have antimicrobial and antioxidant activities and modulate immune responses and angiogenesis. As inflammatory lung diseases have been correlated to environmental pollutants exposure and no reports addressing the effects of dietary supplementation with anacardic acids on lung inflammation in vivo have been evidenced, we investigated the effects of supplementation with anacardic acids in a model of diesel exhaust particle- (DEP-) induced lung inflammation. BALB/c mice received an intranasal instillation of 50 μg of DEP for 20 days. Ten days prior to DEP instillation, animals were pretreated orally with 50, 150, or 250 mg/kg of anacardic acids or vehicle (100 μL of cashew nut oil) for 30 days. The biomarkers of inflammatory and antioxidant responses in the alveolar parenchyma, bronchoalveolar lavage fluid (BALF), and pulmonary vessels were investigated. All doses of anacardic acids ameliorated antioxidant enzyme activities and decreased vascular adhesion molecule in vessels. Animals that received 50 mg/kg of anacardic acids showed decreased levels of neutrophils and tumor necrosis factor in the lungs and BALF, respectively. In summary, we demonstrated that AAs supplementation has a potential protective role on oxidative and inflammatory mechanisms in the lungs. PMID:23533495

Reduction in (pro-)inflammatory responses of lung cells exposed in vitro to diesel exhaust treated with a non-catalyzed diesel particle filter

NASA Astrophysics Data System (ADS)

Steiner, Sandro; Czerwinski, Jan; Comte, Pierre; Müller, Loretta L.; Heeb, Norbert V.; Mayer, Andreas; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

2013-12-01

Increasingly stringent regulation of particulate matter emissions from diesel vehicles has led to the widespread use of diesel particle filters (DPFs), the effect of which on exhaust toxicity is so far poorly understood. We exposed a cellular model of the human respiratory epithelium at the air-liquid interface to non-catalyzed wall-flow DPF-filtered diesel exhaust and compared the resulting biological responses to the ones observed upon exposure to unfiltered exhaust. Filtered diesel exhaust acted highly oxidative, even though to a lesser extent than unfiltered exhaust (quantification of total reduced glutathione), and both exhaust types triggered comparable responses to oxidative stress (measurement of heme-oxygenase 1 (HMOX1) and superoxide-dismutase (SOD1) gene expression). Further, diesel exhaust filtration significantly reduced pro-inflammatory responses (measurement of tumor necrosis factor (TNF) and interleukin-8 (IL-8) gene expression and quantification of the secretion of their gene products TNF-α and IL-8). Because inflammatory processes are central to the onset of adverse respiratory health effects caused by diesel exhaust inhalation, our results imply that DPFs may make a valuable contribution to the detoxification of diesel vehicle emissions. The induction of significant oxidative stress by filtered diesel exhaust however, also implies that the non-particulate exhaust components also need to be considered for lung cell risk assessment.

Influence of aging in the modulation of epigenetic biomarkers of carcinogenesis after exposure to air pollution.

PubMed

Fougère, Bertrand; Landkocz, Yann; Lepers, Capucine; Martin, Perrine J; Armand, Lucie; Grossin, Nicolas; Verdin, Anthony; Boulanger, Eric; Gosset, Pierre; Sichel, François; Shirali, Pirouz; Billet, Sylvain

2018-05-31

Classified as carcinogenic to humans by the IARC in 2013, fine air particulate matter (PM 2.5 ) can be inhaled and retained into the lung or reach the systemic circulation. This can cause or exacerbate numerous pathologies to which the elderly are often more sensitive. In order to estimate the influence of age on the development of early cellular epigenetic alterations involved in carcinogenesis, peripheral blood mononuclear cells sampled from 90 patients from three age classes (25-30, 50-55 and 75-80 years old) were ex vivo exposed to urban PM 2.5 . Particles exposure led to variations in telomerase activity and telomeres length in all age groups without any influence of age. Conversely, P16 INK4A gene expression increased significantly with age after exposure to PM 2.5 . Age could enhance MGMT gene expression after exposure to particles, by decreasing the level of promoter methylation in the oldest people. Hence, our results demonstrated several tendencies in cells modification depending on age, even if all epigenetic assays were carried out after a limited exposure time allowing only one or two cell cycles. Since lung cancer symptoms appear only at an advanced stage, our results underline the needs for further investigation on the studied biomarkers for early diagnosis of carcinogenesis to improve survival. Copyright © 2018 Elsevier Inc. All rights reserved.

Inhibition of catalase activity in vitro by diesel exhaust particles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mori, Yoki; Murakami, Sumika; Sagae, Toshiyuki

1996-02-09

The effect of diesel exhaust particles (DEP) on the activity of catalase, an intracellular anti-oxidant, was investigated because H{sub 2}O{sub 2} is a cytotoxic oxidant, and catalase released from alveolar cells is an important antioxidant in the epithelial lining fluid in the lung. DEP inhibited the activity of bovine liver catalase dose-dependently, to 25-30% of its original value. The inhibition of catalase by DEP was observed only in the presence of anions such as Cl{sup {minus}}, Br{sup {minus}}, or thiocyanate. Other anions, such as CH{sub 3}COO{sup {minus}} or SO{sub 4}{sup {minus}}, and cations such as K{sup +}, Na{sup +}, Mg{supmore » 2+}, or Fe{sup 2+}, did not affect the activity of catalase, even in the presence of DEP extract. Catalase from guinea pig alveolar cells and catalase from red blood cells were also inhibited by DEP extracts, as was catalase from bovine liver. These results suggest that DEP taken up in the lung and located on alveolar spaces might cause cell injury by inhibiting the activity of catalase in epithelial lining fluid, enhancing the toxicity of H{sub 2}O{sub 2} generated from cells in addition to that of O{sub 2}{sup {minus}} generated by the chemical reaction of DEP with oxygen. 10 refs., 6 figs.« less

Contribution of air pollution to COPD and small airway dysfunction.

PubMed

Berend, Norbert

2016-02-01

Although in many Western countries levels of ambient air pollution have been improving with the setting of upper limits and better urban planning, air pollution in developing countries and particularly those with rapid industrialization has become a major global problem. Together with increased motor vehicle ownership and traffic congestion, there is a growing issue with airborne particles of respirable size. These particles are thought responsible for respiratory and cardiovascular effects and have also been implicated in cancer pathogenesis. The pathologic effects in the lung are mediated via inflammatory pathways and involve oxidative stress similar to cigarette smoking. These effects are seen in the peripheral airways where the smaller particle fractions are deposited and lead to airway remodelling. However, emphysema and loss of bronchioles seen with cigarette smoking have not been described with ambient air pollution, and there are few studies specifically looking at peripheral airway function. Definitive evidence of air pollution causing COPD is lacking and a different study design is required to link air pollution and COPD. © 2015 Asian Pacific Society of Respirology.

Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design.

PubMed

Ticehurst, Martyn David; Marziano, Ivan

2015-06-01

This review seeks to offer a broad perspective that encompasses an understanding of the drug product attributes affected by active pharmaceutical ingredient (API) physical properties, their link to solid form selection and the role of particle engineering. While the crucial role of active pharmaceutical ingredient (API) solid form selection is universally acknowledged in the pharmaceutical industry, the value of increasing effort to understanding the link between solid form, API physical properties and drug product formulation and manufacture is now also being recognised. A truly holistic strategy for drug product development should focus on connecting solid form selection, particle engineering and formulation design to both exploit opportunities to access simpler manufacturing operations and prevent failures. Modelling and predictive tools that assist in establishing these links early in product development are discussed. In addition, the potential for differences between the ingoing API physical properties and those in the final product caused by drug product processing is considered. The focus of this review is on oral solid dosage forms and dry powder inhaler products for lung delivery. © 2015 Royal Pharmaceutical Society.

Mitochondrial biogenesis in the pulmonary vasculature during inhalation lung injury and fibrosis

EPA Science Inventory

Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammatio...

Experimental and computational study of the effect of breath-actuated mechanism built in the NEXThaler® dry powder inhaler.

PubMed

Farkas, Árpád; Lewis, David; Church, Tanya; Tweedie, Alan; Mason, Francesca; Haddrell, Allen E; Reid, Jonathan P; Horváth, Alpár; Balásházy, Imre

2017-11-25

The breath-actuated mechanism (BAM) is a mechanical unit included in NEXThaler ® with the role of delaying the emission of the drug until the inhalation flow rate of the patient is sufficiently high to detach the drug particles from their carriers. The main objective of this work was to analyse the effect of the presence of BAM on the size distribution of the emitted drug and its airway deposition efficiency and distribution. Study of the hygroscopic growth of the emitted drug particles and its effect on the deposition was another goal of this study. Size distributions of Foster ® NEXThaler ® drug particles emitted by dry powder inhalers with and without BAM have been measured by a Next Generation Impactor. Three characteristic inhalation profiles of asthmatic patients (low, moderate and high flow rates) were used for both experimental and modelling purposes. Particle hygroscopic growth was determined by a new method, where experimental measurements are combined with simulations. Upper airway and lung deposition fractions were computed assuming 5s and 10s breath-hold times. By the inclusion of BAM the fine particle fraction of the steroid component increased from 24 to 30% to 47-51%, while that of bronchodilator from 25-34% to 52-55%. The predicted upper airway steroid and bronchodilator doses decreased from about 60% to 35-40% due to BAM. At the same time, predicted lung doses increased from about 20%-35% (steroid) and from 22% to 38% (bronchodilator) for the moderate flow profile and from about 25% to 40% (steroid) and from 29% to 47% (bronchodilator) for the high inhalation flow profile. Although BDP and FF upper airway doses decreased by a factor of about two when BAM was present, lung doses of both components were about the same in the BAM and no-BAM configurations at the weakest flow profile. However, lung dose increased by 2-3% even for this profile when hygroscopic growth was taken into account. In conclusion, the NEXThaler ® BAM mechanism is a unique feature enabling high emitted fine particle fraction and enhanced drug delivery to the lungs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

MODELING DEPOSITION OF INHALED PARTICLES

EPA Science Inventory

Modeling Deposition of Inhaled Particles: ABSTRACT

The mathematical modeling of the deposition and distribution of inhaled aerosols within human lungs is an invaluable tool in predicting both the health risks associated with inhaled environmental aerosols and the therapeut...

Health effects of acute exposure to air polllution. Part II: Healthy subjects exposed to cencentrated ambient particles

EPA Science Inventory

The purpose of this study was to assess the impact of short-term exposure to concentrated ambient particles (CAPs*) on lung function and on inflammatory parameters in blood and airways of healthy human subjects. Particles were concentrated from the ambient air in Chapel Hill, Nor...

Incomplete lung recovery following sub-acute inhalation of combustion-derived ultrafine particles in mice.

PubMed

Noël, A; Xiao, R; Perveen, Z; Zaman, H M; Rouse, R L; Paulsen, D B; Penn, A L

2016-02-24

Particulate matter (PM) is one of the six criteria pollutant classes for which National Ambient Air Quality Standards have been set by the United States Environmental Protection Agency. Exposures to PM have been correlated with increased cardio-pulmonary morbidity and mortality. Butadiene soot (BDS), generated from the incomplete combustion of 1,3-butadiene (BD), is both a model PM mixture and a real-life example of a petrochemical product of incomplete combustion. There are numerous events, including wildfires, accidents at refineries and tank car explosions that result in sub-acute exposure to high levels of airborne particles, with the people exposed facing serious health problems. These real-life events highlight the need to investigate the health effects induced by short-term exposure to elevated levels of PM, as well as to assess whether, and if so, how well these adverse effects are resolved over time. In the present study, we investigated the extent of recovery of mouse lungs 10 days after inhalation exposures to environmentally-relevant levels of BDS aerosols had ended. Female BALB/c mice exposed to either HEPA-filtered air or to BDS (5 mg/m(3) in HEPA filtered air, 4 h/day, 21 consecutive days) were sacrificed immediately, or 10 days after the final BDS exposure. Bronchoalveolar lavage fluid (BALF) was collected for cytology and cytokine analysis. Lung proteins and RNA were extracted for protein and gene expression analysis. Lung histopathology evaluation also was performed. Sub-acute exposures of mice to hydrocarbon-rich ultrafine particles induced: (1) BALF neutrophil elevation; (2) lung mucosal inflammation, and (3) increased BALF IL-1β concentration; with all three outcomes returning to baseline levels 10 days post-exposure. In contrast, (4) lung connective tissue inflammation persisted 10 days post-exposure; (5) we detected time-dependent up-regulation of biotransformation and oxidative stress genes, with incomplete return to baseline levels; and (6) we observed persistent particle alveolar load following 10 days of recovery. These data show that 10 days after a 21-day exposure to 5 mg/m(3) of BDS has ended, incomplete lung recovery promotes a pro-biotransformation, pro-oxidant, and pro-inflammatory milieu, which may be a starting point for potential long-term cardio-pulmonary effects.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frank, Evan A.; Birch, M. Eileen; Yadav, Jagjit S., E-mail: Jagjit.Yadav@uc.edu

Carbon nanotubes (CNTs) are rapidly emerging as high-priority occupational toxicants. CNT powders contain fibrous particles that aerosolize readily in places of manufacture and handling, posing an inhalation risk for workers. Studies using animal models indicate that lung exposure to CNTs causes prolonged inflammatory responses and diffuse alveolar injury. The mechanisms governing CNT-induced lung inflammation are not fully understood but have been suggested to involve alveolar macrophages (AMs). In the current study, we sought to systematically assess the effector role of AMs in vivo in the induction of lung inflammatory responses to CNT exposures and investigate their cell type-specific mechanisms. Multi-wallmore » CNTs characterized for various physicochemical attributes were used as the CNT type. Using an AM-specific depletion and repopulation approach in a mouse model, we unambiguously demonstrated that AMs are major effector cells necessary for the in vivo elaboration of CNT-induced lung inflammation. We further investigated in vitro AM responses and identified molecular targets which proved critical to pro-inflammatory responses in this model, namely MyD88 as well as MAPKs and Ca{sup 2} {sup +}/CamKII. We further demonstrated that MyD88 inhibition in donor AMs abrogated their capacity to reconstitute CNT-induced inflammation when adoptively transferred into AM-depleted mice. Taken together, this is the first in vivo demonstration that AMs act as critical effector cell types in CNT-induced lung inflammation and that MyD88 is required for this in vivo effector function. AMs and their cell type-specific mechanisms may therefore represent potential targets for future therapeutic intervention of CNT-related lung injury. - Highlights: • Demonstrated in vivo effector role of alveolar macrophages (AMs) in CNT toxicity • MyD88, MAPKs, and Ca{sup 2} {sup +}/CamKII are required for AM inflammatory responses in vitro. • MyD88 signaling is required for in vivo effector function of AMs. • MyD88 may be a potential target for intervention in CNT lung exposures.« less

Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model.

PubMed

Liu, Xiaoyu; Ma, Cuiqing; Wang, Xiaoyu; Wang, Wenjing; Li, Zhu; Wang, Xiansheng; Wang, Pengyu; Sun, Wuzhuang; Xue, Baojian

2017-01-01

Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease caused by harmful gases or particles. Recent studies have shown that 2% hydrogen or hydrogen water is effective in the treatment and prevention of a variety of diseases. This study investigated the beneficial effects and the possible mechanisms of different hydrogen concentrations on COPD. A rat COPD model was established through smoke exposure methods, and inhalation of different concentrations of hydrogen was used as the intervention. The daily condition of rats and the weight changes were observed; lung function and right ventricular hypertrophy index were assessed. Also, white blood cells were assessed in bronchoalveolar lavage fluid. Pathologic changes in the lung tissue were analyzed using light microscopy and electron microscopy; cardiovascular structure and pulmonary arterial pressure changes in rats were observed using ultrasonography. Tumor necrosis factor alpha, interleukin (IL)-6, IL-17, IL-23, matrix metalloproteinase-12, tissue inhibitor of metalloproteinase-1, caspase-3, caspase-8 protein, and mRNA levels in the lung tissue were determined using immunohistochemistry, Western blot, and real-time polymerase chain reaction. The results showed that hydrogen inhalation significantly reduced the number of inflammatory cells in the bronchoalveolar lavage fluid, and the mRNA and protein expression levels of tumor necrosis factor alpha, IL-6, IL-17, IL-23, matrix metalloproteinase-12, caspase-3, and caspase-8, but increased the tissue inhibitor of metalloproteinase-1 expression. Furthermore, hydrogen inhalation ameliorated lung pathology, lung function, and cardiovascular function and reduced the right ventricular hypertrophy index. Inhalation of 22% and 41.6% hydrogen showed better outcome than inhalation of 2% hydrogen. These results suggest that hydrogen inhalation slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Higher concentrations of hydrogen may represent a more effective way for the rat model.

Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model

PubMed Central

Liu, Xiaoyu; Ma, Cuiqing; Wang, Xiaoyu; Wang, Wenjing; Li, Zhu; Wang, Xiansheng; Wang, Pengyu; Sun, Wuzhuang; Xue, Baojian

2017-01-01

Background Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease caused by harmful gases or particles. Recent studies have shown that 2% hydrogen or hydrogen water is effective in the treatment and prevention of a variety of diseases. This study investigated the beneficial effects and the possible mechanisms of different hydrogen concentrations on COPD. Methods A rat COPD model was established through smoke exposure methods, and inhalation of different concentrations of hydrogen was used as the intervention. The daily condition of rats and the weight changes were observed; lung function and right ventricular hypertrophy index were assessed. Also, white blood cells were assessed in bronchoalveolar lavage fluid. Pathologic changes in the lung tissue were analyzed using light microscopy and electron microscopy; cardiovascular structure and pulmonary arterial pressure changes in rats were observed using ultrasonography. Tumor necrosis factor alpha, interleukin (IL)-6, IL-17, IL-23, matrix metalloproteinase-12, tissue inhibitor of metalloproteinase-1, caspase-3, caspase-8 protein, and mRNA levels in the lung tissue were determined using immunohistochemistry, Western blot, and real-time polymerase chain reaction. Results The results showed that hydrogen inhalation significantly reduced the number of inflammatory cells in the bronchoalveolar lavage fluid, and the mRNA and protein expression levels of tumor necrosis factor alpha, IL-6, IL-17, IL-23, matrix metalloproteinase-12, caspase-3, and caspase-8, but increased the tissue inhibitor of metalloproteinase-1 expression. Furthermore, hydrogen inhalation ameliorated lung pathology, lung function, and cardiovascular function and reduced the right ventricular hypertrophy index. Inhalation of 22% and 41.6% hydrogen showed better outcome than inhalation of 2% hydrogen. Conclusion These results suggest that hydrogen inhalation slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Higher concentrations of hydrogen may represent a more effective way for the rat model. PMID:28496315

Comparison of cell counting methods in rodent pulmonary toxicity studies: automated and manual protocols and considerations for experimental design

PubMed Central

Zeidler-Erdely, Patti C.; Antonini, James M.; Meighan, Terence G.; Young, Shih-Houng; Eye, Tracy J.; Hammer, Mary Ann; Erdely, Aaron

2016-01-01

Pulmonary toxicity studies often use bronchoalveolar lavage (BAL) to investigate potential adverse lung responses to a particulate exposure. The BAL cellular fraction is counted, using automated (i.e. Coulter Counter®), flow cytometry or manual (i.e. hemocytometer) methods, to determine inflammatory cell influx. The goal of the study was to compare the different counting methods to determine which is optimal for examining BAL cell influx after exposure by inhalation or intratracheal instillation (ITI) to different particles with varying inherent pulmonary toxicities in both rat and mouse models. General findings indicate that total BAL cell counts using the automated and manual methods tended to agree after inhalation or ITI exposure to particle samples that are relatively nontoxic or at later time points after exposure to a pneumotoxic particle when the response resolves. However, when the initial lung inflammation and cytotoxicity was high after exposure to a pneumotoxic particle, significant differences were observed when comparing cell counts from the automated, flow cytometry and manual methods. When using total BAL cell count for differential calculations from the automated method, depending on the cell diameter size range cutoff, the data suggest that the number of lung polymorphonuclear leukocytes (PMN) varies. Importantly, the automated counts, regardless of the size cutoff, still indicated a greater number of total lung PMN when compared with the manual method, which agreed more closely with flow cytometry. The results suggest that either the manual method or flow cytometry would be better suited for BAL studies where cytotoxicity is an unknown variable. PMID:27251196

Comparison of cell counting methods in rodent pulmonary toxicity studies: automated and manual protocols and considerations for experimental design.

PubMed

Zeidler-Erdely, Patti C; Antonini, James M; Meighan, Terence G; Young, Shih-Houng; Eye, Tracy J; Hammer, Mary Ann; Erdely, Aaron

2016-08-01

Pulmonary toxicity studies often use bronchoalveolar lavage (BAL) to investigate potential adverse lung responses to a particulate exposure. The BAL cellular fraction is counted, using automated (i.e. Coulter Counter®), flow cytometry or manual (i.e. hemocytometer) methods, to determine inflammatory cell influx. The goal of the study was to compare the different counting methods to determine which is optimal for examining BAL cell influx after exposure by inhalation or intratracheal instillation (ITI) to different particles with varying inherent pulmonary toxicities in both rat and mouse models. General findings indicate that total BAL cell counts using the automated and manual methods tended to agree after inhalation or ITI exposure to particle samples that are relatively nontoxic or at later time points after exposure to a pneumotoxic particle when the response resolves. However, when the initial lung inflammation and cytotoxicity was high after exposure to a pneumotoxic particle, significant differences were observed when comparing cell counts from the automated, flow cytometry and manual methods. When using total BAL cell count for differential calculations from the automated method, depending on the cell diameter size range cutoff, the data suggest that the number of lung polymorphonuclear leukocytes (PMN) varies. Importantly, the automated counts, regardless of the size cutoff, still indicated a greater number of total lung PMN when compared with the manual method, which agreed more closely with flow cytometry. The results suggest that either the manual method or flow cytometry would be better suited for BAL studies where cytotoxicity is an unknown variable.

The Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary Disease.

PubMed

Nurwidya, Fariz; Damayanti, Triya; Yunus, Faisal

2016-01-01

Chronic obstructive pulmonary disease (COPD) is a chronic and progressive inflammatory disease of the airways and lungs that results in limitations of continuous airflow and is caused by exposure to noxious gasses and particles. A major cause of morbidity and mortality in adults, COPD is a complex disease pathologically mediated by many inflammatory pathways. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are the key inflammatory cells involved in COPD. Recently, the non-coding small RNA, micro-RNA, have also been intensively investigated and evidence suggest that it plays a role in the pathogenesis of COPD. Here, we discuss the accumulated evidence that has since revealed the role of each inflammatory cell and their involvement in the immunopathogenesis of COPD. Mechanisms of steroid resistance in COPD will also be briefly discussed.

Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Husain, Mainul, E-mail: mainul.husain@hc-sc.gc.ca; Saber, Anne T., E-mail: ats@nrcwe.dk; Guo, Charles, E-mail: charles.guo@hc-sc.gc.ca

2013-06-15

We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO{sub 2}). Female C57BL/6 mice were exposed to rutile nano-TiO{sub 2} via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO{sub 2} in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analyzed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO{sub 2} in the lungs upmore » to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (± 1.3 fold; p < 0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, were associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO{sub 2} in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities. - Highlights: • Pulmonary effects following exposure to low doses of nano-TiO{sub 2} were examined. • Particle retention in lungs was assessed using nanoscale hyperspectral microscopy. • Particles persisted up to 28 days in lungs in all dose groups. • Inflammation was the pathway affected in the high dose group at all time points. • Ion homeostasis and muscle activity pathways were affected in the low dose group.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mason, G.R.; Duane, G.B.; Effros, R.M.

Because infection with Pheumocystis carinii pneumonia (PCP) causes alteration of the type I epithelial cells as the primary event, the authors studied patients with PCP to determine if PCP causes rapid clearance of Tc-99m DTPA. Twenty normal non-smoking subjects and 7 non-smoking patients with histologically proven PCP were studied. Serial studies were obtained in three patients. Following a two-minute inhalation of 1.6 ..mu..m aerosol particles of Tc-99m DTPA in saline, the activity over three peripheral regions of interest (ROI) of each lung was monitored for the next 7 minutes. The rate of decline of activity over each ROI was expressedmore » as per cent decline/min. In 7 patients with PCP, the average clearance was 7.5 +- 3.6% min., normal, 1.3 +- 0.6% min.(SD). Three patients studied from 5 to 38 days following therapy had improvement in the rate of clearance. This has been demonstrated to be persistent even after clinical recovery of the patient. The ability to quantitate injury to the pulmonary epithelium may directly reflect the ability of Pneumocystis carinii to invade the lung. The authors conclude that Tc-99m DTPA clearance may be a useful test to help diagnosis and monitor the activity of PCP infections.« less

Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

PubMed Central

Rajavelu, Priya; Chen, Gang; Xu, Yan; Kitzmiller, Joseph A.; Korfhagen, Thomas R.; Whitsett, Jeffrey A.

2015-01-01

Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef–/– mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen. PMID:25866971

Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jessop, Forrest; Hamilton, Raymond F.; Rhoderick,

NLRP3 inflammasome activation occurs in response to hazardous particle exposures and is critical for the development of particle-induced lung disease. Mechanisms of Lysosome Membrane Permeabilization (LMP), a central pathway for activation of the NLRP3 inflammasome by inhaled particles, are not fully understood. We demonstrate that the lysosomal vATPases inhibitor Bafilomycin A1 blocked LMP in vitro and ex vivo in primary murine macrophages following exposure to silica, multi-walled carbon nanotubes, and titanium nanobelts. Bafilomycin A1 treatment of particle-exposed macrophages also resulted in decreased active cathepsin L in the cytosol, a surrogate measure for leaked cathepsin B, which was associated with lessmore » NLRP3 inflammasome activity. Silica-induced LMP was partially dependent upon lysosomal cathepsins B and L, whereas nanoparticle-induced LMP occurred independent of cathepsin activity. Furthermore, inhibition of lysosomal cathepsin activity with CA-074-Me decreased the release of High Mobility Group Box 1. Together, these data support the notion that lysosome acidification is a prerequisite for particle-induced LMP, and the resultant leak of lysosome cathepsins is a primary regulator of ongoing NLRP3 inflammasome activity and release of HMGB1. - Highlights: • Silica and nanoparticles cause LMP in macrophages in vitro and in vivo. • Phagolysosome acidification is required for particle-induced LMP. • Cathepsin B and L are not required for nanoparticle-induced LMP. • Cathepsin B/L regulate the secretion of HMGB1 with particle exposure.« less

Lung abscess caused by Streptococcus pneumoniae serotype 6B.

PubMed

Ito, Yuhei; Toyoshima, Hirokazu; Suzuki, Takehiro; Iwamoto, Keisuke; Sasano, Hajime; Itani, Hidetoshi; Kondo, Shigeto; Tanigawa, Motoaki

2018-01-01

Lung abscess has been considered to be a rare complication of pneumococcal infection, and most cases are reported to be Streptococcus pneumoniae serotype 3. A 67-year-old man presented with fever and was diagnosed to have lung abscess caused by S. pneumoniae serotype 6B. The minimal inhibitory concentration (MIC) of penicillin for the isolate was 1 μg/mL. He was treated with high-dose intravenous sulbactam/ampicillin as definitive therapy based on susceptibility testing for S. pneumoniae and recovered successfully without surgical intervention. S. pneumoniae serotype 6B can cause lung abscess.

ACETALDEHYDE (CH3CH0) PRODUCTION IN RODENT LUNG AFTER EXPOSURE TO A METAL-RICH PARTICLES

EPA Science Inventory

Epidemiological reports demonstrate an association between increased human morbidity and mortality with exposure to air pollution particulate matter (PM). Metal-catalyzed oxidative stress has been postulated to contribute to lung injury in response to PM exposure. We studied the ...

Role of circulating granulocytes in sheep lung injury produced by phorbol myristate acetate.

PubMed

Dyer, E L; Snapper, J R

1986-02-01

Phorbol myristate acetate (PMA) and endotoxin cause pulmonary granulocyte sequestration and alteration in lung fluid and solute exchange in awake sheep that are felt to be analogous to the adult respiratory distress syndrome in humans. The basic hypothesis that PMA causes lung injury by activating circulating granulocytes has never been tested. The effects of infused PMA on lung mechanics and the cellular constituents of lung lymph have also not been reported. We therefore characterized the effects of intravenous PMA, 5 micrograms/kg, on lung mechanics, pulmonary hemodynamics, lung fluid and solute exchange, pulmonary gas exchange, blood and lymph leukocyte counts, and plasma and lymph cyclooxygenase products of arachidonate metabolism in 10 awake sheep with normal granulocyte counts and after granulocyte depletion with hydroxyurea. PMA significantly altered lung mechanics from base line in both nongranulocyte depleted and granulocyte-depleted sheep. Dynamic compliance decreased by over 50% and resistance to airflow across the lungs increased over threefold acutely following PMA infusion in both sets of experiments. Changes in lung mechanics, pulmonary hemodynamics, lung fluid and solute exchange, pulmonary gas exchange, and plasma and lymph arachidonate metabolites were not significantly affected by greater than 99% depletion of circulating granulocytes. We conclude that the lung injury caused by PMA in chronically instrumented awake sheep probably is not a result of activation of circulating granulocytes.

Effective biological dose from occupational exposure during nanoparticle synthesis

NASA Astrophysics Data System (ADS)

Demou, Evangelia; Tran, Lang; Housiadas, Christos

2009-02-01

Nanomaterial and nanotechnology safety require the characterization of occupational exposure levels for completing a risk assessment. However, equally important is the estimation of the effective internal dose via lung deposition, transport and clearance mechanisms. An integrated source-to-biological dose assessment study is presented using real monitoring data collected during nanoparticle synthesis. Experimental monitoring data of airborne exposure levels during nanoparticle synthesis of CaSO4 and BiPO4 nanoparticles in a research laboratory is coupled with a human lung transport and deposition model, which solves in an Eulerian framework the general dynamic equation for polydisperse aerosols using particle specific physical-chemical properties. Subsequently, the lung deposition model is coupled with a mathematical particle clearance model providing the effective biological dose as well as the time course of the biological dose build-up after exposure. The results for the example of BiPO4 demonstrate that even short exposures throughout the day can lead to particle doses of 1.10·E+08#/(kg-bw·8h-shift), with the majority accumulating in the pulmonary region. Clearance of particles is slow and is not completed within a working shift following a 1 hour exposure. It mostly occurs via macrophage activity in the alveolar region, with small amounts transported to the interstitium and less to the lymph nodes.

Inhalational System for Etoposide Liposomes: Formulation Development and In Vitro Deposition

PubMed Central

Parmar, J. J.; Singh, D. J.; Lohade, A. A.; Hegde, Darshana D.; Soni, P. S.; Samad, A.; Menon, Mala D.

2011-01-01

Etoposide is a semisynthetic compound, widely used in treatment of non small cell lung cancer. However, frequent dosing and adverse effects remain a major concern in the use of etoposide. Liposomal systems for pulmonary drug delivery have been particularly attractive because of their compatibility with lung surfactant components. In the present investigation, pulmonary liposomal delivery system of etoposide was prepared by film hydration method. Various parameters were optimized with respect to entrapment efficiency as well as particle size of etoposide liposomes. For better shelf life of etoposide liposomes, freeze drying using trehalose as cryoprotectant was carried out. The liposomes were characterized for entrapment efficiency, particle size, surface topography, and in vitro drug release was carried out in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction was determined by using twin stage impinger. The stability study of freeze dried as well as aqueous liposomal systems was carried out at 2-8° and at ambient temperature (28±4°). The freeze dried liposomes showed better fine particle fraction and drug content over the period of six months at ambient as well as at 2-8° storage condition compared to aqueous dispersion of liposomes. PMID:23112400

Comparison of effects of glass fibre and glass powder on guinea-pig lungs

PubMed Central

Botham, Susan K.; Holt, P. F.

1973-01-01

Botham, Susan K., and Holt, P. F. (1973).British Journal of Industrial Medicine,30, 232-236. Comparison of effects of glass fibre and glass powder on guinea-pig lungs. Following 24 hours inhalation by guinea-pigs of powdered glass dust, the pulmonary effects over the succeeding month differed from those previously observed to follow inhalation of glass fibre in that (1) fewer erythrocytes escaped from the capillaries, (2) very few giant cells were produced, (3) erythrocytes and intracellular glass particles were cleared more readily because junctions between respiratory and terminal bronchioles were not blocked by giant cells, (4) intracellular granules containing Perls-positive material did not appreciably increase in number or intensity of staining during the month, and (5) particles were not coated with Perls-positive material during the time that pseudo-asbestos bodies would be formed from glass fibres. The difference between the effects of chemically similar glass powder and fibre during a month in a guinea-pig lung is considered to be due to the morphology of the inhaled particle. Images PMID:4124978

Lung Abscess: An Early Complication of Lung Transplantation in a Patient with Cystic Fibrosis.

PubMed

Markelić, I; Jakopović, M; Klepetko, W; Džubur, F; Hećimović, A; Makek, M J; Samaržija, M; Dugac, A V

2017-01-01

A 22-year-old woman with cystic fibrosis (CF) developed lung abscess, as a rare complication caused by multidrug-resistant (MDR) Acinetobacter baumannii infection, after lung transplantation (LT). After 6 months of long-term antibiotic therapy, the abscess was successfully eliminated. In reviewed published literature, no previous report was found describing this kind of complication caused by MDR A. baumannii in post-LT patient with CF. In our experience, lung abscess in LT recipients with CF can be successfully treated with prolonged antibiotic therapy.

Lung abscess-etiology, diagnostic and treatment options.

PubMed

Kuhajda, Ivan; Zarogoulidis, Konstantinos; Tsirgogianni, Katerina; Tsavlis, Drosos; Kioumis, Ioannis; Kosmidis, Christoforos; Tsakiridis, Kosmas; Mpakas, Andrew; Zarogoulidis, Paul; Zissimopoulos, Athanasios; Baloukas, Dimitris; Kuhajda, Danijela

2015-08-01

Lung abscess is a type of liquefactive necrosis of the lung tissue and formation of cavities (more than 2 cm) containing necrotic debris or fluid caused by microbial infection. It can be caused by aspiration, which may occur during altered consciousness and it usually causes a pus-filled cavity. Moreover, alcoholism is the most common condition predisposing to lung abscesses. Lung abscess is considered primary (60%) when it results from existing lung parenchymal process and is termed secondary when it complicates another process, e.g., vascular emboli or follows rupture of extrapulmonary abscess into lung. There are several imaging techniques which can identify the material inside the thorax such as computerized tomography (CT) scan of the thorax and ultrasound of the thorax. Broad spectrum antibiotic to cover mixed flora is the mainstay of treatment. Pulmonary physiotherapy and postural drainage are also important. Surgical procedures are required in selective patients for drainage or pulmonary resection. In the current review we will present all current information from diagnosis to treatment.

Lung abscess-etiology, diagnostic and treatment options

PubMed Central

Kuhajda, Ivan; Zarogoulidis, Konstantinos; Tsirgogianni, Katerina; Tsavlis, Drosos; Kioumis, Ioannis; Kosmidis, Christoforos; Tsakiridis, Kosmas; Mpakas, Andrew; Zissimopoulos, Athanasios; Baloukas, Dimitris; Kuhajda, Danijela

2015-01-01

Lung abscess is a type of liquefactive necrosis of the lung tissue and formation of cavities (more than 2 cm) containing necrotic debris or fluid caused by microbial infection. It can be caused by aspiration, which may occur during altered consciousness and it usually causes a pus-filled cavity. Moreover, alcoholism is the most common condition predisposing to lung abscesses. Lung abscess is considered primary (60%) when it results from existing lung parenchymal process and is termed secondary when it complicates another process, e.g., vascular emboli or follows rupture of extrapulmonary abscess into lung. There are several imaging techniques which can identify the material inside the thorax such as computerized tomography (CT) scan of the thorax and ultrasound of the thorax. Broad spectrum antibiotic to cover mixed flora is the mainstay of treatment. Pulmonary physiotherapy and postural drainage are also important. Surgical procedures are required in selective patients for drainage or pulmonary resection. In the current review we will present all current information from diagnosis to treatment. PMID:26366400

The Effects of High Frequency Oscillatory Flow on Particles' Deposition in Upper Human Lung Airways

NASA Astrophysics Data System (ADS)

Bonifacio, Jeremy; Rahai, Hamid; Taherian, Shahab

2016-11-01

The effects of oscillatory inspiration on particles' deposition in upper airways of a human lung during inhalation/exhalation have been numerically investigated and results of flow characteristics, and particles' deposition pattern have been compared with the corresponding results without oscillation. The objective of the investigation was to develop an improved method for drug delivery for Asthma and COPD patients. Previous clinical investigations of using oral airway oscillations have shown enhanced expectoration in cystic fibrosis (CF) patients, when the frequency of oscillation was at 8 Hz with 9:1 inspiratory/expiratory (I:E) ratio. Other investigations on oscillatory ventilation had frequency range of 0.5 Hz to 2.5 Hz. In the present investigations, the frequency of oscillation was changed between 2 Hz to 10 Hz. The particles were injected at the inlet and particle velocity was equal to the inlet air velocity. One-way coupling of air and particles was assumed. Lagrangian phase model was used for transport and depositions of solid 2.5 micron diameter round particles with 1200 kg/m3 density. Preliminary results have shown enhanced PM deposition with oscillatory flow with lower frequency having a higher deposition rate Graduate Assistant.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, K L; Steele, P T; Bogan, M J

Two similar mycobacteria, Mycobacteria tuberculosis H37Ra and Mycobacteria smegmatis are rapidly detected and identified within samples containing a complex background of respiratory effluents using Single Particle Aerosol Mass Spectrometry (SPAMS). M. tuberculosis H37Ra (TBa), an avirulent strain, is used as a surrogate for virulent tuberculosis (TBv); M. smegmatis (MSm) is utilized as a near neighbor confounder for TBa. Bovine lung surfactant and human exhaled breath condensate are used as first-order surrogates for infected human lung expirations from patients with pulmonary tuberculosis. This simulated background sputum is mixed with TBa or MSm and nebulized to produce conglomerate aerosol particles, single particlesmore » that contain a bacterium embedded within a background respiratory matrix. Mass spectra of single conglomerate particles exhibit ions associated with both respiratory effluents and mycobacteria. Spectral features distinguishing TBa from MSm in pure and conglomerate particles are shown. SPAMS pattern matching alarm algorithms are able to distinguish TBa containing particles from background matrix and MSm for >50% of the test particles, which is sufficient to enable a high probability of detection and a low false alarm rate if an adequate number of such particles are present. These results indicate the potential usefulness of SPAMS for rapid, reagentless tuberculosis screening.« less

3D imaging of particle tracks in Solid State Nuclear Track Detectors

NASA Astrophysics Data System (ADS)

Wertheim, D.; Gillmore, G.; Brown, L.; Petford, N.

2009-04-01

Inhalation of radon gas (222Rn) and associated ionizing decay products is known to cause lung cancer in human. In the U.K., it has been suggested that 3 to 5 % of total lung cancer deaths can be linked to elevated radon concentrations in the home and/or workplace. Radon monitoring in buildings is therefore routinely undertaken in areas of known risk. Indeed, some organisations such as the Radon Council in the UK and the Environmental Protection Agency in the USA, advocate a ‘to test is best' policy. Radon gas occurs naturally, emanating from the decay of 238U in rock and soils. Its concentration can be measured using CR?39 plastic detectors which conventionally are assessed by 2D image analysis of the surface; however there can be some variation in outcomes / readings even in closely spaced detectors. A number of radon measurement methods are currently in use (for examples, activated carbon and electrets) but the most widely used are CR?39 solid state nuclear track?etch detectors (SSNTDs). In this technique, heavily ionizing alpha particles leave tracks in the form of radiation damage (via interaction between alpha particles and the atoms making up the CR?39 polymer). 3D imaging of the tracks has the potential to provide information relating to angle and energy of alpha particles but this could be time consuming. Here we describe a new method for rapid high resolution 3D imaging of SSNTDs. A ‘LEXT' OLS3100 confocal laser scanning microscope was used in confocal mode to successfully obtain 3D image data on four CR?39 plastic detectors. 3D visualisation and image analysis enabled characterisation of track features. This method may provide a means of rapid and detailed 3D analysis of SSNTDs. Keywords: Radon; SSNTDs; confocal laser scanning microscope; 3D imaging; LEXT

Lung Entrapment between the Pectus Bar and Chest Wall after Pectus Surgery: An Incidental Finding during Video-Assisted Thoracoscopic Surgery

PubMed Central

Kim, Kyung Soo; Hyun, Kwanyong; Kim, Do Yeon; Choi, Kukbin; Choi, Hahng Joon; Park, Hyung Joo

2015-01-01

We report a case of an entrapped lung after the pectus bar repair of a pectus deformity. The entrapped lung was found incidentally during video-assisted thoracoscopic surgery (VATS) for pneumothorax. Based on VATS exploration, multiple bullae seemed to be the cause of the pneumothorax, but the entrapped lung was suspected to have been a cause of the air leakage. PMID:26509135

& Source apportionment of particulate matter in the United States and associations with lung inflammatory Markers

EPA Science Inventory

Size-fractionated particulate matter (PM) samples were collected from six U.S. cities and chemically analyzed as part of the Multiple Air Pollutant Study. Particles were administered to cultured lung cells and the production of three different proinflammatory markers was measured...

DEPLETION OF IRON AND ASCORBATE IN RODENTS DIMINISHES LUNG INJURY AFTER SILICA

EPA Science Inventory

Exposures of the lung to iron chelates can be associated with an injury. The catalysis of oxygen-based free radicals is postulated to participate in this injury. Such oxidant generation by mineral oxide particles can be dependent on availability of both iron and a reductant. We t...

ROLE OF CELL SIGNALING IN PROTECTION FROM DIESEL AND LPS INDUCED ACUTE LUNG INJURY

EPA Science Inventory

We have previously demonstrated in CD-1 mice that pre-administration of N-acetyl cysteine (NAC) or the p38 MAP kinase inhibitor (SB203580) reduces acute lung injury and inflammation following pulmonary exposures to diesel exhaust particles (DEP) or lipopolysaccharide (LPS). Here ...

Alveolar proteinosis associated with aluminium dust inhalation.

PubMed

Chew, R; Nigam, S; Sivakumaran, P

2016-08-01

Secondary alveolar proteinosis is a rare lung disease which may be triggered by a variety of inhaled particles. The diagnosis is made by detection of anti-granulocyte-macrophage colony-stimulating factor antibodies in bronchoalveolar lavage fluid, which appears milky white and contains lamellar bodies. Aluminium has been suggested as a possible cause, but there is little evidence in the literature to support this assertion. We report the case of a 46-year-old former boilermaker and boat builder who developed secondary alveolar proteinosis following sustained heavy aluminium exposure. The presence of aluminium was confirmed both by histological examination and metallurgical analysis of a mediastinal lymph node. Despite cessation of exposure to aluminium and treatment with whole-lung lavage which normally results in improvements in both symptoms and lung function, the outcome was poor and novel therapies are now being used for this patient. It may be that the natural history in aluminium-related alveolar proteinosis is different, with the metal playing a mediating role in the disease process. Our case further supports the link between aluminium and secondary alveolar proteinosis and highlights the need for measures to prevent excessive aluminium inhalation in relevant industries. © The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effects of intratracheally instilled laser printer-emitted engineered nanoparticles in a mouse model: A case study of toxicological implications from nanomaterials released during consumer use

PubMed Central

Pirela, Sandra V.; Lu, Xiaoyan; Miousse, Isabelle; Sisler, Jennifer D.; Qian, Yong; Guo, Nancy; Koturbash, Igor; Castranova, Vincent; Thomas, Treye; Godleski, John; Demokritou, Philip

2016-01-01

Incorporation of engineered nanomaterials (ENMs) into toners used in laser printers has led to countless quality and performance improvements. However, the release of ENMs during printing (consumer use) has raised concerns about their potential adverse health effects. The aim of this study was to use “real world” printer-emitted particles (PEPs), rather than raw toner powder, and assess the pulmonary responses following exposure by intratracheal instillation. Nine-week old male Balb/c mice were exposed to various doses of PEPs (0.5, 2.5 and 5 mg/kg body weight) by intratracheal instillation. These exposure doses are comparable to real world human inhalation exposures ranging from 13.7 to 141.9 h of printing. Toxicological parameters reflecting distinct mechanisms of action were evaluated, including lung membrane integrity, inflammation and regulation of DNA methylation patterns. Results from this in vivo toxicological analysis showed that while intratracheal instillation of PEPs caused no changes in the lung membrane integrity, there was a pulmonary immune response, indicated by an elevation in neutrophil and macrophage percentage over the vehicle control and low dose PEPs groups. Additionally, exposure to PEPs upregulated expression of the Ccl5 (Rantes), Nos1 and Ucp2 genes in the murine lung tissue and modified components of the DNA methylation machinery (Dnmt3a) and expression of transposable element (TE) LINE-1 compared to the control group. These genes are involved in both the repair process from oxidative damage and the initiation of immune responses to foreign pathogens. The results are in agreement with findings from previous in vitro cellular studies and suggest that PEPs may cause immune responses in addition to modifications in gene expression in the murine lung at doses that can be comparable to real world exposure scenarios, thereby raising concerns of deleterious health effects. PMID:26989787

Multidimensional effects of biologically synthesized silver nanoparticles in Helicobacter pylori, Helicobacter felis, and human lung (L132) and lung carcinoma A549 cells.

PubMed

Gurunathan, Sangiliyandi; Jeong, Jae-Kyo; Han, Jae Woong; Zhang, Xi-Feng; Park, Jung Hyun; Kim, Jin-Hoi

2015-01-01

Silver nanoparticles (AgNPs) are prominent group of nanomaterials and are recognized for their diverse applications in various health sectors. This study aimed to synthesize the AgNPs using the leaf extract of Artemisia princeps as a bio-reductant. Furthermore, we evaluated the multidimensional effect of the biologically synthesized AgNPs in Helicobacter pylori, Helicobacter felis, and human lung (L132) and lung carcinoma (A549) cells. UV-visible (UV-vis) spectroscopy confirmed the synthesis of AgNPs. X-ray diffraction (XRD) indicated that the AgNPs are specifically indexed to a crystal structure. The results from Fourier transform infrared spectroscopy (FTIR) indicate that biomolecules are involved in the synthesis and stabilization of AgNPs. Dynamic light scattering (DLS) studies showed the average size distribution of the particle between 10 and 40 nm, and transmission electron microscopy (TEM) confirmed that the AgNPs were significantly well separated and spherical with an average size of 20 nm. AgNPs caused dose-dependent decrease in cell viability and biofilm formation and increase in reactive oxygen species (ROS) generation and DNA fragmentation in H. pylori and H. felis. Furthermore, AgNPs induced mitochondrial-mediated apoptosis in A549 cells; conversely, AgNPs had no significant effects on L132 cells. The results from this study suggest that AgNPs could cause cell-specific apoptosis in mammalian cells. Our findings demonstrate that this environmentally friendly method for the synthesis of AgNPs and that the prepared AgNPs have multidimensional effects such as anti-bacterial and anti-biofilm activity against H. pylori and H. felis and also cytotoxic effects against human cancer cells. This report describes comprehensively the effects of AgNPs on bacteria and mammalian cells. We believe that biologically synthesized AgNPs will open a new avenue towards various biotechnological and biomedical applications in the near future.

Multidimensional effects of biologically synthesized silver nanoparticles in Helicobacter pylori, Helicobacter felis, and human lung (L132) and lung carcinoma A549 cells

NASA Astrophysics Data System (ADS)

Gurunathan, Sangiliyandi; Jeong, Jae-Kyo; Han, Jae Woong; Zhang, Xi-Feng; Park, Jung Hyun; Kim, Jin-Hoi

2015-02-01

Silver nanoparticles (AgNPs) are prominent group of nanomaterials and are recognized for their diverse applications in various health sectors. This study aimed to synthesize the AgNPs using the leaf extract of Artemisia princeps as a bio-reductant. Furthermore, we evaluated the multidimensional effect of the biologically synthesized AgNPs in Helicobacter pylori, Helicobacter felis, and human lung (L132) and lung carcinoma (A549) cells. UV-visible (UV-vis) spectroscopy confirmed the synthesis of AgNPs. X-ray diffraction (XRD) indicated that the AgNPs are specifically indexed to a crystal structure. The results from Fourier transform infrared spectroscopy (FTIR) indicate that biomolecules are involved in the synthesis and stabilization of AgNPs. Dynamic light scattering (DLS) studies showed the average size distribution of the particle between 10 and 40 nm, and transmission electron microscopy (TEM) confirmed that the AgNPs were significantly well separated and spherical with an average size of 20 nm. AgNPs caused dose-dependent decrease in cell viability and biofilm formation and increase in reactive oxygen species (ROS) generation and DNA fragmentation in H. pylori and H. felis. Furthermore, AgNPs induced mitochondrial-mediated apoptosis in A549 cells; conversely, AgNPs had no significant effects on L132 cells. The results from this study suggest that AgNPs could cause cell-specific apoptosis in mammalian cells. Our findings demonstrate that this environmentally friendly method for the synthesis of AgNPs and that the prepared AgNPs have multidimensional effects such as anti-bacterial and anti-biofilm activity against H. pylori and H. felis and also cytotoxic effects against human cancer cells. This report describes comprehensively the effects of AgNPs on bacteria and mammalian cells. We believe that biologically synthesized AgNPs will open a new avenue towards various biotechnological and biomedical applications in the near future.

Fluorescence imaging and targeted distribution of bacterial magnetic particles in nude mice.

PubMed

Tang, Tao; Zhang, Lianfeng; Gao, Ran; Dai, Yunping; Meng, Fanchao; Li, Ying

2012-04-01

Bacterial magnetic particles (BMPs) are of interest as potential carriers of bioactive macromolecules, drugs, or liposomes. In this study, a high-pressure homogenizer was used to disrupt Magnetospirillum gryphiswaldense strain MSR-1 cells, and BMPs were purified. BMPs were labeled with fluorescence reagent 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocianin perchlorate (DiI) and injected into the tail vein of BALB/c nude mice. Distribution of fluorescence signals of DiI-BMPs in vivo was examined using a whole-body fluorescence imaging system. The result showed that fluorescence signals were detected in liver, stomach, intestine, lungs, and spleen. However, transmission electron microscopy of ultrathin sections indicated that BMPs were mainly present in liver and lungs, but not in the other organs. BMPs could be useful as carriers for targeted drug therapy of diseases of the liver or lung.

Radiopharmaceutical considerations for using Tc-99m MAA in lung transplant patients.

PubMed

Ponto, James A

2010-01-01

To elucidate radiopharmaceutical considerations for using technetium Tc-99m albumin aggregated (Tc-99m MAA) in lung transplant patients and to establish an appropriate routine dose and preparation procedure. Tertiary care academic hospital during May 2007 to May 2009. Nuclear pharmacist working in nuclear medicine department. Radiopharmaceutical considerations deemed important for the use of Tc-99m MAA in lung transplant patients included radioactivity dose, particulate dose, rate of the radiolabeling reaction (preparation time), and final radiochemical purity. Evaluation of our initial 12-month experience, published literature, and professional practice guidelines provided the basis for establishing an appropriate dose and preparation procedure of Tc-99m MAA for use in lung transplant patients. Radiochemical purity at typical incubation times and image quality in subsequent lung transplant patients imaged during the next 12 months. Based on considerations of radioactivity dose, particulate dose, rate of the radiolabeling reaction (preparation time), and final radiochemical purity, a routine dose consisting of 3 mCi (111 MBq) and 100,000 particles of Tc-99m MAA for planar perfusion lung imaging of adult lung transplant patients was established as reasonable and appropriate. MAA kits were prepared with a more reasonable amount of Tc-99m and yielded high radiochemical purity values in typical incubation times. Images have continued to be of high diagnostic quality. Tc-99m MAA used for lung transplant imaging can be readily prepared with high radiochemical purity to provide a dose of 3 mCi (111 GBq)/100,000 particles, which provides images of high diagnostic quality.

Effects of amorphous silica coating on cerium oxide nanoparticles induced pulmonary responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Jane, E-mail: jym1@cdc.gov; Mercer, Robert R.; Barger, Mark

2015-10-01

Recently cerium compounds have been used in a variety of consumer products, including diesel fuel additives, to increase fuel combustion efficiency and decrease diesel soot emissions. However, cerium oxide (CeO{sub 2}) nanoparticles have been detected in the exhaust, which raises a health concern. Previous studies have shown that exposure of rats to nanoscale CeO{sub 2} by intratracheal instillation (IT) induces sustained pulmonary inflammation and fibrosis. In the present study, male Sprague–Dawley rats were exposed to CeO{sub 2} or CeO{sub 2} coated with a nano layer of amorphous SiO{sub 2} (aSiO{sub 2}/CeO{sub 2}) by a single IT and sacrificed at variousmore » times post-exposure to assess potential protective effects of the aSiO{sub 2} coating. The first acellular bronchoalveolar lavage (BAL) fluid and BAL cells were collected and analyzed from all exposed animals. At the low dose (0.15 mg/kg), CeO{sub 2} but not aSiO{sub 2}/CeO{sub 2} exposure induced inflammation. However, at the higher doses, both particles induced a dose-related inflammation, cytotoxicity, inflammatory cytokines, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP at 1 day post-exposure. Morphological analysis of lung showed an increased inflammation, surfactant and collagen fibers after CeO{sub 2} (high dose at 3.5 mg/kg) treatment at 28 days post-exposure. aSiO{sub 2} coating significantly reduced CeO{sub 2}-induced inflammatory responses in the airspace and appeared to attenuate phospholipidosis and fibrosis. Energy dispersive X-ray spectroscopy analysis showed Ce and phosphorous (P) in all particle-exposed lungs, whereas Si was only detected in aSiO{sub 2}/CeO{sub 2}-exposed lungs up to 3 days after exposure, suggesting that aSiO{sub 2} dissolved off the CeO{sub 2} core, and some of the CeO{sub 2} was transformed to CePO{sub 4} with time. These results demonstrate that aSiO{sub 2} coating reduce CeO{sub 2}-induced inflammation, phospholipidosis and fibrosis. - Highlights: • Both CeO{sub 2} and aSiO{sub 2}/CeO{sub 2} particles were detected in the respective particle-exposed lungs. • The dissolution of aSiO{sub 2} coating from CeO{sub 2} particle core with time was demonstrated in the particle-exposed lungs. • aSiO{sub 2} coating significantly protected CeO{sub 2}-induced pulmonary inflammatory responses. • aSiO{sub 2} coating showed a protective effect on CeO{sub 2}-induced lung fibrosis.« less

Gene Therapy for Human Lung Adenocarcinoma Using a Suicide Gene Driven by a Lung-Specific Promoter Delivered by JC Virus-Like Particles.

PubMed

Chao, Chun-Nun; Lin, Mien-Chun; Fang, Chiung-Yao; Chen, Pei-Lain; Chang, Deching; Shen, Cheng-Huang; Wang, Meilin

2016-01-01

Lung adenocarcinoma, the most commonly diagnosed type of lung cancer, has a poor prognosis even with combined surgery, chemotherapy, or molecular targeted therapies. Most patients are diagnosed with an in-operable advanced or metastatic disease, both pointing to the necessity of developing effective therapies for lung adenocarcinoma. Surfactant protein B (SP-B) has been found to be overexpressed in lung adenocarcinoma. In addition, it has also been demonstrated that human lung adenocarcinoma cells are susceptible to the JC polyomavirus (JCPyV) infection. Therefore, we designed that the JCPyV virus-like particle (VLP) packaged with an SP-B promoter-driven thymidine kinase suicide gene (pSPB-tk) for possible gene therapy of human lung adenocarcinoma. Plasmids expressing the GFP (pSPB-gfp) or thymidine kinase gene (pSPB-tk) under the control of the human SP-B promoter were constructed. The promoter's tissue specificity was tested by transfection of pSPB-gfp into A549, CH27, and H460 human lung carcinoma cells and non-lung cells. The JCPyV VLP's gene transfer efficiency and the selective cytotoxicity of pSPB-tk combined with ganciclovir (GCV) were tested in vitro and in a xenograft mouse model. In the current study, we found that SP-B promoter-driven GFP was specifically expressed in human lung adenocarcinoma (A549) and large cell carcinoma (H460) cells. JCPyV VLPs were able to deliver a GFP reporter gene into A549 cells for expression. Selective cytotoxicity was observed in A549 but not non-lung cells that were transfected with pSPB-tk or infected with pSPB-tk-carrying JCPyV VLPs. In mice injected with pSPB-tk-carrying JCPyV VLPs through the tail vein and treated with ganciclovir (GCV), a potent 80% inhibition of growth of human lung adenocarcinoma nodules resulted. The JCPyV VLPs combined with the use of SP-B promoter demonstrates effectiveness as a potential gene therapy against human lung adenocarcinoma.

Rheumatoid Arthritis: Can It Affect the Lungs?

MedlinePlus

Rheumatoid arthritis: Can it affect the lungs? Can rheumatoid arthritis affect your lungs? Answers from April Chang-Miller, M.D. Although rheumatoid arthritis primarily affects joints, it sometimes causes lung disease ...

Pulmonary exposure to diesel exhaust particles enhances coagulatory disturbance with endothelial damage and systemic inflammation related to lung inflammation.

PubMed

Inoue, Ken-Ichiro; Takano, Hirohisa; Sakurai, Miho; Oda, Toshio; Tamura, Hiroshi; Yanagisawa, Rie; Shimada, Akinori; Yoshikawa, Toshikazu

2006-11-01

Pulmonary exposure to diesel exhaust particles (DEP) enhances lung inflammation related to bacterial endotoxin (lipopolysaccharide [LPS]) in mice. Severe lung inflammation can reportedly induce coagulatory abnormalities and systemic inflammation. This study examined the effects of components of DEP on lung inflammation, pulmonary permeability, coagulatory changes, systemic inflammatory response, and lung-to-systemic translocation of LPS in a murine model of lung inflammation. ICR mice were divided into six experimental groups that intratracheally received vehicle, LPS (2.5 mg/kg), organic chemicals in DEP (DEP-OC; 4 mg/kg) extracted with dicloromethane), residual carbonaceous nuclei of DEP (washed DEP: 4 mg/kg), DEP-OC + LPS, or washed DEP + LPS. Both DEP components exacerbated lung inflammation, vascular permeability, and the increased fibrinogen and E-selectin levels induced by LPS. With overall trends, the exacerbation was more prominent with washed DEP than with DEP-OC. Washed DEP + LPS significantly decreased activated protein C and antithrombin-III and elevated circulatory levels of interleukin (IL)-6, keratinocyte chemoattractant (KC), and LPS as compared with LPS alone, whereas DEP-OC + LPS elevated IL-6, KC, and LPS without significance. These results show that DEP components, especially washed DEP, amplify the effects if LPS on the respiratory system and suggest that they contribute to the adverse health effects of particulate air pollution on the sensitive populations with predisposing vascular and/or pulmonary diseases, including ischemic vascular diseases and respiratory infection.

Volume-controlled Ventilation Does Not Prevent Injurious Inflation during Spontaneous Effort.

PubMed

Yoshida, Takeshi; Nakahashi, Susumu; Nakamura, Maria Aparecida Miyuki; Koyama, Yukiko; Roldan, Rollin; Torsani, Vinicius; De Santis, Roberta R; Gomes, Susimeire; Uchiyama, Akinori; Amato, Marcelo B P; Kavanagh, Brian P; Fujino, Yuji

2017-09-01

Spontaneous breathing during mechanical ventilation increases transpulmonary pressure and Vt, and worsens lung injury. Intuitively, controlling Vt and transpulmonary pressure might limit injury caused by added spontaneous effort. To test the hypothesis that, during spontaneous effort in injured lungs, limitation of Vt and transpulmonary pressure by volume-controlled ventilation results in less injurious patterns of inflation. Dynamic computed tomography was used to determine patterns of regional inflation in rabbits with injured lungs during volume-controlled or pressure-controlled ventilation. Transpulmonary pressure was estimated by using esophageal balloon manometry [Pl(es)] with and without spontaneous effort. Local dependent lung stress was estimated as the swing (inspiratory change) in transpulmonary pressure measured by intrapleural manometry in dependent lung and was compared with the swing in Pl(es). Electrical impedance tomography was performed to evaluate the inflation pattern in a larger animal (pig) and in a patient with acute respiratory distress syndrome. Spontaneous breathing in injured lungs increased Pl(es) during pressure-controlled (but not volume-controlled) ventilation, but the pattern of dependent lung inflation was the same in both modes. In volume-controlled ventilation, spontaneous effort caused greater inflation and tidal recruitment of dorsal regions (greater than twofold) compared with during muscle paralysis, despite the same Vt and Pl(es). This was caused by higher local dependent lung stress (measured by intrapleural manometry). In injured lungs, esophageal manometry underestimated local dependent pleural pressure changes during spontaneous effort. Limitation of Vt and Pl(es) by volume-controlled ventilation could not eliminate harm caused by spontaneous breathing unless the level of spontaneous effort was lowered and local dependent lung stress was reduced.

REGULATION OF CYTOKINE PRODUCTION IN HUMAN ALVEOLAR MACHROPHAGES AND AIRWAY EPITHELIAL CELLS IN RESPONSE TO AMBIENT AIR POLLUTION PARTICLES: FURTHER MECHANISTIC STUDIES

EPA Science Inventory

In order to better understand how ambient air particulate matter (PM) affect lung health, the two main airway cell types likely to interact with inhaled particles, alveolar macrophages (AM) and airway epithelial cells have been exposed to particles in vitro and followed for endp...

Components of Diesel Exhaust Particles Diversely Enhance a Variety of Respiratory Diseases Related to Infection or Allergy: Extracted Organic Chemicals and the Residual Particles after Extraction Differently Affect Respiratory Diseases

PubMed Central

Takano, Hirohisa; Yanagisawa, Rie; Inoue, Ken-ichiro

2007-01-01

Experimental and epidemiological studies have reported that diesel exhaust particles (DEP) can aggravate a variety of respiratory diseases including infection or allergy. However, the responsible components in DEP for the enhancement have not been identified. The present review demonstrates the different effects of the components of DEP on the respiratory diseases related to infection or allergy. We exposed mice to the organic chemicals (DEP-OC) and the residual carbonaceous nuclei (washed DEP) derived from DEP in the presence or absence of bacterial endotoxin (lipopolysaccharide: LPS) or allergen. In our first series of experiments, washed DEP combined with LPS synergistically exacerbated lung injury, which was concomitant with the enhanced lung expression of proinflammatory cytokines and chemokines, whereas DEP-OC combined with LPS did not. In contrast, our second series of experiments showed that DEP-OC, rather than washed DEP, enhanced allergen-related eosinophilic inflammation and proliferation of goblet cells in the airway epithelium, which was paralleled by the enhanced lung expression of eotaxin and interleukin-5. However, washed DEP with ovalbmin showed less change and increased the lung expression of interferon-γ. It is suggested that DEP components diversely affect various types of respiratory diseases, while the combination of organic chemicals and carbonaceous nuclei (whole DEP) mostly aggravate respiratory diseases. PMID:18188411

Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

PubMed Central

Saber, Anne T; Jacobsen, Nicklas R; Bornholdt, Jette; Kjær, Sanna L; Dybdahl, Marianne; Risom, Lotte; Loft, Steffen; Vogel, Ulla; Wallin, Håkan

2006-01-01

Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF) has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs). Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6) and the chemokines, monocyte chemoattractant protein (Mcp-1), macrophage inflammatory protein-2 (Mip-2) and keratinocyte derived chemokine (Kc) in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1. PMID:16504008

Lung injury after cigarette smoking is particle-related

EPA Science Inventory

That specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking have yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure and retention of particles...

Susceptibility of Cytokine-treated Lung Epithelial Cells to Particles:Influence of Organic Carbon Particle Content.

EPA Science Inventory

Exposure of individuals with airways inflammatory disease (asthma, chronic bronchitis, COPD) to near-road air pollution correlates epidemiologically with deleterious health outcome. Associated pulmonary toxicity purportedly involves generation of reactive oxygen species (ROS) and...

Increased Expression of FoxM1 Transcription Factor in Respiratory Epithelium Inhibits Lung Sacculation and Causes Clara Cell Hyperplasia

PubMed Central

Wang, I-Ching; Zhang, Yufang; Snyder, Jonathan; Sutherland, Mardi J.; Burhans, Michael S.; Shannon, John M.; Park, Hyun Jung; Whitsett, Jeffrey A.; Kalinichenko, Vladimir V.

2010-01-01

Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer. PMID:20816795

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene.

PubMed

Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

2014-05-12

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

NASA Astrophysics Data System (ADS)

Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

2014-05-01

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

PubMed Central

MINAMI, Kosuke; OKAMOTO, Koji; DOI, Kent; HARANO, Koji; NOIRI, Eisei; NAKAMURA, Eiichi

2014-01-01

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications. PMID:24814863

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

PubMed Central

Naikawadi, Ram P.; Disayabutr, Supparerk; Mallavia, Benat; Donne, Matthew L.; Green, Gary; La, Janet L.; Rock, Jason R.; Looney, Mark R.; Wolters, Paul J.

2016-01-01

Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1fl/fl mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction. PMID:27699234

Post-mortem CT: Hounsfield unit profiles obtained in the lungs with respect to the cause of death assessment.

PubMed

Schober, Daniel; Schwendener, Nicole; Zech, Wolf-Dieter; Jackowski, Christian

2017-01-01

Segmentation of the lungs using post-mortem computed tomography (PMCT) data was so far not feasible due to post-mortem changes such as internal livores. Recently, an Osirix plug-in has been developed allowing automatically segmenting lungs also in PMCT data. The aim of this study was to investigate if the Hounsfield unit (HU) profiles obtained in PMCT data of the segmented lung tissue present with specific behaviour in relation to the cause of death. In 105 PMCT data sets of forensic cases, the entire lung volumes were segmented using the Mia Lite plug-in on Osirix. HU profiles of the lungs were generated and correlated to cause of death groups as assessed after forensic autopsy (cardiac death, fatal haemorrhage, craniocerebral injury, intoxication, drowning, hypothermia, hanging and suffocation). Especially cardiac death cases, intoxication cases, fatal haemorrhage cases and hypothermia cases showed very specific HU profiles. In drowning, the profiles showed two different behaviours representing wet and dry drowning. HU profiles rather varied in craniocerebral injury cases, hanging cases as well as in suffocation cases. HU profiles of the lungs segmented from PMCT data may support the cause of death diagnosis as they represent specific morphological changes in the lungs such as oedema, congestion or blood loss. Especially in cardiac death, intoxication, fatal haemorrhage, hypothermia and drowning cases, HU profiles may be very supportive for the forensic pathologist.

A brief review of chronic obstructive pulmonary disease.

PubMed

Hogg, James C

2012-01-01

A recent study, based on a combination of multidetector computed tomography scanning of an intact specimen with microcomputed tomography and histological analysis of lung tissue samples, reported that the number of terminal bronchioles were reduced from approximately 44,500/lung pair in control (donor) lungs to approximately 4800/lung pair in lungs donated by individuals with very severe (Global initiative for chronic Obstructive Lung Disease stage 4) chronic obstructive pulmonary disease (COPD) treated by lung transplantation. The present short review discusses the hypothesis that a rapid rate of terminal bronchiolar destruction causes the rapid decline in lung function leading to advanced COPD. With respect to why the terminal bronchioles are targeted for destruction, the postulated mechanisms of this destruction and the possibility that new treatments are able to either prevent or reverse the underlying cause of airway obstruction in COPD are addressed.

A Comparative Study of Rat Lung Decellularization by Chemical Detergents for Lung Tissue Engineering

PubMed Central

Tebyanian, Hamid; Karami, Ali; Motavallian, Ebrahim; Aslani, Jafar; Samadikuchaksaraei, Ali; Arjmand, Babak; Nourani, Mohammad Reza

2017-01-01

BACKGROUND: Lung disease is the most common cause of death in the world. The last stage of pulmonary diseases is lung transplantation. Limitation and shortage of donor organs cause to appear tissue engineering field. Decellularization is a hope for producing intact ECM in the development of engineered organs. AIM: The goal of the decellularization process is to remove cellular and nuclear material while retaining lung three-dimensional and molecular proteins. Different concentration of detergents was used for finding the best approach in lung decellularization. MATERIAL AND METHODS: In this study, three-time approaches (24, 48 and 96 h) with four detergents (CHAPS, SDS, SDC and Triton X-100) were used for decellularizing rat lungs for maintaining of three-dimensional lung architecture and ECM protein composition which have significant roles in differentiation and migration of stem cells. This comparative study determined that variable decellularization approaches can cause significantly different effects on decellularized lungs. RESULTS: Results showed that destruction was increased with increasing the detergent concentration. Single detergent showed a significant reduction in maintaining of three-dimensional of lung and ECM proteins (Collagen and Elastin). But, the best methods were mixed detergents of SDC and CHAPS in low concentration in 48 and 96 h decellularization. CONCLUSION: Decellularized lung tissue can be used in the laboratory to study various aspects of pulmonary biology and physiology and also, these results can be used in the continued improvement of engineered lung tissue. PMID:29362610

Second Hand Smoke Exposure and Excess Heart Disease and Lung Cancer Mortality among Hospital Staff in Crete, Greece: A Case Study

PubMed Central

Vardavas, Constantine I.; Mpouloukaki, Izolde; Linardakis, Manolis; Ntzilepi, Penelope; Tzanakis, Nikos; Kafatos, Anthony

2008-01-01

Exposure to secondhand smoke (SHS) is a serious threat to public health, and a significant cause of lung cancer and heart disease among non-smokers. Even though Greek hospitals have been declared smoke free since 2002, smoking is still evident. Keeping the above into account, the aim of this study was to quantify the levels of exposure to environmental tobacco smoke and to estimate the attributed lifetime excess heart disease and lung cancer deaths per 1000 of the hospital staff, in a large Greek public hospital. Environmental airborne respirable suspended particles (RSP) of PM2.5 were performed and the personnpel’s excess mortality risk was estimated using risk prediction formulas. Excluding the intensive care unit and the operating theatres, all wards and clinics were polluted with environmental tobacco smoke. Mean SHS-RSP measurements ranged from 11 to 1461 μg/m3 depending on the area. Open wards averaged 84 μg/m3 and the managing wards averaged 164 μg/m3 thus giving an excess lung cancer and heart disease of 1.12 (range 0.23–1.88) and 11.2 (range 2.3–18.8) personnel in wards and 2.35 (range 0.55–12.2) and 23.5 (range 5.5–122) of the managing staff per 1000 over a 40-year lifespan, respectively. Conclusively, SHS exposure in hospitals in Greece is prevalent and taking into account the excess heart disease and lung cancer mortality risk as also the immediate adverse health effects of SHS exposure, it is clear that proper implementation and enforcement of the legislation that bans smoking in hospitals is imperative to protect the health of patients and staff alike. PMID:19139529

Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung.

PubMed

Jiang, Wen; Wang, Xiang; Osborne, Olivia J; Du, Yingjie; Chang, Chong Hyun; Liao, Yu-Pei; Sun, Bingbing; Jiang, Jinhong; Ji, Zhaoxia; Li, Ruibin; Liu, Xiangsheng; Lu, Jianqin; Lin, Sijie; Meng, Huan; Xia, Tian; Nel, André E

2017-02-28

We have recently shown that the toxicological potential of GaAs and InAs particulates in cells is size- and dissolution-dependent, tending to be more pronounced for nano- vs micron-sized particles. Whether the size-dependent dissolution and shedding of ionic III-V materials also apply to pulmonary exposure is unclear. While it has been demonstrated that micron-sized III-V particles, such as GaAs and InAs, are capable of inducing hazardous pulmonary effects in an occupational setting as well as in animal studies, the effect of submicron particles (e.g., the removal of asperities during processing of semiconductor wafers) is unclear. We used cytokine profiling to compare the pro-inflammatory effects of micron- and nanoscale GaAs and InAs particulates in cells as well as the murine lung 40 h and 21 days after oropharyngeal aspiration. Use of cytokine array technology in macrophage and epithelial cell cultures demonstrated a proportionally higher increase in the levels of matrix metalloproteinase inducer (EMMPRIN), macrophage migration inhibitory factor (MIF), and interleukin 1β (IL-1β) by nanosized (n) GaAs and n-InAs as well as As(III). n-GaAs and n-InAs also triggered higher neutrophil counts in the bronchoalveolar lavage fluid (BALF) of mice than micronscale particles 40 h post-aspiration, along with increased production of EMMPRIN and MIF. In contrast, in animals sacrificed 21 days after exposure, only n-InAs induced fibrotic lung changes as determined by increased lung collagen as well as increased levels of TGF-β1 and PDGF-AA in the BALF. A similar trend was seen for EMMPRIN and matrix metallopeptidase (MMP-9) levels in the BALF. Nano- and micron-GaAs had negligible subacute effects. Importantly, the difference between the 40 h and 21 days data appears to be biopersistence of n-InAs, as demonstrated by ICP-OES analysis of lung tissue. Interestingly, an ionic form of In, InCl 3 , also showed pro-fibrogenic effects due to the formation of insoluble In(OH) 3 nanostructures. All considered, these data indicate that while nanoscale particles exhibit increased pro-inflammatory effects in the lung, most effects are transient, except for n-InAs and insoluble InCl 3 species that are biopersistent and trigger pro-fibrotic effects. These results are of potential importance for the understanding the occupational health effects of III-V particulates.

Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung

PubMed Central

Jiang, Wen; Wang, Xiang; Osborne, Olivia J.; Du, Yingjie; Chang, Chong Hyun; Liao, Yu-Pei; Sun, Bingbing; Jiang, Jinhong; Ji, Zhaoxia; Li, Ruibin; liu, Xiangsheng; Lu, Jianqin; Lin, Sijie; Meng, Huan; Xia, Tian; Nel, André E.

2017-01-01

We have recently shown that the toxicological potential of GaAs and InAs particulates in cells is size- and dissolution-dependent, tending to be more pronounced for nano- vs. micron-sized particles. Whether the size-dependent dissolution and shedding of ionic III-V materials also apply to pulmonary exposure is unclear. While has been demonstrated that micron-sized III-V particles, such as GaAs and InAs, are capable of inducing hazardous pulmonary effects in an occupational setting, as well as in animal studies, the effect of sub-micron particles (e.g., the removal of asperities during processing of semiconductor wafers) is unclear. We used cytokine profiling to compare the pro-inflammatory effects of micron- and nanoscale GaAs and InAs particulates in cells as well as the murine lung 40 h and 21 days after oropharyngeal aspiration. Use of cytokine array technology in macrophage and epithelial cell cultures demonstrated a proportionally higher increase in the levels of extracellular matrix metalloproteinase inducer (EMMPRIN), macrophage migration inhibitory factor (MIF), and interleukin 1β (IL-1β) by nano-sized (n) GaAs and n-InAs as well as As(III). n-GaAs and n-InAs also triggered higher neutrophil counts in the bronchoalveolar lavage fluid (BALF) of mice than micronscale particles 40 h post-aspiration, along with increased production of EMMPRIN and MIF. In contrast, in animals sacrificed 21 days after exposure, only n-InAs induced fibrotic lung changes as determined by increased lung collagen as well as increased levels of TGF-β1 and PDGF-AA in the BALF. A similar trend was seen for EMMPRIN and matrix metallopeptidase (MMP-9) levels in the BALF. Nano- and micron-GaAs had negligible sub-acute effects. Importantly, the difference between the 40 h and 21 days data appears to be biopersistence of n-InAs, as demonstrated by ICP-OES analysis of lung tissue. Interestingly, an ionic form of In, InCl3, also showed pro-fibrogenic effects due to the formation of insoluble In(OH)3 nanostructures. All considered, these data indicate that while nanoscale particles exhibit increased pro-inflammatory effects in the lung, most effects are transient, except for n-InAs and insoluble InCl3 species that are biopersistent and trigger pro-fibrotic effects. These results are of potential importance for the understanding the occupational health effects of III-V particulates. PMID:28177603

[Evaluation of Cellular Effects Caused by Lunar Regolith Simulant Including Fine Particles].

PubMed

Horie, Masanori; Miki, Takeo; Honma, Yoshiyuki; Aoki, Shigeru; Morimoto, Yasuo

2015-06-01

The National Aeronautics and Space Administration has announced a plan to establish a manned colony on the surface of the moon, and our country, Japan, has declared its participation. The surface of the moon is covered with soil called lunar regolith, which includes fine particles. It is possible that humans will inhale lunar regolith if it is brought into the spaceship. Therefore, an evaluation of the pulmonary effects caused by lunar regolith is important for exploration of the moon. In the present study, we examine the cellular effects of lunar regolith simulant, whose components are similar to those of lunar regolith. We focused on the chemical component and particle size in particular. The regolith simulant was fractionated to < 10 μm, < 25 μm and 10-25 μm by gravitational sedimentation in suspensions. We also examined the cellular effects of fine regolith simulant whose primary particle size is 5.10 μm. These regolith simulants were applied to human lung carcinoma A549 cells at concentrations of 0.1 and 1.0 mg/ml. Cytotoxicity, oxidative stress and immune response were examined after 24 h exposure. Cell membrane damage, mitochondrial dysfunction and induction of Interleukin-8 (IL-8) were observed at the concentration of 1.0 mg/ml. The cellular effects of the regolith simulant at the concentration of 0.1 mg/ml were small, as compared with crystalline silica as a positive control. Secretion of IL-1β and tumor necrosis factor-α (TNF-α) was observed at the concentration of 1.0 mg/ml, but induction of gene expression was not observed at 24 h after exposure. Induction of cellular oxidative stress was small. Although the cellular effects tended to be stronger in the < 10 μm particles, there was no remarkable difference. These results suggest that the chemical components and particle size have little relationship to the cellular effects of lunar regolith simulant such as cell membrane damage, induction of oxidative stress and proinflammatory effect.

Derivation of occupational exposure levels (OELs) of low-toxicity isometric biopersistent particles: How can the kinetic lung overload paradigm be used for improved inhalation toxicity study design and OEL-derivation?

PubMed

Pauluhn, Jürgen

2014-12-20

Convincing evidence suggests that poorly soluble low-toxicity particles (PSP) exert two unifying major modes of action (MoA), in which one appears to be deposition-related acute, whilst the other is retention-related and occurs with particle accumulation in the lung and associated persistent inflammation. Either MoA has its study- and cumulative dose-specific adverse outcome and metric. Modeling procedures were applied to better understand as to which extent protocol variables may predetermine any specific outcome of study. The results from modeled and empirical studies served as basis to derive OELs from modeled and empirically confirmed directions. This analysis demonstrates that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study design may not always be appropriate to unequivocally discriminate the surface thermodynamics-related acute adversity from the cumulative retention volume-related chronic adversity. Thus, in the absence of kinetically designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. It is concluded that the degree of dissolution of particles in the pulmonary environment seems to be generally underestimated with the possibility to attribute to toxicity due to decreased particle size and associated changes in thermodynamics and kinetics of dissolution. Accordingly, acute deposition-related outcomes become an important secondary variable within the pulmonary microenvironment. In turn, lung-overload related chronic adversities seem to be better described by the particle volume metric. This analysis supports the concept that 'self-validating', hypothesis-based computational study design delivers the highest level of unifying information required for the risk characterization of PSP. In demonstrating that the PSP under consideration is truly following the generic PSP-paradigm, this higher level of mechanistic information reduces the potential uncertainty involved with OEL derivation.

Determinants of aerosol lung-deposited surface area variation in an urban environment.

PubMed

Reche, Cristina; Viana, Mar; Brines, Mariola; Pérez, Noemí; Beddows, David; Alastuey, Andrés; Querol, Xavier

2015-06-01

Ultrafine particles are characterized by a high surface area per mass. Particle surface has been reported to play a significant role in determining the toxicological activity of ultrafine particles. In light of this potential role, the time variation of lung deposited surface area (LDSA) concentrations in the alveolar region was studied at the urban background environment of Barcelona (Spain), aiming to asses which processes and sources govern this parameter. Simultaneous data on Black Carbon (BC), total particle number (N) and particle number size distribution were correlated with LDSA. Average LDSA concentrations in Barcelona were 37 ± 26 μm(2)cm(-3), levels which seem to be characteristic for urban environments under traffic influence across Europe. Results confirm the comparability between LDSA data provided by the online monitor and those calculated based on particle size distributions (by SMPS), and reveal that LDSA concentrations are mainly influenced by particles in the size range 50-200 nm. A set of representative daily cycles for LDSA concentrations was obtained by means of a k-means cluster technique. The contribution of traffic emissions to daily patterns was evidenced in all the clusters, but was quantitatively different. Traffic events under stable atmospheric conditions increased mean hourly background LDSA concentrations up to 6 times, attaining levels higher than 200 μm(2)cm(-3). However, under warm and relatively clean atmospheric conditions, the traffic rush hour contribution to the daily LDSA mean appeared to be lower and the contribution of new urban particle formation events (by photochemically induced nucleation) was detected. These nucleation events were calculated to increase average background LDSA concentrations by 15-35% (maximum LDSA levels=45-50 μm(2)cm(-3)). Thereby, it may be concluded that in the urban background of Barcelona road traffic is the main source increasing the aerosol surface area which can deposit on critical regions of the human lung, followed by nucleation episodes. Copyright © 2015 Elsevier B.V. All rights reserved.

The oncogenic transforming potential of the passage of single α particles through mammalian cell nuclei

PubMed Central

Miller, Richard C.; Randers-Pehrson, Gerhard; Geard, Charles R.; Hall, Eric J.; Brenner, David J.

1999-01-01

Domestic, low-level exposure to radon gas is considered a major environmental lung-cancer hazard involving DNA damage to bronchial cells by α particles from radon progeny. At domestic exposure levels, the relevant bronchial cells are very rarely traversed by more than one α particle, whereas at higher radon levels—at which epidemiological studies in uranium miners allow lung-cancer risks to be quantified with reasonable precision—these bronchial cells are frequently exposed to multiple α-particle traversals. Measuring the oncogenic transforming effects of exactly one α particle without the confounding effects of multiple traversals has hitherto been unfeasible, resulting in uncertainty in extrapolations of risk from high to domestic radon levels. A technique to assess the effects of single α particles uses a charged-particle microbeam, which irradiates individual cells or cell nuclei with predefined exact numbers of particles. Although previously too slow to assess the relevant small oncogenic risks, recent improvements in throughput now permit microbeam irradiation of large cell numbers, allowing the first oncogenic risk measurements for the traversal of exactly one α particle through a cell nucleus. Given positive controls to ensure that the dosimetry and biological controls were comparable, the measured oncogenicity from exactly one α particle was significantly lower than for a Poisson-distributed mean of one α particle, implying that cells traversed by multiple α particles contribute most of the risk. If this result applies generally, extrapolation from high-level radon risks (involving cellular traversal by multiple α particles) may overestimate low-level (involving only single α particles) radon risks. PMID:9874764

Causes of death in long-term lung cancer survivors: a SEER database analysis.

PubMed

Abdel-Rahman, Omar

2017-07-01

Long-term (>5 years) lung cancer survivors represent a small but distinct subgroup of lung cancer patients and information about the causes of death of this subgroup is scarce. The Surveillance, Epidemiology and End Results (SEER) database (1988-2008) was utilized to determine the causes of death of long-term survivors of lung cancer. Survival analysis was conducted using Kaplan-Meier analysis and multivariate analysis was conducted using a Cox proportional hazard model. Clinicopathological characteristics and survival outcomes were assessed for the whole cohort. A total of 78,701 lung cancer patients with >5 years survival were identified. This cohort included 54,488 patients surviving 5-10 years and 24,213 patients surviving >10 years. Among patients surviving 5-10 years, 21.8% were dead because of primary lung cancer, 10.2% were dead because of other cancers, 6.8% were dead because of cardiac disease and 5.3% were dead because of non-malignant pulmonary disease. Among patients surviving >10 years, 12% were dead because of primary lung cancer, 6% were dead because of other cancers, 6.9% were dead because of cardiac disease and 5.6% were dead because of non-malignant pulmonary disease. On multivariate analysis, factors associated with longer cardiac-disease-specific survival in multivariate analysis include younger age at diagnosis (p < .0001), white race (vs. African American race) (p = .005), female gender (p < .0001), right-sided disease (p = .003), adenocarcinoma (vs. large cell or small cell carcinoma), histology and receiving local treatment by surgery rather than radiotherapy (p < .0001). The probability of death from primary lung cancer is still significant among other causes of death even 20 years after diagnosis of lung cancer. Moreover, cardiac as well as non-malignant pulmonary causes contribute a considerable proportion of deaths in long-term lung cancer survivors.

Primary lung abscess caused by Staphylococcus lugdunensis.

PubMed

Chou, Deng-Wei; Lee, Chao-Tai

2017-11-01

Staphylococcus lugdunensis, a strain of coagulase-negative staphylococci, is part of the normal flora of human skin but can cause multiple infections at various sites. This microorganism has emerged as a major human pathogen. However, no study has reported primary lung abscess caused by S. lugdunensis. A 54-year-old alcoholic man without relevant past medical history was admitted because of primary lung abscesses. Empirical amoxicillin/clavulanate therapy was initially administered; however, the patient had persistent pleuritic chest pain and fever. He subsequently underwent resection of the lung abscess and removal of exudative pleural effusion on the fourth hospital day. Histopathologic examination confirmed the diagnosis of lung abscess, and colonies of gram-positive bacteria were identified. The culture specimen from the abscess was positive for S. lugdunensis, which was susceptible to amoxicillin/clavulanate, cefazolin, ciprofloxacin, clindamycin, erythromycin, oxacillin, teicoplanin, tetracycline, and vancomycin. Following resection and 3 weeks of amoxicillin/clavulanate therapy, the patient eventually recovered well without relapse. This case report is the first to describe S. lugdunensis as a cause of primary lung abscess; this microorganism should be considered a potential monomicrobial pathogen in primary lung abscess. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Lung cancer mortality and airways obstruction among metal miners exposed to silica and low levels of radon daughters.

PubMed

Carta, P; Cocco, P; Picchiri, G

1994-04-01

Starting from a cross-sectional survey in 1973, the mortality of two cohorts of Sardinian metal miners was followed through December 31, 1988. In mine A, the quartz concentration in respirable dust ranged between 0.2% and 2.0% and the exposure to radon daughters averaged 0.13 working level (WL), with the highest estimated cumulative exposure around 80-120 WLM. In mine B, the silica content was much higher (6.5-29%), but exposure to radon daughters was significantly lower than in mine A. More than 98% of the overall work force in 1973 (1,741 miners) entered the cohort, providing 25,842.5 person-years. Smoking, occupational history, chest radiographs, and lung function tests were available for the cohort members at admission. Mortality for all causes was slightly lower than expected. A significant excess for nonmalignant chronic respiratory diseases was noticed in both mines. Twenty-four subjects died of lung cancer, 17 from mine A (SMR: 128; 95% confidence interval [CI]: 75-205) and 7 from mine B (SMR: 85; 95% CI: 34-175). The SMR for lung cancer was highest among the underground workers from mine A (SMR: 148; 95% CI: 74-265), with a significant upward trend by duration of employment in underground jobs. Mine B underground miners showed lung cancer SMRs close to 100 without a significant trend by duration of employment. Among underground miners with spirometric airways obstruction in 1973, those from mine A showed the highest risk (SMR: 316; 95% CI: 116-687). The relationship did not change after adjusting for age and smoking. Based on the present findings, crystalline silica per se does not appear to affect lung cancer mortality. A slight association between lung cancer mortality and exposure to radon daughters, though within relatively low levels, may be considered for underground miners from mine A. Impaired pulmonary function may be an independent predictor of lung cancer and an important risk factor enhancing the residence time of inhaled carcinogens, i.e., alpha particles or PAHs, by impairing their bronchial and alveolar clearance.

Lung Cancer in Chinese Women: Evidence for an Interaction between Tobacco Smoking and Exposure to Inhalants in the Indoor Environment

PubMed Central

Tang, Li; Lim, Wei-Yen; Eng, Philip; Leong, Swan Swan; Lim, Tow Keang; Ng, Alan W.K.; Tee, Augustine; Seow, Adeline

2010-01-01

Background Epidemiologic data suggest that Chinese women have a high incidence of lung cancer in relation to their smoking prevalence. In addition to active tobacco smoke exposure, other sources of fumes and airborne particles in the indoor environment, such as cooking and burning of incense and mosquito coils, have been considered potential risk factors for lung cancer. Objectives We used a case–control study to explore effects of inhalants from combustion sources common in the domestic environment on lung cancer and their modification by active tobacco smoking. Methods We analyzed 703 primary lung cancer cases and 1,578 controls. Data on demographic background and relevant exposures were obtained by face-to-face interviews in the hospital. Results We observed a positive relationship with daily exposure to incense or mosquito coils and to cooking fumes only among smokers, and no association among lifetime nonsmokers. Interactions between smoking and frequency of cooking, or exposure to incense or mosquito coils were statistically significant and consistent with synergistic effects on lung cancer. The odds ratio (OR) comparing smokers without daily incense or mosquito coil exposure with nonsmokers without daily exposure was 2.80 [95% confidence interval (CI), 1.86–4.21], whereas the OR comparing smokers with daily exposure to the same referent group was 4.61 (95% CI, 3.41–6.24). In contrast, daily exposure to incense or mosquito coils was not associated with lung cancer among nonsmokers (OR = 0.91; 95% CI, 0.72–1.16). We observed the same pattern of associations for smokers without (OR = 2.31; 95% CI, 1.52–3.51) and with (OR = 4.50; 95% CI, 3.21–6.30) daily cooking exposure compared with nonsmokers, with no evidence of an association with daily cooking exposure among nonsmokers. Conclusion Our results suggest that active tobacco smoking not only is an important risk factor for development of lung cancer, but also may cause smokers to be more susceptible to the risk-enhancing effects of other inhalants. PMID:20472525

Effects of exposure to ambient ultrafine particles on respiratory health and systemic inflammation in children.

PubMed

Clifford, Sam; Mazaheri, Mandana; Salimi, Farhad; Ezz, Wafaa Nabil; Yeganeh, Bijan; Low-Choy, Samantha; Walker, Katy; Mengersen, Kerrie; Marks, Guy B; Morawska, Lidia

2018-05-01

It is known that ultrafine particles (UFP, particles smaller than 0.1 μm) can penetrate deep into the lungs and potentially have adverse health effects. However, epidemiological data on the health effects of UFP is limited. Therefore, our objective was to test the hypothesis that exposure to UFPs is associated with respiratory health status and systemic inflammation among children aged 8 to 11 years. We conducted a cross-sectional study among 655 children (43.3% male) attending 25 primary (elementary) schools in the Brisbane Metropolitan Area, Australia. Ultrafine particle number concentration (PNC) was measured at each school and modelled at homes using Land Use Regression to derive exposure estimates. Health outcomes were respiratory symptoms and diagnoses, measured by parent-completed questionnaire, spirometric lung function, exhaled nitric oxide (FeNO), and serum C reactive protein (CRP). Exposure-response models, adjusted for potential personal and environmental confounders measured at the individual, home and school level, were fitted using Bayesian methods. PNC was not independently associated with respiratory symptoms, asthma diagnosis or spirometric lung function. However, PNC was positively associated with an increase in CRP (1.188-fold change per 1000 UFP cm -3 day/day (95% credible interval 1.077 to 1.299)) and an increase in FeNO among atopic participants (1.054 fold change per 1000 UFP cm -3 day/day (95% CrI 1.005 to 1.106)). UFPs do not affect respiratory health outcomes in children but do have systemic effects, detected here in the form of a positive association with a biomarker for systemic inflammation. This is consistent with the known propensity of UFPs to penetrate deep into the lung and circulatory system. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cardiogenic mixing increases aerosol deposition in the human lung in the absence of gravity.

PubMed

Prisk, G Kim; Sá, Rui Carlos; Darquenne, Chantal

2013-11-01

Exposure to extraterrestrial dusts is an almost inevitable consequence of any proposed planetary exploration. Previous studies in humans showed reduced deposition in low-gravity compared with normal gravity (1G). However, the reduced sedimentation means that fewer particles deposit in the airways, increasing the number of particles transported to the lung periphery where they eventually deposit albeit at a smaller rate than in 1G. In this study, we determined the role that gravity and other mechanisms such as cardiogenic mixing play in peripheral lung deposition during breath holds. Eight healthy subjects inhaled boluses of 0.5 μm-diameter particles to penetration volumes (V p ) of 300 and 1200ml that were followed by breath holds of up to 10 sec. Tests were performed in 1G and during short periods of microgravity (μG) aboard the NASA Microgravity Research Aircraft. Aerosol deposition and dispersion were calculated from these data. Results show that, for both V p , deposition in 1G was significantly higher than in μG. In contrast, while dispersion was significantly higher in 1G compared to μG at V p =1200ml, there was no significant gravitational effect on dispersion at V p =300ml. Finally, for each G level and V p , deposition and dispersion significantly increased with increasing breath-hold time. The most important finding of this study is that, even in the absence of gravity, aerosol deposition in the lung periphery increased with increasing residence time. Because the particles used in this study were too large to be significantly affected by Brownian diffusion, the increase in deposition is likely due to cardiogenic motion effects.

RADON PROGENY AS AN EXPERIMENTAL TOOL FOR DOSIMETRY OF NANOAEROSOLS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruzer, Lev; Ruzer, Lev S.; Apte, Michael G.

2008-02-25

The study of aerosol exposure and dosimetry measurements and related quantitation of health effects are important to the understanding of the consequences of air pollution, and are discussed widely in the scientific literature. During the last 10 years the need to correlate aerosol exposure and biological effects has become especially important due to rapid development of a new, revolutionary industry ?-- nanotechnology. Nanoproduct commerce is predicted to top $1 trillion by 2015. Quantitative assessment of aerosol particle behavior in air and in lung deposition, and dosimetry in different parts of the lung, particularly for nanoaerosols, remains poor despite several decadesmore » of study. Direct measurements on humans are still needed in order to validate the hollow cast, animal studies, and lung deposition modeling. We discuss here the use of nanoscale radon decay products as an experimental tool in the study of local deposition and lung dosimetry for nanoaerosols. The issue of the safe use of radon progeny in such measurements is discussed based on a comparison of measured exposure in 3 settings: general population, miners, and in a human experiment conducted at the Paul Scherer Institute (PSI) in Switzerland. One of the properties of radon progeny is that they consist partly of 1 nm radioactive particles called unattached activity; having extremely small size and high diffusion coefficients, these particles can be potentially useful as radioactive tracers in the study of nanometer-sized aerosols. We present a theoretical and experimental study of the correlation between the unattached activity and aerosol particle surface area, together with a description of its calibration and method for measurement of the unattached fraction.« less

Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

2015-07-24

While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

2014-08-26

While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

The rapid alveolar absorption of diesel soot-adsorbed benzo[a]pyrene: bioavailability, metabolism and dosimetry of an inhaled particle-borne carcinogen.

PubMed

Gerde, P; Muggenburg, B A; Lundborg, M; Dahl, A R

2001-05-01

Exposure to diesel exhaust may contribute to lung cancer in humans. It remains unclear whether the carbonaceous core of the soot particle or its coat of adsorbed/condensed organics contributes most to cancer risk. Equally unclear are the extent and rate at which organic procarcinogens desorb from soot particles in the lungs following inhalation exposure and the extent of their metabolic activation in the lungs. To explore the basic relationship between a model polycyclic aromatic hydrocarbon (PAH) and a typical carrier particle, we investigated the rate and extent of release and metabolic fate of benzo[a]pyrene (BaP) adsorbed on the carbonaceous core of diesel soot. The native organic content of the soot had been denuded by toluene extraction. Exogenous BaP was adsorbed onto the denuded soot as a surface coating corresponding to 25% of a monomolecular layer. Dogs were exposed by inhalation to an aerosol bolus of the soot-adsorbed BAP: Following deposition in the alveolar region a fraction of BaP was rapidly desorbed from the soot and quickly absorbed into the circulation. Release rates then decreased drastically. When coatings reached approximately 16% of a monolayer the remaining BaP was not bioavailable and was retained on the particles after 5.6 months in the lung. However, the bioavailability of particles transported to the lymph nodes was markedly higher; after 5.6 months the surface coating of BaP was reduced to 10%. BaP that remained adsorbed on the soot surface after this period was approximately 30% parent compound. In contrast, the rapidly released pulse of BaP, which was quickly absorbed through the alveolar epithelium after inhalation, appeared mostly unmetabolized in the circulation, along with low concentrations of phase I and phase II BaP metabolites. However, within approximately 1 h this rapidly absorbed fraction of BaP was systemically metabolized into mostly conjugated phase II metabolites. The results indicate that absorption through the alveolar epithelium is an important route of entry to the circulation of unmetabolized PAHS:

Inflammation-Related Effects of Diesel Engine Exhaust Particles: Studies on Lung Cells In Vitro

PubMed Central

Schwarze, P. E.; Totlandsdal, A. I.; Låg, M.; Refsnes, M.; Holme, J. A.; Øvrevik, J.

2013-01-01

Diesel exhaust and its particles (DEP) have been under scrutiny for health effects in humans. In the development of these effects inflammation is regarded as a key process. Overall, in vitro studies report similar DEP-induced changes in markers of inflammation, including cytokines and chemokines, as studies in vivo. In vitro studies suggest that soluble extracts of DEP have the greatest impact on the expression and release of proinflammatory markers. Main DEP mediators of effects have still not been identified and are difficult to find, as fuel and engine technology developments lead to continuously altered characteristics of emissions. Involved mechanisms remain somewhat unclear. DEP extracts appear to comprise components that are able to activate various membrane and cytosolic receptors. Through interactions with receptors, ion channels, and phosphorylation enzymes, molecules in the particle extract will trigger various cell signaling pathways that may lead to the release of inflammatory markers directly or indirectly by causing cell death. In vitro studies represent a fast and convenient system which may have implications for technology development. Furthermore, knowledge regarding how particles elicit their effects may contribute to understanding of DEP-induced health effects in vivo, with possible implications for identifying susceptible groups of people and effect biomarkers. PMID:23509760

6 Common Cancers - Lung Cancer

MedlinePlus

... Bar Home Current Issue Past Issues 6 Common Cancers - Lung Cancer Past Issues / Spring 2007 Table of Contents For ... Desperate Housewives. (Photo ©2005 Kathy Hutchins / Hutchins) Lung Cancer Lung cancer causes more deaths than the next ...

Role of epithelial-mesenchymal transition (EMT) and fibroblast function in cerium oxide nanoparticles-induced lung fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Jane

The emission of cerium oxide nanoparticles (CeO{sub 2}) from diesel engines, using cerium compounds as a catalyst to lower the diesel exhaust particles, is a health concern. We have previously shown that CeO{sub 2} induced pulmonary inflammation and lung fibrosis. The objective of the present study was to investigate the modification of fibroblast function and the role of epithelial-mesenchymal transition (EMT) in CeO{sub 2}-induced fibrosis. Male Sprague-Dawley rats were exposed to CeO{sub 2} (0.15 to 7 mg/kg) by a single intratracheal instillation and sacrificed at various times post-exposure. The results show that at 28 days after CeO{sub 2} (3.5 mg/kg)more » exposure, lung fibrosis was evidenced by increased soluble collagen in bronchoalveolar lavage fluid, elevated hydroxyproline content in lung tissues, and enhanced sirius red staining for collagen in the lung tissue. Lung fibroblasts and alveolar type II (ATII) cells isolated from CeO{sub 2}-exposed rats at 28 days post-exposure demonstrated decreasing proliferation rate when compare to the controls. CeO{sub 2} exposure was cytotoxic and altered cell function as demonstrated by fibroblast apoptosis and aggregation, and ATII cell hypertrophy and hyperplasia with increased surfactant. The presence of stress fibers, expressed as α-smooth muscle actin (SMA), in CeO{sub 2}-exposed fibroblasts and ATII cells was significantly increased compared to the control. Immunohistofluorescence analysis demonstrated co-localization of TGF-β or α-SMA with prosurfactant protein C (SPC)-stained ATII cells. These results demonstrate that CeO{sub 2} exposure affects fibroblast function and induces EMT in ATII cells that play a role in lung fibrosis. These findings suggest potential adverse health effects in response to CeO{sub 2} nanoparticle exposure. - Highlights: • CeO{sub 2} exposure induced lung fibrosis. • CeO{sub 2} were detected in lung tissue, alveolar type II (ATII) cells and fibroblasts. • CeO{sub 2} caused ATII cell hypertrophy and hyperplasia and altered fibroblast function. • Increased α-SMA in CeO{sub 2}-exposed lung fibroblasts indicating myofibroblast formation. • CeO{sub 2} induced EMT in ATII cells demonstrated as increased α-SMA expression.« less

Computational analysis of non-spherical particle transport and deposition in shear flow with application to lung aerosol dynamics--a review.

PubMed

Kleinstreuer, Clement; Feng, Yu

2013-02-01

All naturally occurring and most man-made solid particles are nonspherical. Examples include air-pollutants in the nano- to micro-meter range as well as blood constituents, drug particles, and industrial fluid-particle streams. Focusing on the modeling and simulation of inhaled aerosols, theories for both spherical and nonspherical particles are reviewed to analyze the contrasting transport and deposition phenomena of spheres and equivalent spheres versus ellipsoids and fibers.

DEVELOPMENT OF THE HUMAN LUNG MEASURED BY AEROSOL-DERIVED AIRWAY MORPHEMETRY (ADAM).

EPA Science Inventory

We measured, in vivo, the airspace calibers of the small airways and alveoli by ADAM in the lungs of children of ages 6 to 18 years and adults aged 18 to 80 years. ADAM utilizes the gravitational settling time of inhaled monodisperse particles to infer the vertical distance to th...

MATRILYSIN PARTICIPATES IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PRODUCTS

EPA Science Inventory

ROLE OF MATRILYSIN IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PARTICLES.

K L Dreher1, WY Su2 and C L Wilson3. 1US Environmental Protection Agency, Research Triangle Park, NC; 2Duke University, Durham, NC;3Washington University, St. Louis, MO.

Mechanisms by ...

Increased lung resistance after diesel particulate and ozone co-exposure not associated with enhanced lung inflammation in allergic mice*

EPA Science Inventory

Exposure to diesel exhaust particle matter (DEP) exacerbates asthma. Likewise, similar effects have been reported with exposure to the oxidizing air pollutant ozone (03) . Since levels of both pollutants in ambient air tend to be simultaneously elevated, we investigated the possi...

Empirical model for conveniently predicting total and regional lung deposition of inhaled aerosols

EPA Science Inventory

Accurate estimate of a dose of inhaled aerosols is a key factor for estimating potential health risks to exposure to ambient pollutant particulate matter on the one hand, and the therapeutic efficacy of inhaled drug aerosols on the other hand. Particle deposition in the lung is d...

First in vivo magnetic particle imaging of lung perfusion in rats

NASA Astrophysics Data System (ADS)

Zhou, Xinyi Y.; Jeffris, Kenneth E.; Yu, Elaine Y.; Zheng, Bo; Goodwill, Patrick W.; Nahid, Payam; Conolly, Steven M.

2017-05-01

Pulmonary embolism (PE), along with the closely related condition of deep vein thrombosis, affect an estimated 600 000 patients in the US per year. Untreated, PE carries a mortality rate of 30%. Because many patients experience mild or non-specific symptoms, imaging studies are necessary for definitive diagnosis of PE. Iodinated CT pulmonary angiography is recommended for most patients, while nuclear medicine-based ventilation/perfusion (V/Q) scans are reserved for patients in whom the use of iodine is contraindicated. Magnetic particle imaging (MPI) is an emerging tracer imaging modality with high image contrast (no tissue background signal) and sensitivity to superparamagnetic iron oxide (SPIO) tracer. Importantly, unlike CT or nuclear medicine, MPI uses no ionizing radiation. Further, MPI is not derived from magnetic resonance imaging (MRI); MPI directly images SPIO tracers via their strong electronic magnetization, enabling deep imaging of anatomy including within the lungs, which is very challenging with MRI. Here, the first high-contrast in vivo MPI lung perfusion images of rats are shown using a novel lung perfusion agent, MAA-SPIOs.

Women's knowledge of the leading causes of cancer death.

PubMed

Healton, Cheryl G; Gritz, Ellen R; Davis, Kevin C; Homsi, Ghada; McCausland, Kristen; Haviland, M Lyndon; Vallone, Donna

2007-07-01

This paper describes adult women's knowledge of the leading causes of cancer mortality among women. Exposure to antismoking advertisements or media messages also is examined as a potentially effective mechanism for changing inaccurate beliefs. We used data from the 2002 and 2003 American Smoking and Health Survey (ASHES), a national telephone survey of adults, to measure women's knowledge about cancer mortality. Logistic regression models were used to estimate the likelihoods of women indicating either breast or lung cancer as the leading cause of cancer mortality among women. The independent influence of individual characteristics such as race, smoking status, education, and awareness of antismoking messages or advertising on women's knowledge of cancer mortality was assessed. Overall, 66.7% of women inaccurately indicated breast cancer as the leading cause of cancer death among women, whereas 29.7% of women correctly indicated lung cancer. Black women were 43% less likely than White women to indicate lung cancer as the leading cause of cancer mortality among women. Current smokers were 35% less likely than noncurrent smokers to state that lung cancer is the leading cause of cancer mortality among women. Awareness of antismoking messages or advertisements was associated with a higher probability of correctly indicating lung cancer as the leading cause of cancer mortality among women. Our evidence suggests that antismoking media messages may help to correct inaccurate beliefs about the leading causes of cancer death among women.

[What is new in the epidemiology of lung cancer: non-smokers, women and the role of cannabis?].

PubMed

Quoix, Elisabeth

2009-09-20

Lung cancer is in France, like in other countries, the first cause of death by cancer in men. It has become the third one in women in a few years span. If smoking is the main cause of lung cancer, other causes have been quite neglected for years such as occupational risk mainly asbestos exposure. Lung cancer in non-smokers has increased during the last years. This may be a real increase or the consequence of ageing of the general population with increased incidence of lung cancer rather due to age than to tobacco. The considerable increase in women's incidence of lung cancer is partly due to the development of smoking habits since 1960 in France. The possibility of an increased suceptibility to tobacco smoke in women is biologically plausible but still very controversial. The role of cannabis smoke is also controversial since it is very difficult to isolate the effects of cannabis which is in the majority of cases smoked with tobacco. However, recent studies are in favor of an independent role of cannabis in the development of lung cancers.

In Vitro Toxicity of Silver Nanoparticles in Human Lung Epithelial Cells

DTIC Science & Technology

2009-03-01

software from the particle distributions measured and the polydispersity index (PdI) given is a measure of the size ranges present in the solution...Transmission Electron Microscopy Figure 22 shows the TEM primary particles size and distribution determined from measurement of over 100 particles from...nm uncoated. (B) Ag 80 nm uncoated. (C) Ag 10 nm coated. (D) Ag 80 nm coated Table 4 shows the TEM primary particles size and distribution

The Murine Lung Microbiome Changes During Lung Inflammation and Intranasal Vancomycin Treatment

PubMed Central

Barfod, Kenneth Klingenberg; Vrankx, Katleen; Mirsepasi-Lauridsen, Hengameh Chloé; Hansen, Jitka Stilund; Hougaard, Karin Sørig; Larsen, Søren Thor; Ouwenhand, Arthur C.; Krogfelt, Karen Angeliki

2015-01-01

Most microbiome research related to airway diseases has focused on the gut microbiome. This is despite advances in culture independent microbial identification techniques revealing that even healthy lungs possess a unique dynamic microbiome. This conceptual change raises the question; if lung diseases could be causally linked to local dysbiosis of the local lung microbiota. Here, we manipulate the murine lung and gut microbiome, in order to show that the lung microbiota can be changed experimentally. We have used four different approaches: lung inflammation by exposure to carbon nano-tube particles, oral probiotics and oral or intranasal exposure to the antibiotic vancomycin. Bacterial DNA was extracted from broncho-alveolar and nasal lavage fluids, caecum samples and compared by DGGE. Our results show that: the lung microbiota is sex dependent and not just a reflection of the gut microbiota, and that induced inflammation can change lung microbiota. This change is not transferred to offspring. Oral probiotics in adult mice do not change lung microbiome detectible by DGGE. Nasal vancomycin can change the lung microbiome preferentially, while oral exposure does not. These observations should be considered in future studies of the causal relationship between lung microbiota and lung diseases. PMID:26668669

OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

PubMed Central

SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

2014-01-01

Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

PubMed

Snapper, J R; Hutchison, A A; Ogletree, M L; Brigham, K L

1983-07-01

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

Transoral tracheal intubation of rodents using a fiberoptic laryngoscope.

PubMed

Costa, D L; Lehmann, J R; Harold, W M; Drew, R T

1986-06-01

A fiberoptic laryngoscope which allows direct visualization of the deep pharynx and epiglottis has been developed for transoral tracheal intubation of small laboratory mammals. The device has been employed in the intubation and instillation of a variety of substances into the lungs of rats, and with minor modification, has had similar application in mice, hamsters, and guinea pigs. The simplicity and ease of handling of the laryngoscope permits one person to intubate large numbers of enflurane anesthetized animals either on an open counter top or in a glove-box, as may be required for administration of carcinogenic materials. Instillation of 7Be-labeled carbon particles into the lungs of mice, hamsters, rats, and guinea pigs resulted in reasonably consistent interlobal distribution of particles for each test animal species with minimal tracheal deposition. However, actual lung tissue doses of carbon exhibited some species dependence.

Epithelia transmembrane transport of orally administered ultrafine drug particles evidenced by environment sensitive fluorophores in cellular and animal studies.

PubMed

Xie, Yike; Shi, Baokui; Xia, Fei; Qi, Jianping; Dong, Xiaochun; Zhao, Weili; Li, Tonglei; Wu, Wei; Lu, Yi

2018-01-28

Little is known about the in vivo fate of drug particles taken orally, in particular, the drug release kinetics and interaction with the gastrointestinal (GI) membrane. Lacking is analytical means that can reliably identify the integrity of drug particles under the complexity of biological environment. Herein, we explored fluorescent probes whose signals become quenched upon being released from drug carriers. Taking advantage of so-called the aggregation caused quenching (ACQ), particles may be identified by the integrated fluorophores, which are "turned off" when the particles become destructed and dyes are released. In the current study, ultrafine amorphous particles (UAPs) of cyclosporin A (CsA) were prepared with synthesized ACQ dyes physically entrapped. The fluorescence intensity of suspension of these UAPs was found correlated well with the dissolution of the particles. When given to rats orally, it was found that some of the administered UAPs could survive the animal's GI tracts for as long as 18h. Whole-body fluorescence imaging detected fluorescent signals in the liver and lungs. Particularly noticed in sections of jejunum and ileum, the detection suggested the possibility of direct absorption of UAPs through epithelial membranes. Moreover, 250nm particles were absorbed faster via transepithelia than larger ones (550nm), while the latter were preferably taken up by M cells in the follicle-associated epithelium (FAE) region of Peyer's patches. In vitro permeation studies with Caco-2 cells confirmed the transmembrane transport of the dye-integrated UAPs. Our study supports the idea of using ACQ fluorophores for imaging and characterizing the fate of intact particles in a biological environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice.

PubMed

Hansen, Jitka S; Nørgaard, Asger W; Koponen, Ismo K; Sørli, Jorid B; Paidi, Maya D; Hansen, Søren W K; Clausen, Per Axel; Nielsen, Gunnar D; Wolkoff, Peder; Larsen, Søren Thor

2016-11-01

Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone-limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone-limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy.

Arsenic, asbestos and radon: emerging players in lung tumorigenesis

PubMed Central

2012-01-01

The cause of lung cancer is generally attributed to tobacco smoking. However lung cancer in never smokers accounts for 10 to 25% of all lung cancer cases. Arsenic, asbestos and radon are three prominent non-tobacco carcinogens strongly associated with lung cancer. Exposure to these agents can lead to genetic and epigenetic alterations in tumor genomes, impacting genes and pathways involved in lung cancer development. Moreover, these agents not only exhibit unique mechanisms in causing genomic alterations, but also exert deleterious effects through common mechanisms, such as oxidative stress, commonly associated with carcinogenesis. This article provides a comprehensive review of arsenic, asbestos, and radon induced molecular mechanisms responsible for the generation of genetic and epigenetic alterations in lung cancer. A better understanding of the mode of action of these carcinogens will facilitate the prevention and management of lung cancer related to such environmental hazards. PMID:23173984

Deaths in Canada from lung cancer due to involuntary smoking.

PubMed Central

Wigle, D T; Collishaw, N E; Kirkbride, J; Mao, Y

1987-01-01

Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure. PMID:3567810

Persistence of deposited metals in the lungs after stainless steel and mild steel welding fume inhalation in rats.

PubMed

Antonini, James M; Roberts, Jenny R; Stone, Samuel; Chen, Bean T; Schwegler-Berry, Diane; Chapman, Rebecca; Zeidler-Erdely, Patti C; Andrews, Ronnee N; Frazer, David G

2011-05-01

Welding generates complex metal fumes that vary in composition. The objectives of this study were to compare the persistence of deposited metals and the inflammatory potential of stainless and mild steel welding fumes, the two most common fumes used in US industry. Sprague-Dawley rats were exposed to 40 mg/m(3) of stainless or mild steel welding fumes for 3 h/day for 3 days. Controls were exposed to filtered air. Generated fume was collected, and particle size and elemental composition were determined. Bronchoalveolar lavage was done on days 0, 8, 21, and 42 after the last exposure to assess lung injury/inflammation and to recover lung phagocytes. Non-lavaged lung samples were analyzed for total and specific metal content as a measure of metal persistence. Both welding fumes were similar in particle morphology and size. Following was the chemical composition of the fumes-stainless steel: 57% Fe, 20% Cr, 14% Mn, and 9% Ni; mild steel: 83% Fe and 15% Mn. There was no effect of the mild steel fume on lung injury/inflammation at any time point compared to air control. Lung injury and inflammation were significantly elevated at 8 and 21 days after exposure to the stainless steel fume compared to control. Stainless steel fume exposure was associated with greater recovery of welding fume-laden macrophages from the lungs at all time points compared with the mild steel fume. A higher concentration of total metal was observed in the lungs of the stainless steel welding fume at all time points compared with the mild steel fume. The specific metals present in the two fumes were cleared from the lungs at different rates. The potentially more toxic metals (e.g., Mn, Cr) present in the stainless steel fume were cleared from the lungs more quickly than Fe, likely increasing their translocation from the respiratory system to other organs.

The Influence of Large-Scale Airborne Particle Decline and Traffic-Related Exposure on Children’s Lung Function

PubMed Central

Sugiri, Dorothea; Ranft, Ulrich; Schikowski, Tamara; Krämer, Ursula

2006-01-01

Between 1991 and 2000, ambient air pollution in East Germany changed to resemble West German pollution levels: The concentration of total suspended particles (TSPs) decreased on a broad scale while traffic increased. During that time, we analyzed total lung capacity (TLC) and airway resistance (Raw) of East and West German children. We tested children 5–7 years of age (n = 2,574) with cooperation-independent body plethysmography in repeated cross sections. We used random-effect models to determine the mutually adjusted association between lung function and short-term and chronic particle exposure and its interaction with living near a busy road. Annual averages of TSPs declined from 77 to 44 μg/m3; averages on the day of investigation declined from 133 to 30 μg/m3. Differences in lung function between East and West German children vanished during the investigation time. The association of TSPs with Raw and TLC was stronger in children living > 50 m away from busy roads. East German children from this group had an Raw 2.5% higher [95% confidence interval (CI), 0.0–5.1%] per 40-μg/m3 increase of daily TSP averages. TLC decreased by 6.2% (95% CI, 0.04–11.6%) per 40-μg/m3 increase in annual mean TSPs, and this effect was equally pronounced in East and West Germany. TSP exposure decreased on a broad scale between 1991 and 2000. Lower concentrations of TSPs were associated with better measures of lung function in 6-year-old children. For children living near busy roads, this effect was diminished. PMID:16451868

Influence of Particle Size on Persistence and Clearance of Aerosolized Silver Nanoparticles in the Rat Lung

PubMed Central

Anderson, Donald S.; Patchin, Esther S.; Silva, Rona M.; Uyeminami, Dale L.; Sharmah, Arjun; Guo, Ting; Das, Gautom K.; Brown, Jared M.; Shannahan, Jonathan; Gordon, Terry; Chen, Lung Chi; Pinkerton, Kent E.; Van Winkle, Laura S.

2015-01-01

The growing use of silver nanoparticles (AgNPs) in consumer products raises concerns about potential health effects. This study investigated the persistence and clearance of 2 different size AgNPs (20 and 110 nm) delivered to rats by single nose-only aerosol exposures (6 h) of 7.2 and 5.4 mg/m3, respectively. Rat lung tissue was assessed for silver accumulations using inductively-coupled plasma mass spectrometry (ICP-MS), autometallography, and enhanced dark field microscopy. Involvement of tissue macrophages was assessed by scoring of silver staining in bronchoalveolar lavage fluid (BALF). Silver was abundant in most macrophages at 1 day post-exposure. The group exposed to 20 nm AgNP had the greatest number of silver positive BALF macrophages at 56 days post-exposure. While there was a significant decrease in the amount of silver in lung tissue at 56 days post-exposure compared with 1 day following exposure, at least 33% of the initial delivered dose was still present for both AgNPs. Regardless of particle size, silver was predominantly localized within the terminal bronchial/alveolar duct junction region of the lung associated with extracellular matrix and within epithelial cells. Inhalation of both 20 and 110 nm AgNPs resulted in a persistence of silver in the lung at 56 days post-exposure and local deposition as well as accumulation of silver at the terminal bronchiole alveolar duct junction. Further the smaller particles, 20 nm AgNP, produced a greater silver burden in BALF macrophages as well as greater persistence of silver positive macrophages at later timepoints (21 and 56 days). PMID:25577195

Ultrafine particles affect the balance of endogenous pro- and anti-inflammatory lipid mediators in the lung: in-vitro and in-vivo studies

PubMed Central

2012-01-01

Background Exposure to ultrafine particles exerts diverse harmful effects including aggravation of pulmonary diseases like asthma. Recently we demonstrated in a mouse model for allergic airway inflammation that particle-derived oxidative stress plays a crucial role during augmentation of allergen-induced lung inflammation by ultrafine carbon particle (UfCP) inhalation. The mechanisms how particle inhalation might change the inflammatory balance in the lungs, leading to accelerated inflammatory reactions, remain unclear. Lipid mediators, known to be immediately generated in response to tissue injury, might be strong candidates for priming this particle-triggered change of the inflammatory balance. Methods We hypothesize that inhalation of UfCP may disturb the balance of pro- and anti-inflammatory lipid mediators in: i) a model for acute allergic pulmonary inflammation, exposing mice for 24 h before allergen challenge to UfCP inhalation (51.7 nm, 507 μg/m3), and ii) an in-vitro model with primary rat alveolar macrophages (AM) incubated with UfCP (10 μg/1 x 106 cells/ml) for 1 h. Lungs and AM were analysed for pro- and anti-inflammatory lipid mediators, namely leukotriene B4 (LTB4), prostaglandin E2 (PGE2), 15(S)-hydroxy-eicosatetraenoic acid (15(S)-HETE), lipoxin A4 (LXA4) and oxidative stress marker 8-isoprostane by enzyme immunoassays and immunohistochemistry. Results In non-sensitized mice UfCP exposure induced a light non-significant increase of all lipid mediators. Similarly but significantly in rat AM all lipid mediators were induced already within 1 h of UfCP stimulation. Also sensitized and challenge mice exposed to filtered air showed a partially significant increase in all lipid mediators. In sensitized and challenged mice UfCP exposure induced highest significant levels of all lipid mediators in the lungs together with the peak of allergic airway inflammation on day 7 after UfCP inhalation. The levels of LTB4, 8-isoprostane and PGE2 were significantly increased also one day after UfCP exposure. Immunohistochemistry localized highest concentrations of PGE2 especially in AM one day after UfCP exposure. Conclusion Our results suggest that UfCP exposure affects the balance between pro- and anti-inflammatory lipid mediators. In allergic mice, where the endogenous balance of pro- and anti-inflammatory mediators is already altered, UfCP exposure aggravates the inflammation and the increase in anti-inflammatory, pro-resolving lipid mediators is insufficient to counterbalance the extensive inflammatory response. This may be a contributing mechanism that explains the increased susceptibility of asthmatic patients towards particle exposure. PMID:22809365

Exposing a deadly alliance: novel insights into the biological links between COPD and lung cancer.

PubMed

Vermaelen, K; Brusselle, G

2013-10-01

Chronic obstructive pulmonary disease (COPD) affects more than 200 million people worldwide and is expected to become the third leading cause of death in 2020. COPD is characterized by progressive airflow limitation, due to a combination of chronic inflammation and remodeling of the small airways (bronchiolitis) and loss of elastic recoil caused by destruction of the alveolar walls (emphysema). Lung cancer is the most important cause of cancer-related death in the world. (Cigarette) smoking is the principal culprit causing both COPD and lung cancer; in addition, exposure to environmental tobacco smoke, biomass fuel smoke, coal smoke and outdoor air pollution have also been associated with an increased incidence of both diseases. Importantly, smokers with COPD--defined as either not fully reversible airflow limitation or emphysema--have a two- to four-fold increased risk to develop lung cancer. In this review, we highlight several of the genetic, epigenetic and inflammatory mechanisms, which link COPD and carcinogenesis in the lungs. Elucidating the biological pathways and networks, which underlie the increased susceptibility of lung cancer in patients with COPD, has important implications for screening, prevention, diagnosis and treatment of these two devastating pulmonary diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

INFLAMMATORY LUNG INJURY AFTER INSTILLATION OF HUMANS WITH AIR POLLUTION PARTICLES

EPA Science Inventory

Epidemiologic investigation has established an association between exposure to particulate matter (PM) and human health in the Utah Valley. Reduction of particle mass during the temporary closure of a local steel mill was associated with diminished morbidity and mortality. We...

Atmospheric particulate matter size distribution and concentration in West Virginia coal mining and non-mining areas.

PubMed

Kurth, Laura M; McCawley, Michael; Hendryx, Michael; Lusk, Stephanie

2014-07-01

People who live in Appalachian areas where coal mining is prominent have increased health problems compared with people in non-mining areas of Appalachia. Coal mines and related mining activities result in the production of atmospheric particulate matter (PM) that is associated with human health effects. There is a gap in research regarding particle size concentration and distribution to determine respiratory dose around coal mining and non-mining areas. Mass- and number-based size distributions were determined with an Aerodynamic Particle Size and Scanning Mobility Particle Sizer to calculate lung deposition around mining and non-mining areas of West Virginia. Particle number concentrations and deposited lung dose were significantly greater around mining areas compared with non-mining areas, demonstrating elevated risks to humans. The greater dose was correlated with elevated disease rates in the West Virginia mining areas. Number concentrations in the mining areas were comparable to a previously documented urban area where number concentration was associated with respiratory and cardiovascular disease.

Ultrafine particles (UFPs) from domestic wood stoves: genotoxicity in human lung carcinoma A549 cells.

PubMed

Marabini, Laura; Ozgen, Senem; Turacchi, Silvia; Aminti, Stefania; Arnaboldi, Francesca; Lonati, Giovanni; Fermo, Paola; Corbella, Lorenza; Valli, Gianluigi; Bernardoni, Vera; Dell'Acqua, Manuela; Vecchi, Roberta; Becagli, Silvia; Caruso, Donatella; Corrado, Galli L; Marinovich, Marina

2017-08-01

In this paper, results on the potential toxicity of ultrafine particles (UFPs d<100nm) emitted by the combustion of logwood and pellet (hardwood and softwood) are reported. The data were collected during the TOBICUP (TOxicity of BIomass COmbustion generated Ultrafine Particles) project, carried out by a team composed of interdisciplinary research groups. The genotoxic evaluation was performed on A549 cells (human lung carcinomacells) using UFPs whose chemical composition was assessed by a suite of analytical techniques. Comet assay and γ-H2AX evaluation show a significant DNA damage after 24h treatment. The interpretation of the results is based on the correlation among toxicological results, chemical-physical properties of UFPs, and the type and efficiency conditions in residential pellet or logwood stoves. Copyright © 2017 Elsevier B.V. All rights reserved.

Spontaneous haemothorax: an unusual presentation of primary lung cancer.

PubMed Central

Chou, S. H.; Cheng, Y. J.; Kao, E. L.; Chai, C. Y.

1993-01-01

An unusual case of spontaneous haemothorax caused by a subpleural primary lung cancer is reported. Tumour invasion of the pulmonary vessels and visceral pleura was the possible cause. Images PMID:8296269

Pneumomediastinum

MedlinePlus

Pneumomediastinum is uncommon. The condition can be caused by injury or disease. Most often, it occurs when air leaks from any part of the lung or airways into the mediastinum. Increased pressure in the lungs or airways may be caused ...

Lung dendritic cells are stimulated by ultrafine particles and play a key role in particle adjuvant activity.

PubMed

de Haar, Colin; Kool, Mirjam; Hassing, Ine; Bol, Marianne; Lambrecht, Bart N; Pieters, Raymond

2008-05-01

The adjuvant activity of air pollution particles on allergic airway sensitization is well known, but the cellular mechanisms underlying this adjuvant potential are not clear. We sough to study the role of dendritic cells and the costimulatory molecules CD80 and CD86 in the adjuvant activity of ultrafine carbon black particles (CBP). The proliferation of CFSE-labeled DO11.10 CD4 cells was studied after intranasal exposure to particles and ovalbumin (OVA). Next the frequency of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells and their expression of CD80 and CD86 were studied in the peribronchial lymph nodes (PBLNs). The expression of costimulatory molecules was also studied on bone marrow-derived mDCs after exposure to CBPs in vitro, and the importance of costimulation in CBP adjuvant activity was assessed by using CD80/CD86-deficient mice or cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-Ig in vivo. Our data show that CBPs plus OVA caused proliferation of DO11.10 CD4 cells and high levels of cytokine production in the PBLNs. Furthermore, the combined CBP plus OVA exposure increased the number of mDCs and expression of costimulatory molecules in the PBLNs. In addition, CBPs upregulated the expression of CD80/CD86 molecules on dendritic cells in vitro, which are necessary for the particle adjuvant effects in vivo. Together this study shows the importance of dendritic cells and costimulation in particle adjuvant activity. Furthermore, we show for the first time that CBPs can also directly induce maturation of dendritic cells.