Evaluating methods of mouse euthanasia on the oocyte quality: cervical dislocation versus isoflurane inhalation.

PubMed

Roustan, Audrey; Perrin, Jeanne; Berthelot-Ricou, Anaïs; Lopez, Erica; Botta, Alain; Courbiere, Blandine

2012-04-01

Cervical dislocation is a commonly used method of mouse euthanasia. Euthanasia by isoflurane inhalation is an alternative method which allows the sacrifice of several mice at the same time with an anaesthesia, in the aim to decrease pain and animal distress. The objective of our study was to assess the impact of these two methods of euthanasia on the quality of mouse oocytes. By administering gonadotropins, we induced a superovulation in CD1 female mice. Mice were randomly assigned to euthanasia with cervical dislocation and isoflurane inhalation. Oviducts were collected and excised to retrieve metaphase II oocytes. After microscopic examination, oocytes were classified into three groups: intact, fragmented/cleaved and atretic. Intact metaphase II oocytes were employed for biomedical research. A total of 1442 oocytes in the cervical dislocation group were compared with 1230 oocytes in the isoflurane group. In the cervical dislocation group, 93.1% of the oocytes were intact, versus 65.8% in the isoflurane group (P ≤ 0.001). In light of these results, we conclude that cervical dislocation is the best method of mouse euthanasia for obtaining intact oocytes for biomedical research.

A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.

PubMed

Filser, Johannes Georg; Klein, Dominik

2018-04-01

Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in-wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Development of Mouse Lung Deposition Models

DTIC Science & Technology

2015-07-01

information on deposition of ultrafine particles in the URT of mice either by measurements or theoretical modeling. Comparison of the nasal structure of... ultrafine particles in rats to be extended to mice. Based on measurements in the nasal casts of rats, Cheng et al. [12] obtained the following...expression for losses of ultrafine particles in the nasal passages of rats by Brownian diffusion during inhalation and exhalation. γβα− − −=η QD

A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened.

PubMed

Erickson, Robert P; Deutsch, Gail; Patil, Ruturaj

2018-05-01

We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 nmf164 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Slight inflammation also occasionally occurred with saline inhalation. There was no difference between the saline-treated, HPBCD-treated, and untreated Npc1 nmf164 homozygous mice for weight, balance beam performance, or coat hanger performance. Interestingly, there was a trend to longer survival in the HPBCD-treated Npc1 nmf164 homozygous mice, which, when combined with the survival times of the saline-treated survivals (each of which was not different), became significant.

Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria.

PubMed

Hwang, John H; Lyes, Matthew; Sladewski, Katherine; Enany, Shymaa; McEachern, Elisa; Mathew, Denzil P; Das, Soumita; Moshensky, Alexander; Bapat, Sagar; Pride, David T; Ongkeko, Weg M; Crotty Alexander, Laura E

2016-06-01

Electronic (e)-cigarette use is rapidly rising, with 20 % of Americans ages 25-44 now using these drug delivery devices. E-cigarette users expose their airways, cells of host defense, and colonizing bacteria to e-cigarette vapor (EV). Here, we report that exposure of human epithelial cells at the air-liquid interface to fresh EV (vaped from an e-cigarette device) resulted in dose-dependent cell death. After exposure to EV, cells of host defense-epithelial cells, alveolar macrophages, and neutrophils-had reduced antimicrobial activity against Staphylococcus aureus (SA). Mouse inhalation of EV for 1 h daily for 4 weeks led to alterations in inflammatory markers within the airways and elevation of an acute phase reactant in serum. Upon exposure to e-cigarette vapor extract (EVE), airway colonizer SA had increased biofilm formation, adherence and invasion of epithelial cells, resistance to human antimicrobial peptide LL-37, and up-regulation of virulence genes. EVE-exposed SA were more virulent in a mouse model of pneumonia. These data suggest that e-cigarettes may be toxic to airway cells, suppress host defenses, and promote inflammation over time, while also promoting virulence of colonizing bacteria. Acute exposure to e-cigarette vapor (EV) is cytotoxic to airway cells in vitro. Acute exposure to EV decreases macrophage and neutrophil antimicrobial function. Inhalation of EV alters immunomodulating cytokines in the airways of mice. Inhalation of EV leads to increased markers of inflammation in BAL and serum. Staphylococcus aureus become more virulent when exposed to EV.

Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled ozone

EPA Science Inventory

Ozone (O(3)) is a respiratory irritant that leads to airway inflammation and pulmonary dysfunction. Animal studies show that neonates are more sensitive to O(3) inhalation than adults, and children represent a potentially susceptible population. This latter notion is not well est...

Differential Lung Toxicity of Biomass Smoke from Smoldering and Flaming Phases Following Acute Inhalation Exposure

EPA Science Inventory

We previously demonstrated that, on a mass basis, lung toxicity associated with particulate matter (PM) from flaming smoke aspirated into mouse lungs is greater than smoldering PM. This finding however has to be validated in inhalation studies to better predict real-world exposu...

Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

PubMed Central

2011-01-01

Background Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse). Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection. PMID:21943386

The effect of zirconium doping of cerium dioxide nanoparticles on pulmonary and cardiovascular toxicity and biodistribution in mice after inhalation.

PubMed

Dekkers, Susan; Miller, Mark R; Schins, Roel P F; Römer, Isabella; Russ, Mike; Vandebriel, Rob J; Lynch, Iseult; Belinga-Desaunay, Marie-France; Valsami-Jones, Eugenia; Connell, Shea P; Smith, Ian P; Duffin, Rodger; Boere, John A F; Heusinkveld, Harm J; Albrecht, Catrin; de Jong, Wim H; Cassee, Flemming R

2017-08-01

Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the influence of redox activity by modification of cerium dioxide nanoparticles (CeO 2 NPs) via zirconium (Zr) doping on the biodistribution, pulmonary and cardiovascular effects in mice following inhalation. Healthy mice (C57BL/6 J), mice prone to cardiovascular disease (ApoE -/- , western-diet fed) and a mouse model of neurological disease (5 × FAD) were exposed via nose-only inhalation to CeO 2 NPs with varying amounts of Zr-doping (0%, 27% or 78% Zr), or clean air, over a four-week period (4 mg/m 3 for 3 h/day, 5 days/week). Effects were assessed four weeks post-exposure. In all three mouse models CeO 2 NP exposure had no major toxicological effects apart from some modest inflammatory histopathology in the lung, which was not related to the amount of Zr-doping. In ApoE -/- mice CeO 2 did not change the size of atherosclerotic plaques, but there was a trend towards increased inflammatory cell content in relation to the Zr content of the CeO 2 NPs. These findings show that subacute inhalation of CeO 2 NPs causes minimal pulmonary and cardiovascular effect four weeks post-exposure and that Zr-doping of CeO 2 NPs has limited effect on these responses. Further studies with nanomaterials with a higher inherent toxicity or a broader range of redox activities are needed to fully assess the influence of redox activity on the toxicity of nanomaterials.

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites.

PubMed

Campbell, Jerry; Van Landingham, Cynthia; Crowell, Susan; Gentry, Robinan; Kaden, Debra; Fiebelkorn, Stacy; Loccisano, Anne; Clewell, Harvey

2015-08-05

1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells)(1) are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions vary throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

DOE PAGES

Campbell, Jerry; Van Landingham, Cynthia; Crowell, Susan; ...

2015-06-12

1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells) 1 are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions varymore » throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD.« less

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

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

Campbell, Jerry; Van Landingham, Cynthia; Crowell, Susan

1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells) 1 are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions varymore » throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD.« less

Method of euthanasia influences the oocyte fertilization rate with fresh mouse sperm.

PubMed

Hazzard, Karen C; Watkins-Chow, Dawn E; Garrett, Lisa J

2014-11-01

In vitro fertilization (IVF) is used to produce mouse embryos for a variety of reasons. We evaluated the effect of the method of euthanasia on the fertilization rate in 2 different IVF protocols. Oocytes collected from C57BL/6J female mice euthanized by CO2 inhalation or cervical dislocation were used in IVF with fresh sperm from either wild-type or genetically engineered C57BL/6J. Compared with CO2 inhalation, cervical dislocation improved the resulting rate of fertilization by 18% in an IVF method using Cook media and by 13% in an IVF method using methyl-B cyclodextrin and reduced glutathione. The lower fertilization rate due to euthanasia by CO2 inhalation was accompanied by changes in blood pH and body temperature despite efforts to minimize temperature drops. In our hands, euthanasia by cervical dislocation improved fertilization rates and consequently reduced the number of egg-donor mice required.

Protective effects of radon inhalation on carrageenan-induced inflammatory paw edema in mice.

PubMed

Kataoka, Takahiro; Teraoka, Junichi; Sakoda, Akihiro; Nishiyama, Yuichi; Yamato, Keiko; Monden, Mayuko; Ishimori, Yuu; Nomura, Takaharu; Taguchi, Takehito; Yamaoka, Kiyonori

2012-04-01

We assessed whether radon inhalation inhibited carrageenan-induced inflammation in mice. Carrageenan (1% v/v) was injected subcutaneously into paws of mice that had or had not inhaled approximately 2,000 Bq/m(3) of radon for 24 h. Radon inhalation significantly increased superoxide dismutase (SOD) and catalase activities and significantly decreased lipid peroxide levels in mouse paws, indicating that radon inhalation activates antioxidative functions. Carrageenan administration induced paw edema and significantly increased tumor necrosis factor-alpha (TNF-α) and nitric oxide in serum. However, radon inhalation significantly reduced carrageenan-induced paw edema. Serum TNF-α levels were lower in the radon-treated mice than in sham-treated mice. In addition, SOD and catalase activities in paws were significantly higher in the radon-treated mice than in the sham-treated mice. These findings indicated that radon inhalation had anti-inflammatory effects and inhibited carrageenan-induced inflammatory paw edema.

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

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

Schneider, Brent C.; Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037; Constant, Stephanie L.

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory responsemore » in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr(VI) may augment severity and alter phenotype of ongoing allergic asthma.« less

Effect of Anticoagulants and Heat on the Detection of Tumor Necrosis Factor in Murine Blood

DTIC Science & Technology

1990-01-01

anesthetized by inhalation of methoxyflurane before obtaining blood by cardiac puncture. The blood from a group of mice was allowed to clot before recovery of...was prepared in homologous normal Mice were anesthetized by inhalation of mouse serum and heated to 56°C for 30 min methoxyflurane immediately before 1

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

PubMed

Grossman, Trudy H; Anderson, Michael S; Drabek, Lindsay; Gooldy, Melanie; Heine, Henry S; Henning, Lisa N; Lin, Winston; Newman, Joseph V; Nevarez, Rene; Siefkas-Patterson, Kaylyn; Radcliff, Anne K; Sutcliffe, Joyce A

2017-10-01

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD 50 ). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD 50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax. Copyright © 2017 American Society for Microbiology.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques

PubMed Central

Anderson, Michael S.; Drabek, Lindsay; Gooldy, Melanie; Heine, Henry S.; Henning, Lisa N.; Lin, Winston; Newman, Joseph V.; Nevarez, Rene; Siefkas-Patterson, Kaylyn; Radcliff, Anne K.; Sutcliffe, Joyce A.

2017-01-01

ABSTRACT The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax. PMID:28784679

Inhalable Particles for "Pincer Therapeutics" Targeting Nitazoxanide as Bactericidal and Host-Directed Agent to Macrophages in a Mouse Model of Tuberculosis.

PubMed

Gupta, Anuradha; Meena, Jairam; Sharma, Deepak; Gupta, Pushpa; Gupta, Umesh Dutta; Kumar, Sadan; Sharma, Sharad; Panda, Amulya K; Misra, Amit

2016-09-06

Nitazoxanide (NTZ) has moderate mycobactericidal activity and is also an inducer of autophagy in mammalian cells. High-payload (40-50% w/w) inhalable particles containing NTZ alone or in combination with antituberculosis (TB) agents isoniazid (INH) and rifabutin (RFB) were prepared with high incorporation efficiency of 92%. In vitro drug release was corrected for drug degradation during the course of study and revealed first-order controlled release. Particles were efficiently taken up in vitro by macrophages and maintained intracellular drug concentrations at one order of magnitude higher than NTZ in solution for 6 h. Dose-dependent killing of Mtb and restoration of lung and spleen architecture were observed in experimentally infected mice treated with inhalations containing NTZ. Adjunct NTZ with INH and RFB cleared culturable bacteria from the lung and spleen and markedly healed tissue architecture. NTZ can be used in combination with INH-RFB to kill the pathogen and heal the host.

Efficacy of bacteriophage therapy in a model of Burkholderia cenocepacia pulmonary infection

PubMed Central

Carmody, Lisa A.; Gill, Jason J.; Summer, Elizabeth J.; Sajjan, Uma S.; Gonzalez, Carlos F.; Young, Ryland F.; LiPuma, John J.

2009-01-01

The therapeutic potential of bacteriophage (phage) in a mouse model of acute B. cenocepacia pulmonary infection was assessed. Phage were administered by either intranasal (i.n.) inhalation or intraperitoneal (i.p.) injection. Bacterial density, macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNFα) levels were significantly reduced in lungs of mice treated with i.p. phage. No significant differences in lung bacterial density or MIP-2 levels were found between untreated mice and mice treated with i.n. phage, i.p. UV-inactivated phage, or i.p. λ phage controls. Mock-infected mice treated with phage showed no significant increase in lung MIP-2 or TNFα levels compared to mock-infected / mock-treated mice. We have demonstrated the efficacy of phage therapy in an acute B. cenocepacia lung infection model. Systemic administration of phage was more effective than inhalational administration, suggesting that circulating phage have better access to bacteria in lung compared to topical phage. PMID:20001604

Method of Euthanasia Influences the Oocyte Fertilization Rate with Fresh Mouse Sperm

PubMed Central

Hazzard, Karen C; Watkins-Chow, Dawn E; Garrett, Lisa J

2014-01-01

In vitro fertilization (IVF) is used to produce mouse embryos for a variety of reasons. We evaluated the effect of the method of euthanasia on the fertilization rate in 2 different IVF protocols. Oocytes collected from C57BL/6J female mice euthanized by CO2 inhalation or cervical dislocation were used in IVF with fresh sperm from either wild-type or genetically engineered C57BL/6J. Compared with CO2 inhalation, cervical dislocation improved the resulting rate of fertilization by 18% in an IVF method using Cook media and by 13% in an IVF method using methyl-B cyclodextrin and reduced glutathione. The lower fertilization rate due to euthanasia by CO2 inhalation was accompanied by changes in blood pH and body temperature despite efforts to minimize temperature drops. In our hands, euthanasia by cervical dislocation improved fertilization rates and consequently reduced the number of egg-donor mice required. PMID:25650969

OSHA's approach to risk assessment for setting a revised occupational exposure standard for 1,3-butadiene.

PubMed Central

Grossman, E A; Martonik, J

1990-01-01

In its 1980 benzene decision [Industrial Union Department, ALF-CIO v. American Petroleum Institute, 448 U.S. 607 (1980)], the Supreme Court ruled that "before he can promulgate any permanent health or safety standard, the Secretary [of Labor] is required to make a threshold finding that a place of employment is unsafe--in the sense that significant risks are present and can be lessened by a change in practices" (448 U.S. at 642). The Occupational Safety and Health Administration (OSHA) has interpreted this to mean that whenever possible, it must quantify the risk associated with occupational exposure to a toxic substance at the current permissible exposure limit (PEL). If OSHA determines that there is significant risk to workers' health at its current standard, then it must quantify the risk associated with a variety of alternative standards to determine at what level, if any, occupational exposure to a substance no longer poses a significant risk. For rulemaking on occupational exposure to 1,3-butadiene, there are two studies that are suitable for quantitative risk assessment. One is a mouse inhalation bioassay conducted by the National Toxicology Program (NTP), and the other is a rat inhalation bioassay conducted by Hazelton Laboratories Europe. Of the four risk assessments that have been submitted to OSHA, all four have used the mouse and/or rat data with a variety of models to quantify the risk associated with occupational exposure to 1,3-butadiene. In addition, OSHA has performed its own risk assessment using the female mouse and female rat data and the one-hit and multistage models.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2401254

Characterization and Application of a Nose-Only Exposure Chamber for Inhalation Delivery of Liposomal Drugs and Nucleic Acids to Mice

PubMed Central

Seshadri, S.; Garbuzenko, O.B.; Han, T.; Wang, Z.; Minko, T.

2013-01-01

Abstract Background A small nose-only exposure chamber was evaluated for inhalation delivery of drug carrier systems (DCSs) to mice for the treatment of lung cancer. The chamber then was used for inhalation delivery of an anticancer drug, antisense oligonucleotides (ASO), and small interfering RNA (siRNA) directly to the cancerous lungs of mice. Methods The uniformity of particle delivery across the ports of the exposure chamber and stability of the DCS (liposomes) during continuous aerosolization by a Collison nebulizer were examined. The mean produced particle size by number was approximately 130 nm, and the mass median diameter was approximately 270 nm. The system was then used to deliver DCS containing doxorubicin (DOX) and ASO or siRNA targeted to multidrug resistance-associated protein 1 (MRP1) mRNA as suppressors of cancer cell resistance. The retention of the drug in the lungs and the effect on tumor size were compared after inhalation delivery and intravenous injection in a nu/nu mouse model of lung cancer. Results The aerosol mass across the four inhalation ports had a coefficient of variation of less than 12%, and approximately 1.4% of the nebulized mass was available for inhalation at each port. The mean size of 130 nm of liposomal DCS did not change significantly during continuous 60-min aerosolization. For inhalation delivery of DCS with DOX+ASO/siRNA, the amount of drugs available for inhalation was lower compared with intravenous injection of DOX; however, the observed lung dose and the retention time were significantly higher. The delivery of DOX+ASO/siRNA via inhalation resulted in tumor volume reduction of more than 90%, whereas only about 40% reduction was achieved after intravenous injection of DOX. Conclusions The investigated exposure system is suitable for inhalation delivery of complex DCS, and its use to deliver DCS containing anticancer drugs and resistance suppressors via inhalation offered a superior method for lung cancer treatment in mice compared with intravenous injections. PMID:23530772

Studies on possibility for alleviation of lifestyle diseases by low-dose irradiation or radon inhalation.

PubMed

Kataoka, Takahiro; Sakoda, Akihiro; Yoshimoto, Masaaki; Nakagawa, Shinya; Toyota, Teruaki; Nishiyama, Yuichi; Yamato, Keiko; Ishimori, Yuu; Kawabe, Atsushi; Hanamoto, Katsumi; Taguchi, Takehito; Yamaoka, Kiyonori

2011-07-01

Our previous studies showed the possibility that activation of the antioxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the antioxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the antioxidative function as a result of irradiation. In addition, radon inhalation enhances the antioxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl(4)) administration. Results showed that radon inhalation alleviates CCl(4)-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of antioxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases.

Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics.

PubMed

Reno, Anita L; Brooks, Edward G; Ameredes, Bill T

2015-01-01

Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body's response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction.

Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics

PubMed Central

Reno, Anita L; Brooks, Edward G; Ameredes, Bill T

2015-01-01

Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body’s response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction. PMID:25922579

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

PubMed

Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Measurements of radon activity concentration in mouse tissues and organs.

PubMed

Ishimori, Yuu; Tanaka, Hiroshi; Sakoda, Akihiro; Kataoka, Takahiro; Yamaoka, Kiyonori; Mitsunobu, Fumihiro

2017-05-01

The purpose of this study is to investigate the biokinetics of inhaled radon, radon activity concentrations in mouse tissues and organs were determined after mice had been exposed to about 1 MBq/m 3 of radon in air. Radon activity concentrations in mouse blood and in other tissues and organs were measured with a liquid scintillation counter and with a well-type HP Ge detector, respectively. Radon activity concentration in mouse blood was 0.410 ± 0.016 Bq/g when saturated with 1 MBq/m 3 of radon activity concentration in air. In addition, average partition coefficients obtained were 0.74 ± 0.19 for liver, 0.46 ± 0.13 for muscle, 9.09 ± 0.49 for adipose tissue, and 0.22 ± 0.04 for other organs. With these results, a value of 0.414 for the blood-to-air partition coefficient was calculated by means of our physiologically based pharmacokinetic model. The time variation of radon activity concentration in mouse blood during exposure to radon was also calculated. All results are compared in detail with those found in the literature.

Diesel exhaust inhalation exposure induces pulmonary arterial hypertension in mice.

PubMed

Liu, Jing; Ye, Xiaoqing; Ji, Dapeng; Zhou, Xiaofei; Qiu, Cong; Liu, Weiping; Yu, Luyang

2018-06-01

Diesel exhaust (DE) is one of the main sources of urban air pollution. An increasing number of evidence showed the association of air pollution with cardiovascular diseases. Pulmonary arterial hypertension (PAH) is one of the most disastrous vascular diseases, which results in right ventricular failure and death. However, the relationship of DE inhalation exposure with PAH is still unknown. In this study, male adult mice were exposed by inhalation to filtered ambient air (negative control), 10% O 2 hypoxia (PAH-phenotype positive control), 350 μg/m 3 particulate matter whole DE, or the combination of DE and hypoxic condition. DE inhalation induced PAH-phenotype accompanied with increased right ventricular systolic pressure (RVSP), right ventricle hypertrophy and pulmonary arterial thickening in a mouse model. DE exposure induced the proliferation of vascular smooth muscle cells (VSMCs) and apoptosis of endothelial cells in pulmonary artery. DE inhalation exposure induced an accumulation of CD45 +  lymphocytes and CD68 +  macrophages surrounding and infiltrating pulmonary arteriole. The levels of pro-inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and IL-13 produced by T helper 17 (Th17) and Th2 cells were markedly elevated in lung tissues of mice after DE inhalation exposure. Our findings suggest DE exposure induces PAH by activating Th17-skewed and Th2-droved responses, stimulating VSMCs proliferation and inducing endothelial cell apoptosis by the production of multifunctional pro-inflammatory cytokines, especially IL-6 and TNF-α. Considering the adverse impact of air pollution on health care, it is imperative to understand air pollution-induced susceptibility of progressive cardiopulmonary disease, such as PAH, and also elucidate critical mechanistic pathways which mediate pulmonary artery vascular remodeling and may serve as targets for preventive measures. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: A randomized clinical trial

PubMed Central

Gladwin, Mark T.; Kato, Gregory J.; Weiner, Debra; Onyekwere, Onyinye C.; Dampier, Carlton; Hsu, Lewis; Hagar, R. Ward; Howard, Thomas; Nuss, Rachelle; Okam, Maureen M.; Tremonti, Carole K.; Berman, Brian; Villella, Anthony; Krishnamurti, Lakshmanan; Lanzkron, Sophie; Castro, Oswaldo; Gordeuk, Victor R.; Coles, Wynona A.; Peters-Lawrence, Marlene; Nichols, James; Hall, Mary K.; Hildesheim, Mariana; Blackwelder, William C.; Baldassarre, James; Casella, James F.

2012-01-01

Context Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). Objective To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care. Design, Setting and Participants Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home. Intervention Inhaled NO gas versus inhaled nitrogen placebo. Results There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. Conclusions Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution. PMID:21364138

A Review of the Comparative Anatomy, Histology, Physiology and Pathology of the Nasal Cavity of Rats, Mice, Dogs and Non-human Primates. Relevance to Inhalation Toxicology and Human Health Risk Assessment.

PubMed

Chamanza, R; Wright, J A

2015-11-01

There are many significant differences in the structural and functional anatomy of the nasal cavity of man and laboratory animals. Some of the differences may be responsible for the species-specific nasal lesions that are often observed in response to inhaled toxicants. This paper reviews the comparative anatomy, physiology and pathology of the nasal cavity of the rat, mouse, dog, monkey and man, highlighting factors that may influence the distribution of nasal lesions. Gross anatomical variations such as turbinate structure, folds or grooves on nasal walls, or presence or absence of accessory structures, may influence nasal airflow and species-specific uptake and deposition of inhaled material. In addition, interspecies variations in the morphological and biochemical composition and distribution of the nasal epithelium may affect the local tissue susceptibility and play a role in the development of species-specific nasal lesions. It is concluded that, while the nasal cavity of the monkey might be more similar to that of man, each laboratory animal species provides a model that responds in a characteristic and species-specific manner. Therefore for human risk assessment, careful consideration must be given to the anatomical differences between a given animal model and man. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sevoflurane Inhalation Accelerates the Long-Term Memory Consolidation via Small GTPase Overexpression in the Hippocampus of Mice in Adolescence.

PubMed

Nakamura, Emi; Kinoshita, Hiroyuki; Feng, Guo-Gang; Hayashi, Hisaki; Satomoto, Maiko; Sato, Motohiko; Fujiwara, Yoshihiro

2016-01-01

Sevoflurane exposure impairs the long-term memory in neonates. Whether the exposure to animals in adolescence affects the memory, however, has been unclear. A small hydrolase enzyme of guanosine triphosphate (GTPase) rac1 plays a role in the F-actin dynamics related to the synaptic plasticity, as well as superoxide production via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The current study was designed to examine whether sevoflurane exposure to mice in early adolescence modifies the long-term learning ability concomitantly with the changes in F-actin constitution as well as superoxide production in the hippocampus according to the levels of rac1 protein expression. Four-week-old mice were subjected to the evaluation of long-term learning ability for three days. On day one, each mouse was allowed to enter a dark chamber for five min to acclimatization. On day two, the procedure was repeated with the addition of an electric shock as soon as a mouse entered the dark chamber. All mice subsequently inhaled 2 L/min air with (Sevoflurane group) and without (Control group) 2.5% sevoflurane for three hours. On day three, each mouse was placed on the platform and retention time, which is the latency to enter the dark chamber, was examined. The brain removed after the behavior test, was used for analyses of immunofluorescence, Western immunoblotting and intracellular levels of superoxide. Sevoflurane exposure significantly prolonged retention time, indicating the enhanced long-term memory. Sevoflurane inhalation augmented F-actin constitution coexisting with the rac1 protein overexpression in the hippocampus whereas it did not alter the levels of superoxide. Sevoflurane exposure to 4-week-old mice accelerates the long-term memory concomitantly with the enhanced F-actin constitution coexisting with the small GTPase rac1 overexpression in the hippocampus. These results suggest that sevoflurane inhalation may amplify long-term memory consolidation via the increased cytoskeleton constitution in the hippocampus of animals in early adolescence.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.

PubMed

Grossman, Trudy H; Anderson, Michael S; Christ, David; Gooldy, Melanie; Henning, Lisa N; Heine, Henry S; Kindt, M Victoria; Lin, Winston; Siefkas-Patterson, Kaylyn; Radcliff, Anne K; Tam, Vincent H; Sutcliffe, Joyce A

2017-08-01

TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 μg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD 50 )/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis . Copyright © 2017 American Society for Microbiology.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

PubMed Central

Anderson, Michael S.; Christ, David; Gooldy, Melanie; Henning, Lisa N.; Heine, Henry S.; Kindt, M. Victoria; Lin, Winston; Siefkas-Patterson, Kaylyn; Radcliff, Anne K.; Tam, Vincent H.; Sutcliffe, Joyce A.

2017-01-01

ABSTRACT TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 μg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis. PMID:28559261

Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition.

PubMed

Sørli, Jorid B; Huang, Yishi; Da Silva, Emilie; Hansen, Jitka S; Zuo, Yi Y; Frederiksen, Marie; Nørgaard, Asger W; Ebbehøj, Niels E; Larsen, Søren T; Hougaard, Karin S

2018-01-01

Private consumers and professionals may experience acute inhalation toxicity after inhaling aerosolized impregnation products. The distinction between toxic and non-toxic products is difficult to make for producers and product users alike, as there is no clearly described relationship between the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21 impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if the products inhibited surfactant function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e., the in vitro method predicted all the products that were toxic for mice to inhale. The specificity of the in vitro test was 63%, i.e., the in vitro method found three false positives in the 21 tested products. Six of the products had been involved in accidental human inhalation where they caused acute inhalation toxicity. All of these six products inhibited lung surfactant function in vitro and were toxic to mice.

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.

PubMed

Welsch, Frank; Elswick, Barbara; James, R Arden; Marr, Melissa C; Myers, Christina B; Tyl, Rochelle W

2003-01-01

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study. Copyright 2003 John Wiley & Sons, Ltd.

Developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses

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

Rogers, J.M.; Mole, M.L.; Chernoff, N.

1993-01-01

Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm on methanol for 7 hr/day on days 6-15 of gestation. On day 17 of gestation, remaining mice were weighed, killed and the gravid uterus was removed. Numbers of implantation sites, live and dead fetuses and resorptions were counted, and fetuses were examined externally and weighed as a litter. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased postimplantation mortality at 7,500 ppm and above (including an increasing incidence of full-litter resorption), and reduced fetal weight at 10,000more » ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study is 1,000 ppm. The results of this study indicate that inhaled methanol is developmentally toxic in the mouse at exposure levels which were not maternally toxic. Litters of pregnant mice gavaged orally with 4 g methanol/kg displayed developmental toxic effects similar to those seen in the 10,000 ppm methanol exposure group. (Copyright (c) 1993 Wiley-Liss, Inc.)« less

Visualization of tumor vascular reactivity in response to respiratory challenges by optical coherence tomography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kim, Hoon Sup; Lee, Songhyun; Lee, Kiri; Eom, Tae Joong; Kim, Jae G.

2016-02-01

We previously reported the potential of using vascular reactivity during respiratory challenges as a marker to predict the response of breast tumor to chemotherapy in a rat model by using a continuous wave near-infrared spectroscopy. However, it cannot visualize how the vascular reactivity from tumor vessel can predict the tumor response to its treatment. In this study, we utilized a spectral domain optical coherence tomography (SD-OCT) system to visualize vascular reactivity of both tumor and normal vasculature during respiratory challenges in a mouse model. We adapted intensity based Doppler variance algorithm to draw angiogram from the ear of mouse (8-week-old Balb/c nu/nu). Animals were anesthetized using 1.5% isoflurane, and the body temperature was maintained by a heating pad. Inhalational gas was switched from air (10min) to 100% oxygen (10min), and a pulse oximeter was used to monitor arterial oxygen saturation and heart rate. OCT angiograms were acquired 5 min after the onset of each gas. The vasoconstriction effect of hyperoxic gas on vasculature was shown by subtracting an en-face image acquired during 100% oxygen from the image acquired during air inhalation. The quantitative change in the vessel diameter was measured from the en-face OCT images of the individual blood vessels. The percentage of blood vessel diameter reduction varied from 1% to 12% depending on arterial, capillary, or venous blood vessel. The vascular reactivity change during breast tumor progression and post chemotherapy will be monitored by OCT angiography.

SUBCHRONIC ENDOTOXIN INHALATION CAUSES PERSISTENT AIRWAY DISEASE

EPA Science Inventory

ABSTRACT

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin ...

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

Estimation of inhalation flow profile using audio-based methods to assess inhaler medication adherence.

PubMed

Taylor, Terence E; Lacalle Muls, Helena; Costello, Richard W; Reilly, Richard B

2018-01-01

Asthma and chronic obstructive pulmonary disease (COPD) patients are required to inhale forcefully and deeply to receive medication when using a dry powder inhaler (DPI). There is a clinical need to objectively monitor the inhalation flow profile of DPIs in order to remotely monitor patient inhalation technique. Audio-based methods have been previously employed to accurately estimate flow parameters such as the peak inspiratory flow rate of inhalations, however, these methods required multiple calibration inhalation audio recordings. In this study, an audio-based method is presented that accurately estimates inhalation flow profile using only one calibration inhalation audio recording. Twenty healthy participants were asked to perform 15 inhalations through a placebo Ellipta™ DPI at a range of inspiratory flow rates. Inhalation flow signals were recorded using a pneumotachograph spirometer while inhalation audio signals were recorded simultaneously using the Inhaler Compliance Assessment device attached to the inhaler. The acoustic (amplitude) envelope was estimated from each inhalation audio signal. Using only one recording, linear and power law regression models were employed to determine which model best described the relationship between the inhalation acoustic envelope and flow signal. Each model was then employed to estimate the flow signals of the remaining 14 inhalation audio recordings. This process repeated until each of the 15 recordings were employed to calibrate single models while testing on the remaining 14 recordings. It was observed that power law models generated the highest average flow estimation accuracy across all participants (90.89±0.9% for power law models and 76.63±2.38% for linear models). The method also generated sufficient accuracy in estimating inhalation parameters such as peak inspiratory flow rate and inspiratory capacity within the presence of noise. Estimating inhaler inhalation flow profiles using audio based methods may be clinically beneficial for inhaler technique training and the remote monitoring of patient adherence.

Estimation of inhalation flow profile using audio-based methods to assess inhaler medication adherence

PubMed Central

Lacalle Muls, Helena; Costello, Richard W.; Reilly, Richard B.

2018-01-01

Asthma and chronic obstructive pulmonary disease (COPD) patients are required to inhale forcefully and deeply to receive medication when using a dry powder inhaler (DPI). There is a clinical need to objectively monitor the inhalation flow profile of DPIs in order to remotely monitor patient inhalation technique. Audio-based methods have been previously employed to accurately estimate flow parameters such as the peak inspiratory flow rate of inhalations, however, these methods required multiple calibration inhalation audio recordings. In this study, an audio-based method is presented that accurately estimates inhalation flow profile using only one calibration inhalation audio recording. Twenty healthy participants were asked to perform 15 inhalations through a placebo Ellipta™ DPI at a range of inspiratory flow rates. Inhalation flow signals were recorded using a pneumotachograph spirometer while inhalation audio signals were recorded simultaneously using the Inhaler Compliance Assessment device attached to the inhaler. The acoustic (amplitude) envelope was estimated from each inhalation audio signal. Using only one recording, linear and power law regression models were employed to determine which model best described the relationship between the inhalation acoustic envelope and flow signal. Each model was then employed to estimate the flow signals of the remaining 14 inhalation audio recordings. This process repeated until each of the 15 recordings were employed to calibrate single models while testing on the remaining 14 recordings. It was observed that power law models generated the highest average flow estimation accuracy across all participants (90.89±0.9% for power law models and 76.63±2.38% for linear models). The method also generated sufficient accuracy in estimating inhalation parameters such as peak inspiratory flow rate and inspiratory capacity within the presence of noise. Estimating inhaler inhalation flow profiles using audio based methods may be clinically beneficial for inhaler technique training and the remote monitoring of patient adherence. PMID:29346430

Lung Inflammatory Effects, Tumorigenesis, and Emphysema Development in a Long-Term Inhalation Study with Cigarette Mainstream Smoke in Mice

PubMed Central

Stabbert, Regina

2013-01-01

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation–induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development. PMID:23104432

Evaulation of cancer and non-cancer effects of cumene ...

EPA Pesticide Factsheets

Cumene, also known as isopropyl benzene, is a volatile liquid. We have systematically reviewed published literature to evaluate cancer and noncancer effects of cumene. Cumene, readily absorbed via inhalation is distributed in several tissues, metabolized extensively by cytochrome P-450 isozymes within hepatic and extra-hepatic tissues and excreted through urine. Although, there are no epidemiological cancer studies for humans, chronic inhalation exposure studies in rat and mouse have shown increased nasal lesions including atrophy, basal cell hyperplasia, atypical hyperplasia and hyperplasia of the olfactory epithelium glands. To present the information at the Society of Toxicology Meeting.

Mouse Sensitization and Exposure Are Associated with Asthma Severity in Urban Children.

PubMed

Grant, Torie; Aloe, Charles; Perzanowski, Matthew; Phipatanakul, Wanda; Bollinger, Mary E; Miller, Rachel; Matsui, Elizabeth C

Mouse sensitization and exposure are associated with uncontrolled asthma, but whether they are associated with asthma severity, an intrinsic disease characteristic and long-term outcome predictor, is unclear. To examine relationships between mouse sensitization and/or exposure and asthma severity in urban children. A total of 645 children (5-17 years) with uncontrolled asthma underwent mouse sensitization evaluation. Sensitized children had mouse allergen measured in bedroom dust. Relationships between mouse sensitization, allergen levels, and asthma severity measures (treatment step and Composite Asthma Severity Index [CASI]) were examined using regression models adjusted for age, sex, atopy, study site, race, ethnicity, and insurance. The study population was predominantly minority (69.6% black, 20.8% Hispanic), low income (61.8%), and mouse sensitized (54.4%). Mean ± SD treatment step was 3.2 ± 1.6, equivalent to medium-dose inhaled corticosteroid. Mean ± SD CASI was 6.5 ± 3.4, reflecting moderate persistent asthma. Mouse sensitization was associated with higher treatment step (3.5 vs 2.9, mouse-sensitized vs nonsensitized, P < .001), independent of potential confounders (β [95% CI], 0.36 [0.07-0.64]; P = .01). Mouse sensitization was associated independently with CASI (β [95% CI], 0.82 [0.16-1.47]; P = .02). Among mouse-sensitized participants, higher bedroom floor and bed Mus m 1 were independently associated with treatment step (β [95% CI], 0.26 [0.09-0.43]; P = .002 and β [95% CI], 0.22 [0.01-0.43]; P = .04), respectively. Higher bedroom floor Mus m 1 was independently associated with CASI (β [95% CI], 0.43 [0.05-0.81]; P = .03). Mouse sensitization and exposure are associated with asthma severity, among low-income, minority children. Further studies are needed to determine whether reducing allergen exposure among mouse-sensitized patients with asthma can reduce severity, ultimately altering childhood asthma natural history. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Expression profiling of Yersinia pestis during mouse pulmonary infection.

PubMed

Lawson, Jonathan N; Lyons, C Rick; Johnston, Stephen Albert

2006-11-01

Yersinia pestis, the causative agent of plague, can be transmitted by infected flea bite or inhaled aerosol. Both routes of infection have a high mortality rate, and pneumonic infections of Y. pestis represent a significant concern as a tool of bioterrorism. Understanding the transcriptional program of this pathogen during pulmonary infection should be valuable in understanding plague pathogenesis, as well as potentially offering insights into new vaccines and therapeutics. Toward this goal we developed a long oligonucleotide microarray to the plague bacillus and evaluated the expression profiles of Y. pestis in vitro and in the mouse pulmonary infection model in vivo. The in vitro analysis compared expression patterns at 27 versus 37 degrees C, as a surrogate of the transition from the flea to the mammalian host. The in vivo analysis used intranasal challenge to the mouse lung. By amplifying the Y. pestis RNA from individual mouse lungs we were able to map the transcriptional profile of plague at postinfection days 1 to 3. Our data present a very different transcriptional profile between in vivo and in vitro expression, suggesting Y. pestis responds to a variety of host signals during infection. Of note was the number of genes found in genomic regions with altered %GC content that are upregulated within the mouse lung environment. These data suggest these regions may provide particularly promising targets for both vaccines and therapeutics.

Surfactant Dysfunction in ARDS and Bronchiolitis is Repaired with Cyclodextrins.

PubMed

Al-Saiedy, Mustafa; Gunasekara, Lasantha; Green, Francis; Pratt, Ryan; Chiu, Andrea; Yang, Ailian; Dennis, John; Pieron, Cora; Bjornson, Candice; Winston, Brent; Amrein, Matthias

2018-03-01

Acute respiratory distress syndrome (ARDS) is caused by many factors including inhalation of toxicants, acute barotrauma, acid aspiration, and burns. Surfactant function is impaired in ARDS and acute airway injury resulting in high surface tension with alveolar and small airway collapse, edema, hypoxemia, and death. In this study, we explore the mechanisms whereby surfactant becomes dysfunctional in ARDS and bronchiolitis and its repair with a cyclodextrin drug that sequesters cholesterol. We used in vitro model systems, a mouse model of ARDS, and samples from patients with acute bronchiolitis. Surface tension was measured by captive bubble surfactometry. Patient samples showed severe surfactant inhibition even in the absence of elevated cholesterol levels. Surfactant was also impaired in ARDS mice where the cholesterol to phospholipid ratio (W/W%) was increased. Methyl-β-cyclodextrin (MβCD) restored surfactant function to normal in both human and animal samples. Model studies showed that the inhibition of surfactant was due to both elevated cholesterol and an interaction between cholesterol and oxidized phospholipids. MβCD was also shown to have anti-inflammatory effects. Inhaled cyclodextrins have potential for the treatment of ARDS. They could be delivered in a portable device carried in combat and used following exposure to toxic gases and fumes or shock secondary to hemorrhage and burns.

Budesonide suppresses pulmonary antibacterial host defense by down-regulating cathelicidin-related antimicrobial peptide in allergic inflammation mice and in lung epithelial cells

PubMed Central

2013-01-01

Background Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells. Results Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro. Conclusions Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP. PMID:23387852

Exposure to Particulate Hexavalent Chromium Exacerbates Allergic Asthma Pathology

PubMed Central

Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

2011-01-01

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. PMID:22178736

Evaluation of oleoresin capsicum of Capsicum frutescenes var. Nagahari containing various percentages of capsaicinoids following inhalation as an active ingredient for tear gas munitions.

PubMed

Kumar, Pravin; Deb, Utsab; Kaushik, M P

2012-08-01

Comparative efficacy as peripheral sensory irritant, oral and inhalation exposure studies were carried out on oleoresin capsicum (OC) of Capsicum frutescence var. Nagahari containing various percentages of capsaicinoids and two synthetic isomers of capsaicin in Swiss albino male mouse model to come up with a suitable active ingredient from natural source for tear gas munitions. The compounds screened were OC having varying percentages of capsaicinoids (20, 40 and 80%, respectively) and synthetic isomers (E and Z) of capsaicin (8-methyl-N-vanillyl-6-nonenamide). Mice were exposed to pyrotechnically generated smoke of the compounds in an all glass static exposure chamber for 15 min to determine acute inhalation toxicity (LC₅₀) and quantitative sensory irritation potential (RD₅₀). Acute oral median lethal dose (LD₅₀) was also evaluated. Safety index of tear gas (SITG), a ratio of lethal concentration 50% (LC₅₀) and the concentration which depresses respiration by 50% (RD₅₀) due to peripheral sensory irritation is also proposed. The compound having highest SITG is considered as the most suitable to be used for tear gas munitions. The study revealed that oleoresin capsicum containing 40% capsaicinoids had the highest SITG among the compounds studied. The oral dosage versus mortality pattern of some compounds did not follow a true dose-response curve (DRC); however, following inhalation, all the compounds followed DRC. It was concluded that oleoresin capsicum (40% capsaicinoids) may be considered as the most suitable and environmental friendly compound from natural source to be used as an active ingredient for tear gas munitions.

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...

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...

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner

PubMed Central

Garcia-Arcos, Itsaso; Geraghty, Patrick; Baumlin, Nathalie; Campos, Michael; Dabo, Abdoulaye Jules; Jundi, Bakr; Cummins, Neville; Eden, Edward; Grosche, Astrid; Salathe, Matthias; Foronjy, Robert

2016-01-01

Background The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Methods Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Results Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Conclusions Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use. PMID:27558745

Study of in vivo exposure of single-walled carbon nanotubes in mouse liver

NASA Astrophysics Data System (ADS)

Lyons, Lyndon L.

Currently, few studies are available that have explored the role of carbon nanoparticles in liver toxicity. The susceptibility of the liver to nanoparticles rises from the inhalation exposure route often encountered during manufacturing and occupational exposure. Persons occupying these types of environmental setting are exposed to airborne nanoparticles less than 100nm, which have unobstructed access to most area of the lungs due to their size. Several reports have shown that single walled carbon nanotubes (SWCNTs) induce oxidative stress and pose the greatest cytotoxicity potential do to their size. Also, studies in mice indicate nanoparticles tend to accumulate in organs such as the spleen, kidney and liver, which is a major concern due to a lack of knowledge as to their fate. Single Wall Carbon Nanotubes (SWCNT's) are able to more easily penetrate through the cell membrane and display higher cell toxicity than Multi walled carbon nanotubes (MWCTs), opening the possibility for crossing various biological barriers within the body. Therefore effective occupational and environmental health risk assessments are significant in controlling the manufacture process of carbon nanotubes (CNTs). The present study was undertaken to determine the toxicity exhibited by SWCNT in mouse liver tissue as a model system. Mouse exposure during inhalation with and without SWCNT and reactive oxygen species (ROS) products were measured by change in fluorescence using dichloro fluorescein (DCF). The result showed no increase ROS on exposure of SWCNT in a dose and time dependent manner. Also, there is no reduction levels of glutathione (GSH) and super oxide dismutase (SOD), the antioxidant protective mechanism present in mouse liver cells upon SWCNT exposure. Lipid Peroxidation (LPO) and Lactate Dehydrogenase (LDH) assays indicated no tissue or protein damage. Additionally, Caspases --8 and --3 assays were conducted in order to understand the apoptotic signaling pathways initiated by oxidative stress. PEPCK and Hexokinase activity in mouse liver measured no hepatic glucokinase activity within the sensitivity of the assays. Based on the assays performed, the liver tolerated the SWCNT's 5mug dosage for 7 days, with no acute toxic effect. Although current tests and procedures may be appropriate to detect many risks associated with the use of these nanoparticles, it cannot be assumed that these assays will detect all potential risks. Given their limitations, specific emphasis should be on investigation in term of distribution in vivo both at the organ and cellular level using proteomics.

Nanostructured Lipid Carriers as Multifunctional Nanomedicine Platform for Pulmonary Co-Delivery of Anticancer Drugs and siRNA

PubMed Central

Taratula, Oleh; Kuzmov, Andriy; Shah, Milin; Garbuzenko, Olga B.; Minko, Tamara

2013-01-01

We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection. The NLCS showed enhanced antitumor activity when compared with intravenous treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs. PMID:23648833

1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta.

PubMed

Taher, Yousef A; van Esch, Betty C A M; Hofman, Gerard A; Henricks, Paul A J; van Oosterhout, Antoon J M

2008-04-15

1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a potent inhibitor of NF-kappaB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)(2)D(3) potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGF-beta are involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA, but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 microg. Interestingly, coadministration of 10 ng of 1,25(OH)(2)D(3) with 100 microg of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGF-beta and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-kappaB pathway using the selective IkappaB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-beta before OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)(2)D(3) potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGF-beta play a crucial role in the effector phase of this mouse model.

MyD88-dependent dendritic and epithelial cell crosstalk orchestrates immune responses to allergens.

PubMed

Thomas, S Y; Whitehead, G S; Takaku, M; Ward, J M; Xu, X; Nakano, K; Lyons-Cohen, M R; Nakano, H; Gowdy, K M; Wade, P A; Cook, D N

2018-05-01

Sensitization to inhaled allergens is dependent on activation of conventional dendritic cells (cDCs) and on the adaptor molecule, MyD88. However, many cell types in the lung express Myd88, and it is unclear how signaling in these different cell types reprograms cDCs and leads to allergic inflammation of the airway. By combining ATAC-seq with RNA profiling, we found that MyD88 signaling in cDCs maintained open chromatin at select loci even at steady state, allowing genes to be rapidly induced during allergic sensitization. A distinct set of genes related to metabolism was indirectly controlled in cDCs through MyD88 signaling in airway epithelial cells (ECs). In mouse models of asthma, Myd88 expression in ECs was critical for eosinophilic inflammation, whereas Myd88 expression in cDCs was required for Th17 cell differentiation and consequent airway neutrophilia. Thus, both cell-intrinsic and cell-extrinsic MyD88 signaling controls gene expression in cDCs and orchestrates immune responses to inhaled allergens.

Thrombomodulin inhibits the activation of eosinophils and mast cells.

PubMed

Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

2015-01-01

Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular Imaging of Smoke-Induced Changes in Nuclear Factor-Kappa B Expression in Murine Tissues Including the Lung.

PubMed

Syrkina, Olga; Hales, Charles H; Bonab, Ali A; Hamrahi, Victoria; Paul, Kasie; Jung, Walter J; Tompkins, Ronald G; Fischman, Alan J; Carter, Edward A

Many inflammatory responses are mediated by activation of the transcription factor, nuclear factor-kappa B (NF-κB), and a wide variety of human diseases involve abnormal regulation of its expression. In this investigation, we evaluated the effect of smoke inhalation injury on NF-κB expression in lung using two strains of NF-κB reporter mice. Groups of reporter mice with viral thymidine kinase (TK) or "fire fly" luciferase (Luc) genes under control by the NF-κB promoter (TK/NF-κB mice and Luc/NF-κB mice) were subjected to nonlethal smoke inhalation injury. Sham-treated animals served as controls. Twenty-four hours (each animal was injected intravenously with either 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (FHBG) (~ 1.0 mCi) or luciferin (1.0 mg). One hour later, the TK/NF-κB mice were studied by micro-positron emission tomography (µ-PET) imaging using a Concord P4 µ-PET camera, and the Luc/NF-κB mice were studied by bioluminescence imaging with a charge-coupled device camera. The µ-PET data demonstrated that smoke injury produced massive increases in NF-κB expression (FHBG-standardized uptake value: 3.1 vs 0.0) 24 hours after smoke inhalation, which was reduced 48 hours after smoke inhalation, but still significantly different than the control. Qualitative analysis of the bioluminescence data revealed a remarkably similar effect of burn NF-κB luciferase expression in vivo. Biodistribution studies of FHBG uptake and luciferase activity in lung tissue demonstrated a similar increase 24 hours after injury, which was reduced 48 hours later, but still significantly higher than the sham. The present data with these models providing longitudinal imaging data on the same mouse may prove useful in the examination of the factors producing lung injury by smoke inhalation, as well as the treatment(s) for the damage produced with and without burn injury.

Modeling Deposition of Inhaled Particles

EPA Science Inventory

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 therapeutic dose delivered by inhaled pharmacological drugs. Howeve...

Long-term exposure to PM2.5 lowers influenza virus resistance via down-regulating pulmonary macrophage Kdm6a and mediates histones modification in IL-6 and IFN-β promoter regions.

PubMed

Ma, Jing-Hui; Song, Shao-Hua; Guo, Meng; Zhou, Ji; Liu, Fang; Peng, Li; Fu, Zhi-Ren

2017-11-18

Atmospheric particulates, especially PM2.5, not only damage the respiratory system, but also play important roles in pulmonary immunity. China is influenced by atmospheric diffusion conditions, industrial manufacturers, and heating and discharging. PM2.5 levels in the air rise substantially in the winter, which is also a period of flu high-incidence. Although an epidemiological link exists between PM2.5 and flu, we do not understand how long-term PM2.5 inhalation affects pulmonary immunity and the influenza virus response. Our study has prepared an in vivo PM2.5 mouse pharyngeal wall drop-in model and has found that PM2.5 exposure leads to mouse inflammatory injuries and furthers influenza A infection. Our results suggest that short-term exposure to PM2.5 significantly enhances the survival rate of influenza A-contaminated mice, while long-term PM2.5 inhalation lowers the capacity of pulmonary macrophages to secrete IL-6 and IFN-β. A disorder in the pulmonary innate defense system results in increased death rates following influenza infection. On a macromolecular level, this mechamism involves Kdm6a down-regulation after long-term exposure to PM 2.5 and a resultant increase in H3K4 and H3K9 methylation in IL-6 and IFN-β promoter regions. In summary, PM2.5 causes injuries of lung tissue cells and downregulates immune defense mechanisms in the lung. Copyright © 2017. Published by Elsevier Inc.

TARGETED DELIVERY OF INHALED PHARMACEUTICALS USING AN IN SILICO DOSIMETRY MODEL

EPA Science Inventory

We present an in silico dosimetry model which can be used for inhalation toxicology (risk assessment of inhaled air pollutants) and aerosol therapy ( targeted delivery of inhaled drugs). This work presents scientific and clinical advances beyond the development of the original in...

Oxidative Stress, Inflammatory Biomarkers and Toxicity in Mouse Lung and Liver after Inhalation Exposure to 100% Biodiesel or Petroleum Diesel Emissions

EPA Science Inventory

BACKGROUND: Over the past decade, biodiesel (BD) has become a first alternative energy source that is economically viable and meets requirements of the Clean Air Act. Due to lower mass emissions and reduced hazardous compounds compared to diesel combustion emissions (CE), BD expo...

Antimalarial activity of the terpene nerolidol.

PubMed

Saito, Alexandre Y; Marin Rodriguez, Adriana A; Menchaca Vega, Danielle S; Sussmann, Rodrigo A C; Kimura, Emília A; Katzin, Alejandro M

2016-12-01

Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent. In this study, the antimalarial activity of nerolidol was investigated in a mouse model of malaria. Mice were infected with Plasmodium berghei ANKA and were treated with 1000 mg/kg/dose nerolidol in two doses delivered by the oral or inhalation route. In mice treated with nerolidol, parasitaemia was inhibited by >99% (oral) and >80% (inhalation) until 14 days after infection (P <0.0001). On Day 30 post-infection, the survival rate of orally treated mice was 90% compared with 16% in controls (P <0.0001). In contrast, inhalation-treated mice showed a survival rate of 50% vs. 42% in controls (P > 0.05). The toxicity of nerolidol administered by either route was not significant, whilst genotoxicity was observed only at the highest dose tested. These results indicate that combined use of nerolidol and other drugs targeting different points of the same isoprenoid pathway may be an effective treatment for malaria. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Hydrodynamics of Low Reynolds Respiratory-type Flows

NASA Astrophysics Data System (ADS)

Connor, Erin; True, Aaron; Crimaldi, John

2017-11-01

Both aquatic and terrestrial animals inhale surrounding fluid for metabolic and sensory purposes. As organisms inhale and exhale, complex fluid interactions occur both internal and external to the physiological orifice. Using both numerical and experimental approaches, we model an idealized respiratory flow consisting of cyclic inhalation and exhalation through a single cylindrical tube. We investigate the effect of varying Reynolds number (Re) as well as the ratio of the inhalation time to the exhalation time (I:E ratio) for a fixed inhalation volume. The numerical model is used for laminar cases at lower Re, whereas the experimental model permits the study to be extended into higher Reynolds numbers that include transitions to turbulence. We map the spatial distribution of both inhaled and exhaled fluid volumes. By comparing these two maps, we can compute the volume of exhaled fluid that is reingested during the subsequent inhalation. The models of interacting inhalation and exhalation exhibit a rich range of flow behaviors across Re number and I:E ratio. This study builds a foundation for more complex studies of animal respiration that will include more realistic morphologies.

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner.

PubMed

Garcia-Arcos, Itsaso; Geraghty, Patrick; Baumlin, Nathalie; Campos, Michael; Dabo, Abdoulaye Jules; Jundi, Bakr; Cummins, Neville; Eden, Edward; Grosche, Astrid; Salathe, Matthias; Foronjy, Robert

2016-12-01

The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kloft, Charlotte

2015-07-01

During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction.

PubMed

Deshpande, Deepak A; Wang, Wayne C H; McIlmoyle, Elizabeth L; Robinett, Kathryn S; Schillinger, Rachel M; An, Steven S; Sham, James S K; Liggett, Stephen B

2010-11-01

Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²(+)](i)) in ASM in a Gβγ-, phospholipase Cβ (PLCβ)- and inositol trisphosphate (IP₃) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by β-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

Arsenic Compromises Conducting Airway Epithelial Barrier Properties in Primary Mouse and Immortalized Human Cell Cultures

PubMed Central

Sherwood, Cara L.; Liguori, Andrew E.; Olsen, Colin E.; Lantz, R. Clark; Burgess, Jefferey L.; Boitano, Scott

2013-01-01

Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 μM) and submicromolar (0.8 μM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway. PMID:24349408

Metabolic Rate M[superscript 0.75] in Human Beings

ERIC Educational Resources Information Center

Agrawal. D. C.

2014-01-01

Human beings consume energy every day. Even at rest, energy is still needed for the working of the internal organs. This is achieved by the metabolism of consumed food in the presence of inhaled oxygen. During the resting state this is called the maintenance rate, and follows the mouse-to-elephant formula, P[subscript met] = 70M[superscript 0.75]…

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig.

PubMed

Gutting, Bradford W; Rukhin, Andrey; Mackie, Ryan S; Marchette, David; Thran, Brandolyn

2015-05-01

The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species. © 2014 Society for Risk Analysis.

Cough and expiration reflexes elicited by inhaled irritant gases are intensified in ovalbumin-sensitized mice.

PubMed

Zhang, Cheng; Lin, Ruei-Lung; Hong, Jeff; Khosravi, Mehdi; Lee, Lu-Yuan

2017-05-01

This study was designed to determine the effect of active sensitization with ovalbumin (Ova) on cough responses to inhaled irritant gases in mice. Conscious mice moved freely in a recording chamber, while the pressure change in the chamber and audio and video signals of the mouse movements were recorded simultaneously to measure the frequencies of cough reflex (CR) and expiration reflex (ER). To further verify the accuracy of cough analysis, the intrapleural pressure was also recorded by a telemetry sensor surgically implanted in the intrapleural space in a subgroup of mice. During the irritant gas inhalation challenge, sulfur dioxide (SO 2 ; 200 and 400 ppm) or ammonia (NH 3 ; 0.1% and 0.2%) was drawn into the chamber at a constant flow rate for 8 min. Ova sensitization and sham sensitization with vehicle (Veh) were performed over a 25-day period in separate groups of mice. Our results showed that 1 ) both SO 2 and NH 3 inhalation challenges increased CR and ER frequencies in a concentration-dependent manner before Ova sensitization; 2 ) the baseline CR frequency was significantly elevated after Ova sensitization, accompanied by pronounced airway inflammation; and 3 ) Ova sensitization also markedly augmented the responses of CR and ER to both SO 2 and NH 3 inhalation challenges; in sharp contrast, the cough responses did not change after sham sensitization in the Veh group. In conclusion, Ova sensitization caused distinct and lingering increases in baseline cough frequency, and also intensified both CR and ER responses to inhaled irritant gases, which probably resulted from an allergic inflammation-induced hypersensitivity of airway sensory nerves. Copyright © 2017 the American Physiological Society.

Mathematical modeling of inhalation exposure

NASA Technical Reports Server (NTRS)

Fiserova-Bergerova, V.

1976-01-01

The paper presents a mathematical model of inhalation exposure in which uptake, distribution and excretion are described by exponential functions, while rate constants are determined by tissue volumes, blood perfusion and by the solubility of vapors (partition coefficients). In the model, tissues are grouped into four pharmokinetic compartments. The model is used to study continuous and interrupted chronic exposures and is applied to the inhalation of Forane and methylene chloride.

Dry deposition of pollutant and marker particles onto live mouse airway surfaces enhances monitoring of individual particle mucociliary transit behaviour.

PubMed

Donnelley, Martin; Morgan, Kaye S; Siu, Karen K W; Parsons, David W

2012-07-01

Particles suspended in the air are inhaled during normal respiration and unless cleared by airway defences, such as the mucociliary transit (MCT) system, they can remain and affect lung and airway health. Synchrotron phase-contrast X-ray imaging (PCXI) methods have been developed to non-invasively monitor the behaviour of individual particles in live mouse airways and in previous studies the MCT behaviour of particles and fibres in the airways of live mice after deposition in a saline carrier fluid have been examined. In this study a range of common respirable pollutant particles (lead dust, quarry dust and fibreglass fibres) as well as marker particles (hollow glass micro-spheres) were delivered into the trachea of live mice using a dry powder insufflator to more accurately mimic normal environmental particulate exposure and deposition via inhalation. The behaviour of the particles once delivered onto the airway surface was tracked over a five minute period via PCXI. All particles were visible after deposition. Fibreglass fibres remained stationary throughout while all other particle types transited the tracheal surface throughout the imaging period. In all cases the majority of the particle deposition and any airway surface activity was located close to the dorsal tracheal wall. Both the individual and bulk motions of the glass bead marker particles were visible and their behaviour enabled otherwise hidden MCT patterns to be revealed. This study verified the value of PCXI for examining the post-deposition particulate MCT behaviour in the mouse trachea and highlighted that MCT is not a uniform process as suggested by radiolabel studies. It also directly revealed the advantages of dry particle delivery for establishing adequate particulate presence for visualizing MCT behaviour. The MCT behaviour and rate seen after dry particle delivery was different from that in previous carrier-fluid studies. It is proposed that dry particle delivery is essential for producing environmentally realistic particle deposition and studying how living airway surfaces handle different types of inhaled particles by MCT processes.

MODELING APPROACHES FOR ESTIMATING THE DOSIMETRY OF INHALED TOXICANTS IN CHILDREN

EPA Science Inventory

Risk assessment of inhaled toxicants has typically focused upon adults, with modeling used to extrapolate dosimetry and risks from laboratory animals to humans. However, behavioral factors such as time spent playing outdoors can lead to more exposure to inhaled toxicants in chil...

Inhalation Frequency Controls Reformatting of Mitral/Tufted Cell Odor Representations in the Olfactory Bulb.

PubMed

Díaz-Quesada, Marta; Youngstrom, Isaac A; Tsuno, Yusuke; Hansen, Kyle R; Economo, Michael N; Wachowiak, Matt

2018-02-28

In mammals, olfactory sensation depends on inhalation, which controls activation of sensory neurons and temporal patterning of central activity. Odor representations by mitral and tufted (MT) cells, the main output from the olfactory bulb (OB), reflect sensory input as well as excitation and inhibition from OB circuits, which may change as sniff frequency increases. To test the impact of sampling frequency on MT cell odor responses, we obtained whole-cell recordings from MT cells in anesthetized male and female mice while varying inhalation frequency via tracheotomy, allowing comparison of inhalation-linked responses across cells. We characterized frequency effects on MT cell responses during inhalation of air and odorants using inhalation pulses and also "playback" of sniffing recorded from awake mice. Inhalation-linked changes in membrane potential were well predicted across frequency from linear convolution of 1 Hz responses; and, as frequency increased, near-identical temporal responses could emerge from depolarizing, hyperpolarizing, or multiphasic MT responses. However, net excitation was not well predicted from 1 Hz responses and varied substantially across MT cells, with some cells increasing and others decreasing in spike rate. As a result, sustained odorant sampling at higher frequencies led to increasing decorrelation of the MT cell population response pattern over time. Bulk activation of sensory inputs by optogenetic stimulation affected MT cells more uniformly across frequency, suggesting that frequency-dependent decorrelation emerges from odor-specific patterns of activity in the OB network. These results suggest that sampling behavior alone can reformat early sensory representations, possibly to optimize sensory perception during repeated sampling. SIGNIFICANCE STATEMENT Olfactory sensation in mammals depends on inhalation, which increases in frequency during active sampling of olfactory stimuli. We asked how inhalation frequency can shape the neural coding of odor information by recording from projection neurons of the olfactory bulb while artificially varying odor sampling frequency in the anesthetized mouse. We found that sampling an odor at higher frequencies led to diverse changes in net responsiveness, as measured by action potential output, that were not predicted from low-frequency responses. These changes led to a reorganization of the pattern of neural activity evoked by a given odorant that occurred preferentially during sustained, high-frequency inhalation. These results point to a novel mechanism for modulating early sensory representations solely as a function of sampling behavior. Copyright © 2018 the authors 0270-6474/18/382189-18$15.00/0.

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.

Protocols to Evaluate Cigarette Smoke-Induced Lung Inflammation and Pathology in Mice.

PubMed

Vlahos, Ross; Bozinovski, Steven

2018-01-01

Cigarette smoking is a major cause of chronic obstructive pulmonary disease (COPD). Inhalation of cigarette smoke causes inflammation of the airways, airway wall remodelling, mucus hypersecretion and progressive airflow limitation. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, in particular skeletal muscle wasting, cardiovascular disease and lung cancer markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. Here we describe a mouse model that we have developed to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the development of comorbidities of COPD.

Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice.

PubMed

Zeidler-Erdely, Patti C; Battelli, Lori A; Stone, Sam; Chen, Bean T; Frazer, David G; Young, Shih-Houng; Erdely, Aaron; Kashon, Michael L; Andrews, Ronnee; Antonini, James M

2011-02-01

Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)×3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice.

The effect of study type on body weight and tumor incidence in B6C3F1 mice fed the NTP-2000 diet.

PubMed

Marino, Dale J

2012-07-01

The B6C3F1 mouse is the standard mouse strain used in National Toxicology Program (NTP) carcinogenesis studies. Over time, increased liver tumorigenesis that was correlated with elevated body weights was noted in males and females. NTP therefore replaced the NIH-07 diet with the NTP-2000 diet and returned to group housing of females as lower body weights were noted in group housed mice. However, recent studies reported study-type differences in body weights at 3 months using the NTP-2000 diet with higher weights evident in drinking water and inhalation studies compared to feed studies. Therefore, body weight and tumor incidence data were collected for untreated control mice from all 2-year NTP feed (12), drinking water (8), water gavage (6) and inhalation (10) studies that used the NTP-2000 diet in order to assess the impact of study type on body weights and tumor incidences. Results show statistically significant elevated body weights and liver tumor incidences in males and females from drinking water, water gavage and inhalation studies compared to results from feed studies. Thus, the elevated body weights and liver tumorigenesis noted in mice using the NIH-07 diet were also evident using the NTP-2000 diet, which was introduced to address body weight elevations. Given the study-type dependent effects noted, these results emphasize the importance of carefully selecting historical control data for B6C3F1 mice. Moreover, because of the association between body weight and liver tumorigenesis, these results may have implications regarding dose-level selection for carcinogenicity studies involving B6C3F1 mice based on the maximum tolerated dose.

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

Fiber inhalability and head deposition in rats and humans. ...

EPA Pesticide Factsheets

Due to their dimensions and long durability, inhaled asbestos fibers clear slowly from lung airways. Retained fibers may injure the epithelium, interact with macrophages, or translocate to the interstitium to result in various respiratory diseases. Therefore, calculations of fiber inhalability, deposition, and retention in respiratory tract regions of both rats and humans are crucial, both to assess the health risk of fiber exposures and to facilitate inferences from rat inhalation studies. Rat inhalation experiments are underway at the EPA and NIEHS. A model of fiber inhalability and initial deposition in the human and rat nasal cavity was developed. Existing models for particles were extended to fibers by replacing particle diameter with an equivalent fiber diameter. Since fiber inhalability into the respiratory tract and deposition in the extra thoracic airways depended mainly on its inertia, equivalent impaction diameters were derived and substituted in expressions for spherical particle diameter to determine fiber inhalability and nasal losses. Fiber impaction diameter depended strongly on its orientation in the air. Highest inhalability was obtained when fibers were aligned perpendicular to the flow streamlines in the inhaled air. However, detailed calculations of fiber transport in slow moving air such as that in the atmosphere and in lung airways showed that fibers stayed primarily aligned (parallel) to the flow. Therefore, for inhalability calculations,

Interactions between ethanol and cigarette smoke in a mouse lung carcinogenesis model.

PubMed

Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Nikolov, Manasi; La Maestra, S; Micale, Rosanna T; Steele, Vernon E; De Flora, Silvio

2016-12-12

Both ethanol and cigarette smoke are classified as human carcinogens. They can synergize, especially in tissues of the upper aerodigestive tract that are targeted by both agents. The main objective of the present study was to evaluate the individual and combined effects of ethanol and smoke in the respiratory tract, either following transplacental exposure and/or postnatal exposure. We designed two consecutive studies in mouse models by exposing Swiss H mice to oral ethanol and/or inhaled mainstream cigarette smoke for up to 4 months, at various prenatal and postnatal life stages. Clastogenic effects and histopathological alterations were evaluated after 4 and 8 months, respectively. Ethanol was per se devoid of clastogenic effects in mouse peripheral blood erythrocytes. However, especially in mice exposed both transplacentally throughout pregnancy and in the postnatal life, ethanol administration was associated not only with liver damage but also with pro-angiogenetic effects in the lung by stimulating the proliferation of blood vessels. In addition, these mice developed pulmonary emphysema, alveolar epithelial hyperplasias, microadenomas, and benign tumors. On the other hand, ethanol interfered in the lung carcinogenesis process resulting from the concomitant exposure of mice to smoke. In fact, ethanol significantly attenuated some smoke-related preneoplastic and neoplastic lesions in the respiratory tract, such as alveolar epithelial hyperplasia, microadenomas, and even malignant tumors. In addition, ethanol attenuated cigarette smoke clastogenicity. In conclusion, preclinical studies provide evidence that, in spite of its pulmonary toxicity, ethanol may mitigate some noxious effects of cigarette smoke in the respiratory tract. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Acceleration of Advanced CN Antidote Agents for Mass Exposure Treatments: DMTS

DTIC Science & Technology

2014-12-01

Intraosseous Injection; Inhalational Delivery 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE...exposure models. We have administered antidotes via intramuscular injection, inhalation, and intraosseous routes. These animal models are all available...injection, inhalation, and intraosseous routes. These animal models are all available for ongoing testing of the novel candidate antidotes as was

Development and evaluation of an innovative model of inter-professional education focused on asthma medication use

PubMed Central

2014-01-01

Background Inter-professional learning has been promoted as the solution to many clinical management issues. One such issue is the correct use of asthma inhaler devices. Up to 80% of people with asthma use their inhaler device incorrectly. The implications of this are poor asthma control and quality of life. Correct inhaler technique can be taught, however these educational instructions need to be repeated if correct technique is to be maintained. It is important to maximise the opportunities to deliver this education in primary care. In light of this, it is important to explore how health care providers, in particular pharmacists and general medical practitioners, can work together in delivering inhaler technique education to patients, over time. Therefore, there is a need to develop and evaluate effective inter-professional education, which will address the need to educate patients in the correct use of their inhalers as well as equip health care professionals with skills to engage in collaborative relationships with each other. Methods This mixed methods study involves the development and evaluation of three modules of continuing education, Model 1, Model 2 and Model 3. A fourth group, Model 4, acting as a control. Model 1 consists of face-to-face continuing professional education on asthma inhaler technique, aimed at pharmacists, general medical practitioners and their practice nurses. Model 2 is an electronic online continuing education module based on Model 1 principles. Model 3 is also based on asthma inhaler technique education but employs a learning intervention targeting health care professional relationships and is based on sociocultural theory. This study took the form of a parallel group, repeated measure design. Following the completion of continuing professional education, health care professionals recruited people with asthma and followed them up for 6 months. During this period, inhaler device technique training was delivered and data on patient inhaler technique, clinical and humanistic outcomes were collected. Outcomes related to professional collaborative relationships were also measured. Discussion Challenges presented included the requirement of significant financial resources for development of study materials and limited availability of validated tools to measure health care professional collaboration over time. PMID:24708800

Development and evaluation of an innovative model of inter-professional education focused on asthma medication use.

PubMed

Bosnic-Anticevich, Sinthia Z; Stuart, Meg; Mackson, Judith; Cvetkovski, Biljana; Sainsbury, Erica; Armour, Carol; Mavritsakis, Sofia; Mendrela, Gosia; Travers-Mason, Pippa; Williamson, Margaret

2014-04-07

Inter-professional learning has been promoted as the solution to many clinical management issues. One such issue is the correct use of asthma inhaler devices. Up to 80% of people with asthma use their inhaler device incorrectly. The implications of this are poor asthma control and quality of life. Correct inhaler technique can be taught, however these educational instructions need to be repeated if correct technique is to be maintained. It is important to maximise the opportunities to deliver this education in primary care. In light of this, it is important to explore how health care providers, in particular pharmacists and general medical practitioners, can work together in delivering inhaler technique education to patients, over time. Therefore, there is a need to develop and evaluate effective inter-professional education, which will address the need to educate patients in the correct use of their inhalers as well as equip health care professionals with skills to engage in collaborative relationships with each other. This mixed methods study involves the development and evaluation of three modules of continuing education, Model 1, Model 2 and Model 3. A fourth group, Model 4, acting as a control.Model 1 consists of face-to-face continuing professional education on asthma inhaler technique, aimed at pharmacists, general medical practitioners and their practice nurses.Model 2 is an electronic online continuing education module based on Model 1 principles.Model 3 is also based on asthma inhaler technique education but employs a learning intervention targeting health care professional relationships and is based on sociocultural theory.This study took the form of a parallel group, repeated measure design. Following the completion of continuing professional education, health care professionals recruited people with asthma and followed them up for 6 months. During this period, inhaler device technique training was delivered and data on patient inhaler technique, clinical and humanistic outcomes were collected. Outcomes related to professional collaborative relationships were also measured. Challenges presented included the requirement of significant financial resources for development of study materials and limited availability of validated tools to measure health care professional collaboration over time.

The role of first use of inhalants within sequencing pattern of first use of drugs among Brazilian university students

PubMed Central

Castaldelli-Maia, João Maurício; Martins, Silvia S.; de Oliveira, Lúcio Garcia; de Andrade, Arthur Guerra; Nicastri, Sérgio

2014-01-01

The present study investigated the role of first use of inhalants within a first drug sequencing pattern. In a representative sample of university students from 27 Brazilian capitals (n=12,711), we analyzed the patterns of transition from/to first use of inhalants to/from the first use of alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, amphetamines, prescription opioids, and tranquilizers. Cox proportional hazards models were used to analyze data. Drugs that were not specified as the pair of drugs tested in each model were included as time-varying covariates in all models. In this sample, first use of inhalants was preceded only by the first use of alcohol and tobacco. However, first use of inhalants preceded first use of cannabis, amphetamines, cocaine, and tranquilizers. First use of inhalants preceded the first use of prescription opioids, and vice versa. This study highlights the need to intervene early with youths who are at risk of or just beginning to use inhalants, since this class of drugs seems to be the first illegal drug in Brazil to be experimented by respondents in our sample. There is also a call for attention to individuals who have already first used inhalants because of their higher chance to experiment with other drugs such as cannabis, cocaine, and prescription drugs. All these findings show an in-transition culture of drug use, which should be tracked through the time, since some classical models (i.e., gateway model) might be outdated and might also not fit within different settings. PMID:25150538

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers.

PubMed

Jonkman, Kelly; Duma, Andreas; Olofsen, Erik; Henthorn, Thomas; van Velzen, Monique; Mooren, René; Siebers, Liesbeth; van den Beukel, Jojanneke; Aarts, Leon; Niesters, Marieke; Dahan, Albert

2017-10-01

Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

PubMed

Zandvliet, Anthe S; Huitema, Alwin D R; de Jonge, Milly E; den Hoed, Rob; Sparidans, Rolf W; Hendriks, Vincent M; van den Brink, Wim; van Ree, Jan M; Beijnen, Jos H

2005-01-01

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice.

PubMed

Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Han, Jin-Young; Kim, Bumseok; Lee, Kyuhong

2018-01-01

Cadmium (Cd) is a toxic metal present in tobacco smoke, air, food, and water. Inhalation is an important route of Cd exposure, and lungs are one of the main target organs for metal-induced toxicity. Cd inhalation is associated with an increased risk of pulmonary diseases. The present study aimed to assess the effects of repeated exposure to low-dose Cd in a mouse model of polyhexamethylene guanidine (PHMG)-induced lung fibrosis. Mice were grouped into the following groups: vehicle control (VC), PHMG, cadmium chloride (CdCl 2 ), and PHMG + CdCl 2 . Animals in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissues. These parameters were exacerbated in mice in the PHMG + CdCl 2 group. In contrast, mice in the CdCl 2 group alone displayed only minimal inflammation in pulmonary tissue. Expression of inflammatory cytokines and fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, expression of these cytokines and mediators was enhanced in pulmonary tissue in mice administered PHMG + CdCl 2 . Data demonstrate that repeated exposure to low-dose Cd may enhance the development of PHMG-induced pulmonary fibrosis.

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.

Endotoxins: The Critical Risk Factor in Reclaimed Water via Inhalation Exposure.

PubMed

Xue, Jinling; Zhang, Jinshan; Xu, Bi; Xie, Jiani; Wu, Wenzhao; Lu, Yun

2016-11-01

The use of reclaimed water for nonpotable uses requires consideration of potential adverse health effects. Considering that inhalation can be a significant route of transmission of microorganisms and inflammatory agents, this study used a mouse model to test the possible adverse effects of reclaimed water use during car washing where aerosols are generated. Intensive innate immune responses were found in the lungs after acute exposure, and the lavage polymorphonuclear cell proportion was the most sensitive end point. Four types of evidence are presented to demonstrate that the main risk factor that initiates innate inflammation is the free endotoxin. (1) Small molecules (<10 kDa) cannot induce inflammation. (2) The endotoxin levels of 11 water samples from five different plants showed positive correlations with inflammatory responses. (3) Actual water samples showed similar activities with free endotoxins other than bacterially bound endotoxins. (4) Specific removal of endotoxins with polymyxin B affinity chromatography further confirmed the role of free endotoxins. It is noteworthy that 62.9% of the investigated tertiary-treated water had endotoxin levels higher than the allowable acute threshold (120 endotoxin units/mL) under the hypothesized car wash condition, which strongly suggests the need to carefully consider the water treatment steps required to produce safe water for various reclaimed water end uses.

The chemo and the mona: inhalants, devotion and street youth in Mexico City.

PubMed

Gigengack, Roy

2014-01-01

This paper understands inhalant use--the deliberate inhalation of volatile solvents or glues with intentions of intoxication--as a socially and culturally constituted practice. It describes the inhalant use of young street people in Mexico City from their perspective ("the vicioso or inhalant fiend's point of view"). Even if inhalant use is globally associated with economic inequality and deprivation, there is a marked lack of ethnography. Incomprehension and indignation have blocked our understanding of inhalant use as a form of marginalised drug use. The current explanation models reduce inhalant consumption to universal factors and individual motives; separating the practice from its context, these models tend to overlook gustatory meanings and experiences. The paper is informed by long-term, on-going fieldwork with young street people in Mexico City. Fieldwork was done from 1990 through 2010, in regular periods of fieldwork and shorter visits, often with Mexican colleagues. We created extensive sets of fieldnotes, which were read and re-read. "Normalcy" is a striking feature of inhalant use in Mexico City. Street-wise inhabitants of popular neighbourhoods have knowledge about inhalants and inhalant users, and act accordingly. Subsequently, Mexico City's elaborate street culture of sniffing is discussed, that is, the range of inhalants used, how users classify the substances, and their techniques for sniffing. The paper also distinguishes three patterns of inhalant use, which more or less correlate with age. These patterns indicate embodiments of street culture: the formation within users of gusto, that is, an acquired appetite for inhalants, and of vicio, the inhalant fiends' devotion to inhalants. What emerges from the ethnographic findings is an elaborate street culture of sniffing, a complex configuration of shared perspectives and embodied practices, which are shaped by and shaping social exclusion. These findings are relevant to appreciate and address the inhalant fiends' acquired appetite and habit. Copyright © 2013 Elsevier B.V. All rights reserved.

Toxicological perspectives of inhaled therapeutics and nanoparticles.

PubMed

Hayes, Amanda J; Bakand, Shahnaz

2014-07-01

The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air-liquid interface. Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system.

Basis for the ICRP’s updated biokinetic model for carbon inhaled as CO 2

DOE PAGES

Leggett, Richard W.

2017-03-02

Here, the International Commission on Radiological Protection (ICRP) is updating its biokinetic and dosimetric models for occupational intake of radionuclides (OIR) in a series of reports called the OIR series. This paper describes the basis for the ICRP's updated biokinetic model for inhalation of radiocarbon as carbon dioxide (CO 2) gas. The updated model is based on biokinetic data for carbon isotopes inhaled as carbon dioxide or injected or ingested as bicarbonatemore » $$({{{\\rm{HCO}}}_{3}}^{-}).$$ The data from these studies are expected to apply equally to internally deposited (or internally produced) carbon dioxide and bicarbonate based on comparison of excretion rates for the two administered forms and the fact that carbon dioxide and bicarbonate are largely carried in a common form (CO 2–H$${{{\\rm{CO}}}_{3}}^{-})$$ in blood. Compared with dose estimates based on current ICRP biokinetic models for inhaled carbon dioxide or ingested carbon, the updated model will result in a somewhat higher dose estimate for 14C inhaled as CO 2 and a much lower dose estimate for 14C ingested as bicarbonate.« less

Basis for the ICRP’s updated biokinetic model for carbon inhaled as CO 2

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

Leggett, Richard W.

Here, the International Commission on Radiological Protection (ICRP) is updating its biokinetic and dosimetric models for occupational intake of radionuclides (OIR) in a series of reports called the OIR series. This paper describes the basis for the ICRP's updated biokinetic model for inhalation of radiocarbon as carbon dioxide (CO 2) gas. The updated model is based on biokinetic data for carbon isotopes inhaled as carbon dioxide or injected or ingested as bicarbonatemore » $$({{{\\rm{HCO}}}_{3}}^{-}).$$ The data from these studies are expected to apply equally to internally deposited (or internally produced) carbon dioxide and bicarbonate based on comparison of excretion rates for the two administered forms and the fact that carbon dioxide and bicarbonate are largely carried in a common form (CO 2–H$${{{\\rm{CO}}}_{3}}^{-})$$ in blood. Compared with dose estimates based on current ICRP biokinetic models for inhaled carbon dioxide or ingested carbon, the updated model will result in a somewhat higher dose estimate for 14C inhaled as CO 2 and a much lower dose estimate for 14C ingested as bicarbonate.« less

Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

PubMed

Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

2016-03-01

Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

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

Nikula, K.J.; Swafford, D.S.; Hoover, M.D.

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2{sup k}) Mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro.more » Responses were similar in both strains of mice. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO{sub 4} in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease. 29 refs., 6 figs., 3 tabs.« less

Inhaled hydrogen sulfide: a rapidly reversible inhibitor of cardiac and metabolic function in the mouse.

PubMed

Volpato, Gian Paolo; Searles, Robert; Yu, Binglan; Scherrer-Crosbie, Marielle; Bloch, Kenneth D; Ichinose, Fumito; Zapol, Warren M

2008-04-01

Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation-like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model. The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment. Breathing H2S at 80 parts per million by volume at 27 degrees C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35 degrees C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27 degrees or 35 degrees C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing. Inhalation of H2S at either 27 degrees or 35 degrees C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature.

Mechanism of Action of Lung Damage Caused by a Nanofilm Spray Product

PubMed Central

Larsen, Søren T.; Dallot, Constantin; Larsen, Susan W.; Rose, Fabrice; Poulsen, Steen S.; Nørgaard, Asger W.; Hansen, Jitka S.; Sørli, Jorid B.; Nielsen, Gunnar D.; Foged, Camilla

2014-01-01

Inhalation of waterproofing spray products has on several occasions caused lung damage, which in some cases was fatal. The present study aims to elucidate the mechanism of action of a nanofilm spray product, which has been shown to possess unusual toxic effects, including an extremely steep concentration-effect curve. The nanofilm product is intended for application on non-absorbing flooring materials and contains perfluorosiloxane as the active film-forming component. The toxicological effects and their underlying mechanisms of this product were studied using a mouse inhalation model, by in vitro techniques and by identification of the binding interaction. Inhalation of the aerosolized product gave rise to increased airway resistance in the mice, as evident from the decreased expiratory flow rate. The toxic effect of the waterproofing spray product included interaction with the pulmonary surfactants. More specifically, the active film-forming components in the spray product, perfluorinated siloxanes, inhibited the function of the lung surfactant due to non-covalent interaction with surfactant protein B, a component which is crucial for the stability and persistence of the lung surfactant film during respiration. The active film-forming component used in the present spray product is also found in several other products on the market. Hence, it may be expected that these products may have a toxicity similar to the waterproofing product studied here. Elucidation of the toxicological mechanism and identification of toxicological targets are important to perform rational and cost-effective toxicological studies. Thus, because the pulmonary surfactant system appears to be an important toxicological target for waterproofing spray products, study of surfactant inhibition could be included in toxicological assessment of this group of consumer products. PMID:24863969

Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide.

PubMed

Dufour, Gilles; Bigazzi, William; Wong, Nelson; Boschini, Frederic; de Tullio, Pascal; Piel, Geraldine; Cataldo, Didier; Evrard, Brigitte

2015-11-30

To achieve an efficient lung delivery and efficacy, both active ingredient aerosolisation properties and permeability through the lung need to be optimized. To overcome these challenges, the present studies aim to develop cyclodextrin-based spray-dried microparticles containing a therapeutic corticosteroid (budesonide) that could be used to control airway inflammation associated with asthma. The complexation between budesonide and hydroxypropyl-β-cyclodextrin (HPBCD) has been investigated. Production of inhalation powders was carried out using a bi-fluid nozzle spray dryer and was optimized based on a design of experiments. Spray-dried microparticles display a specific "deflated-ball like shape" associated with an appropriate size for inhalation. Aerodynamic assessment show that the fine particle fraction was increased compared to a classical lactose-based budesonide formulation (44.05 vs 26.24%). Moreover, the budesonide permeability out of the lung was shown to be reduced in the presence of cyclodextrin complexes. The interest of this sustained budesonide release was evaluated in a mouse model of asthma. The anti-inflammatory effect was compared to a non-complexed budesonide formulation at the same concentration and attests the higher anti-inflammatory activity reach with the cyclodextrin-based formulation. This strategy could therefore be of particular interest for improving lung targeting while decreasing systemic side effects associated with high doses of corticosteroids. In conclusion, this works reports that cyclodextrins could be used in powder for inhalation, both for their abilities to improve active ingredient aerosolisation properties and further to their dissolution in lung fluid, to decrease permeability out of the lungs leading to an optimized activity profile. Copyright © 2015 Elsevier B.V. All rights reserved.

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model

PubMed Central

Jackson, George R.; Maione, Anna G.; Klausner, Mitchell

2018-01-01

Abstract Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal (in vitro) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1–2 and EPA Acute Inhalation Toxicity Category I–II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity. PMID:29904643

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirway In Vitro Human Airway Model.

PubMed

Jackson, George R; Maione, Anna G; Klausner, Mitchell; Hayden, Patrick J

2018-06-01

Introduction: Knowledge of acute inhalation toxicity potential is important for establishing safe use of chemicals and consumer products. Inhalation toxicity testing and classification procedures currently accepted within worldwide government regulatory systems rely primarily on tests conducted in animals. The goal of the current work was to develop and prevalidate a nonanimal ( in vitro ) test for determining acute inhalation toxicity using the EpiAirway™ in vitro human airway model as a potential alternative for currently accepted animal tests. Materials and Methods: The in vitro test method exposes EpiAirway tissues to test chemicals for 3 hours, followed by measurement of tissue viability as the test endpoint. Fifty-nine chemicals covering a broad range of toxicity classes, chemical structures, and physical properties were evaluated. The in vitro toxicity data were utilized to establish a prediction model to classify the chemicals into categories corresponding to the currently accepted Globally Harmonized System (GHS) and the Environmental Protection Agency (EPA) system. Results: The EpiAirway prediction model identified in vivo rat-based GHS Acute Inhalation Toxicity Category 1-2 and EPA Acute Inhalation Toxicity Category I-II chemicals with 100% sensitivity and specificity of 43.1% and 50.0%, for GHS and EPA acute inhalation toxicity systems, respectively. The sensitivity and specificity of the EpiAirway prediction model for identifying GHS specific target organ toxicity-single exposure (STOT-SE) Category 1 human toxicants were 75.0% and 56.5%, respectively. Corrosivity and electrophilic and oxidative reactivity appear to be the predominant mechanisms of toxicity for the most highly toxic chemicals. Conclusions: These results indicate that the EpiAirway test is a promising alternative to the currently accepted animal tests for acute inhalation toxicity.

Breast Cancer Gene Therapy: Development of Novel Non-Invasive Magnetic Resonance Assay to Optimize Efficacy

DTIC Science & Technology

2007-05-01

inhalation-mouse). HFB had been proposed as a veterinary anesthetic and has been used in many species including ponies, sheep, cats, dogs , rats and...anesthetic and has been used in many species including ponies, sheep, cats, dogs , rats and mice, but was abandoned due to its flammability [265...gene activity detection- specifically, using fluorinated substrates of β-galactosidase to reveal gene activity. Our prototype molecule PFONPG (p

Introduction to Nanotechnology for Defense Environment, Health & Safety (EHS) and Research Professionals in Support of the Acquisition Process

DTIC Science & Technology

2011-03-28

www.denix.osd.mil/MERIT Ultra fine particles ~50 1713- Ramazzini described black 197 4- First GMO lung disease mouse created by Jaenisch Diesel...exhaust Engineered NP _____ _,.? • GMO Technology 1985- Oberdorster described inhalation toxicity of Ti02 2003-lssue recognized by EPA, NIOSH...other agencies 2004- California pass broad ban on GMO products Growing Body of EHS Research Far-reaching implications or singular exceptions

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

M.A. Wasiolek

Inhalation exposure pathway modeling has recently been investigated as one of the tasks of the BIOPROTA Project (BIOPROTA 2005). BIOPROTA was set up to address the key uncertainties in long term assessments of contaminant releases into the environment arising from radioactive waste disposal. Participants of this international Project include national authorities and agencies, both regulators and operators, with responsibility for achieving safe and acceptable radioactive waste management. The objective of the inhalation task was to investigate the calculation of doses arising from inhalation of particles suspended from soils within which long-lived radionuclides, particularly alpha emitters, had accumulated. It was recognizedmore » that site-specific conditions influence the choice of conceptual model and input parameter values. Therefore, one of the goals of the task was to identify the circumstances in which different processes included in specific inhalation exposure pathway models were important. This paper discusses evaluation of processes and modeling assumptions specific to the proposed repository at Yucca Mountain as compared to the typical approaches and other models developed for different assessments and project specific contexts. Inhalation of suspended particulates that originate from contaminated soil is an important exposure pathway, particularly for exposure to actinides such as uranium, neptunium and plutonium. Radionuclide accumulation in surface soil arises from irrigation of soil with contaminated water over many years. The level of radionuclide concentration in surface soil depends on the assumed duration of irrigation. Irrigation duration is one of the parameters used on biosphere models and it depends on a specific assessment context. It is one of the parameters addressed in this paper from the point of view of assessment context for the proposed repository at Yucca Mountain. The preferred model for the assessment of inhalation exposure uses atmospheric mass loading approach, which is based on the mass of airborne particulates per unit volume of air that is inhaled by the receptor. This type of model was used by the majority of the BIOPROTA inhalation task participants and is also used in the Yucca Mountain model. Although the mass loading model is conceptually straightforward, there are some considerations that need to be included when using this model. Small particles have larger surface to volume ratio than large particles and this ratio increases in inverse proportion to the particle size. This is particularly important for elements such as plutonium, which have high sorption coefficients, and thus are preferentially attached to small particles of soil. Suspended particulates originating from soil are composed of particles smaller than average soil particles and thus, on average, have larger available surface area, and consequently activity, per unit mass than that of soil. The increase of radionuclide concentration of suspended particulates compared with that of underlying soil is quantified in terms of the enhancement factor, which is included in the inhalation model for the Yucca Mountain repository. In this paper, the use of the enhancement factor in the inhalation exposure models is discussed. Then, enhancement factor values used in the Yucca Mountain model are discussed from the perspective of site-specific conditions as well as the microenvironmental approach to modeling inhalation exposure of the receptor: The receptor can spend specified time in several environments, each of them characterized by an occupancy time, suspended particulate level, enhancement factor and breathing rate. The environment where inhalation exposure is the highest is associated with the receptor being active outdoors and involved in activities that generate high levels of dust by using farm equipment, walking, or conducting other outdoor activities. I n summary, it is important to recognize that site-specific conditions play an important role in constructing conceptual and mathematical models of inhalation exposure.« less

Performance of dry powder inhalers with single dosed capsules in preschool children and adults using improved upper airway models.

PubMed

Lindert, Sandra; Below, Antje; Breitkreutz, Joerg

2014-02-06

The pulmonary administration of pharmaceutical aerosols to patients is affected by age-dependent variations in the anatomy of the upper airways and the inhalation pattern. Considering this aspect, different upper airway models, representing the geometries of adults and preschool children, and a conventional induction port according to the European Pharmacopeia were used for in vitro testing of dry powder inhalers with single dosed capsules (Cyclohaler®, Handihaler® and Spinhaler®). Deposition measurements were performed using steady flow rates of 30 and 60 L/min for the Handihaler®/Spinhaler® and 30, 60 and 75 L/min for the Cyclohaler®. The inhalation volume was set at 1 L. For the Cyclohaler®, the in vitro testing was supplemented by a pediatric inhalation profile. Slight differences of pulmonary deposition between the idealized adult (11%-15%) and pediatric (9%-11%) upper airway model were observed for the Cyclohaler®. The applied pediatric inhalation profile resulted in a reduction of pulmonary deposition by 5% compared to steady conditions and indicated the influence of the inhalation pattern on the amount of pulmonary deposited particles. The comparison of two pediatric upper airway models showed no differences. The performance of the Handihaler® was similar to the Cyclohaler®. The Spinhaler® showed an insufficient performance and limited reproducibility in our investigations.

Linking a dermal permeation and an inhalation model to a simple pharmacokinetic model to study airborne exposure to di(n-butyl) phthalate.

PubMed

Lorber, Matthew; Weschler, Charles J; Morrison, Glenn; Bekö, Gabriel; Gong, Mengyan; Koch, Holger M; Salthammer, Tunga; Schripp, Tobias; Toftum, Jørn; Clausen, Geo

2017-11-01

Six males clad only in shorts were exposed to high levels of airborne di(n-butyl) phthalate (DnBP) and diethyl phthalate (DEP) in chamber experiments conducted in 2014. In two 6 h sessions, the subjects were exposed only dermally while breathing clean air from a hood, and both dermally and via inhalation when exposed without a hood. Full urine samples were taken before, during, and for 48 h after leaving the chamber and measured for key DnBP and DEP metabolites. The data clearly demonstrated high levels of DnBP and DEP metabolite excretions while in the chamber and during the first 24 h once leaving the chamber under both conditions. The data for DnBP were used in a modeling exercise linking dose models for inhalation and transdermal permeation with a simple pharmacokinetic model that predicted timing and mass of metabolite excretions. These models were developed and calibrated independent of these experiments. Tests included modeling of the "hood-on" (transdermal penetration only), "hood-off" (both inhalation and transdermal) scenarios, and a derived "inhalation-only" scenario. Results showed that the linked model tended to duplicate the pattern of excretion with regard to timing of peaks, decline of concentrations over time, and the ratio of DnBP metabolites. However, the transdermal model tended to overpredict penetration of DnBP such that predictions of metabolite excretions were between 1.1 and 4.5 times higher than the cumulative excretion of DnBP metabolites over the 54 h of the simulation. A similar overprediction was not seen for the "inhalation-only" simulations. Possible explanations and model refinements for these overpredictions are discussed. In a demonstration of the linked model designed to characterize general population exposures to typical airborne indoor concentrations of DnBP in the United States, it was estimated that up to one-quarter of total exposures could be due to inhalation and dermal uptake.

EFFECT OF THE LESION DUE TO INFLUENZA VIRUS ON THE RESISTANCE OF MICE TO INHALED PNEUMOCOCCI

PubMed Central

Harford, Carl G.; Leidler, Virginia; Hara, Mary

1949-01-01

1. The normal lung of the mouse possesses the power of reducing markedly its content of Type I pneumococci within 3 hours after inhalation of the organisms in the form of fine droplets. 2. Lungs with fully developed influenza viral pneumonia not only fail to reduce the pulmonary content of pneumococci administered in this manner but, on the contrary, support their growth. 3. After intrabronchial inoculation into mice, influenza virus multiplies rapidly in the lung within 24 hours. 4. Criteria have been established for distinction between true viral lesions of the lung and changes due to the inoculation of diluents as vehicles for the virus. 5. 24 hours after inoculation of virus, there are no macroscopic lesions in the lung and the microscopic changes are due to the diluent. 6. Presence and multiplication of the virus in the lung 24 hours after inoculation have no apparent effect on the power of the lung to reduce rapidly its content of inhaled pneumococci. 7. The effect of the virus in lowering resistance to secondary bacterial infection appears to be due to the presence of the lesion produced by the virus. PMID:18099165

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers, Ellobius talpinus

PubMed Central

Moshkin, M. P.; Petrovski, D. V.; Akulov, A. E.; Romashchenko, A. V.; Gerlinskaya, L. A.; Ganimedov, V. L.; Muchnaya, M. I.; Sadovsky, A. S.; Koptyug, I. V.; Savelov, A. A.; Troitsky, S. Yu; Moshkn, Y. M.; Bukhtiyarov, V. I.; Kolchanov, N. A.; Sagdeev, R. Z.; Fomin, V. M.

2014-01-01

Inhalation of air-dispersed sub-micrometre and nano-sized particles presents a risk factor for animal and human health. Here, we show that nasal aerodynamics plays a pivotal role in the protection of the subterranean mole vole Ellobius talpinus from an increased exposure to nano-aerosols. Quantitative simulation of particle flow has shown that their deposition on the total surface of the nasal cavity is higher in the mole vole than in a terrestrial rodent Mus musculus (mouse), but lower on the olfactory epithelium. In agreement with simulation results, we found a reduced accumulation of manganese in olfactory bulbs of mole voles in comparison with mice after the inhalation of nano-sized MnCl2 aerosols. We ruled out the possibility that this reduction is owing to a lower transportation from epithelium to brain in the mole vole as intranasal instillations of MnCl2 solution and hydrated nanoparticles of manganese oxide MnO · (H2O)x revealed similar uptake rates for both species. Together, we conclude that nasal geometry contributes to the protection of brain and lung from accumulation of air-dispersed particles in mole voles. PMID:25143031

Observing planar cell polarity in multiciliated mouse airway epithelial cells.

PubMed

Vladar, Eszter K; Lee, Yin Loon; Stearns, Tim; Axelrod, Jeffrey D

2015-01-01

The concerted movement of cilia propels inhaled contaminants out of the lungs, safeguarding the respiratory system from toxins, pathogens, pollutants, and allergens. Motile cilia on the multiciliated cells (MCCs) of the airway epithelium are physically oriented along the tissue axis for directional motility, which depends on the planar cell polarity (PCP) signaling pathway. The MCCs of the mouse respiratory epithelium have emerged as an important model for the study of motile ciliogenesis and the PCP signaling mechanism. Unlike other motile ciliated or planar polarized tissues, airway epithelial cells are relatively easily accessible and primary cultures faithfully model many of the essential features of the in vivo tissue. There is growing interest in understanding how cells acquire and polarize motile cilia due to the impact of mucociliary clearance on respiratory health. Here, we present methods for observing and quantifying the planar polarized orientation of motile cilia both in vivo and in primary culture airway epithelial cells. We describe how to acquire and evaluate electron and light microscopy images of ciliary ultrastructural features that reveal planar polarized orientation. Furthermore, we describe the immunofluorescence localization of PCP pathway components as a simple readout for airway epithelial planar polarization and ciliary orientation. These methods can be adapted to observe ciliary orientation in other multi- and monociliated cells and to detect PCP pathway activity in any tissue or cell type. Copyright © 2015 Elsevier Inc. All rights reserved.

Novel and existing data for a future physiological toxicokinetic model of ethylene and its metabolite ethylene oxide in mouse, rat, and human.

PubMed

Filser, Johannes Georg; Artati, Anna; Li, Qiang; Pütz, Christian; Semder, Brigitte; Klein, Dominik; Kessler, Winfried

2015-11-05

The olefin ethylene is a ubiquitously found gas. It originates predominantly from plants, combustion processes and industrial sources. In mammals, inhaled ethylene is metabolized by cytochrome P450-dependent monooxygenases, particularly by cytochrome P450 2E1, to ethylene oxide, an epoxide that directly alkylates proteins and DNA. Ethylene oxide was mutagenic in vitro and in vivo in insects and mammals and carcinogenic in rats and mice. A physiological toxicokinetic model is a most useful tool for estimating the ethylene oxide burden in ethylene-exposed rodents and humans. The only published physiological toxicokinetic model for ethylene and metabolically produced ethylene oxide is discussed. Additionally, existing data required for the development of a future model and for testing its predictive accuracy are reviewed and extended by new gas uptake studies with ethylene and ethylene oxide in B6C3F1 mice and with ethylene in F344 rats. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

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

Belinsky, S. A.; Hoover, M. D.; Bradley, P. L.

This document from the Inhalation Toxicology Research Institute includes annual reports in the following general areas: (I) Aerosol Technology and Characterization of Airborne Materials; (II) Deposition, transport, and clearance of inhaled Toxicants; (III) Metabolism and Markers of Inhaled Toxicants; (IV) Carcinogenic Responses to Toxicants; (V) Mechanisms of carcinogenic response to Toxicants; (VI) Non carcinogenic responses to inhaled toxicants; (VII) Mechanisms of noncarcinogenic Responses to Inhaled Toxicants; (VIII) The application of Mathematical Modeling to Risk Estimates. 9 appendices are also included. Selected papers are indexed separately for inclusion in the Energy Science and Technology Database.

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

PubMed Central

Bogen, Kenneth T.; Benson, Janet M.; Yost, Garold S.; Morris, John B.; Dahl, Alan R.; Clewell, Harvey J.; Krishnan, Kannan; Omiecinski, Curtis J.

2014-01-01

This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9–12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose–response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotoxic naphthalene concentrations. PMID:18191315

Quantification and visualization of injury and regeneration to the ciliated epithelium using quantitative flow imaging and speckle variance optical coherence tomography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Gamm, Ute A.; Huang, Brendan K.; Mis, Emily K.; Khokha, Mustafa K.; Choma, Michael A.

2017-04-01

Mucociliary flow is an important defense mechanism in the lung to remove inhaled pathogens and pollutants. A disruption of ciliary flow can lead to respiratory infections. Even though patients in the intensive care unit (ICU) either have or are very susceptible to respiratory infections, mucociliary flow is not well understood in the ICU setting. We recently demonstrated that hyperoxia, a consequence of administering supplemental oxygen to a patient in respiratory failure, can lead to a significant reduction of cilia-driven fluid flow in mouse trachea. There are other factors that are relevant to ICU medicine that can damage the ciliated tracheal epithelium, including inhalation injury and endotracheal tube placement. In this study we use two animal models, Xenopus embryo and ex vivo mouse trachea, to analyze flow defects in the injured ciliated epithelium. Injury is generated either mechanically with a scalpel or chemically by calcium chloride (CaCl2) shock, which efficiently but reversibly deciliates the embryo skin. In this study we used optical coherence tomography (OCT) and particle tracking velocimetry (PTV) to quantify cilia driven fluid flow over the surface of the Xenopus embryo. We additionally visualized damage to the ciliated epithelium by capturing 3D speckle variance images that highlight beating cilia. Mechanical injury disrupted cilia-driven fluid flow over the injured site, which led to a reduction in cilia-driven fluid flow over the whole surface of the embryo (n=7). The calcium chloride shock protocol proved to be highly effective in deciliating embryos (n=6). 3D speckle variance images visualized a loss of cilia and cilia-driven flow was halted immediately after application. We also applied CaCl2-shock to cultured ex vivo mouse trachea (n=8) and found, similarly to effects in Xenopus embryo, an extensive loss of cilia with resulting cessation of flow. We investigated the regeneration of the ciliated epithelium after an 8 day incubation period, and found that cilia had regrown and flow was completely restored. In conclusion, OCT is a valuable tool to visualize injury of the ciliated epithelium and to quantify reduction of generated flow. This method allows for systematic investigation of focal and diffuse injury of the ciliated epithelium and the assessment of mechanisms to compensate for loss of flow.

Atorvastatin and Simvastatin Promoted Mouse Lung Repair After Cigarette Smoke-Induced Emphysema.

PubMed

Pinho-Ribeiro, Vanessa; Melo, Adriana Correa; Kennedy-Feitosa, Emanuel; Graca-Reis, Adriane; Barroso, Marina Valente; Cattani-Cavalieri, Isabella; Carvalho, Giovanna Marcella Cavalcante; Zin, Walter Araújo; Porto, Luis Cristóvão; Gitirana, Lycia Brito; Lanzetti, Manuella; Valença, Samuel Santos

2017-06-01

Cigarette smoke (CS) induces pulmonary emphysema by inflammation, oxidative stress, and metalloproteinase (MMP) activation. Pharmacological research studies have not focused on tissue repair after the establishment of emphysema but have instead focused on inflammatory stimulation. The aim of our study was to analyze the effects of atorvastatin and simvastatin on mouse lung repair after emphysema caused by CS. Male mice (C57BL/6, n = 45) were divided into the following groups: control (sham-exposed), CSr (mice exposed to 12 cigarettes a day for 60 days and then treated for another 60 days with the vehicle), CSr+A (CSr mice treated with atorvastatin for 60 days), and CSr+S (CSr mice treated with simvastatin for 60 days). The treatment with atorvastatin and simvastatin was administered via inhalation (15 min with 1 mg/mL once a day). Mice were sacrificed 24 h after the completion of the 120-day experimental procedure. We performed biochemical, morphological, and physiological analyses. We observed decreased levels of leukocytes and cytokines in statin-treated mice, accompanied by a reduction in oxidative stress markers. We also observed a morphological improvement confirmed by a mean linear intercept counting in statin-treated mice. Finally, statins also ameliorated lung function. We conclude that inhaled atorvastatin and simvastatin improved lung repair after cigarette smoke-induced emphysema in mice.

Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis

PubMed Central

Shvedova, A. A.; Kisin, E.; Murray, A. R.; Johnson, V. J.; Gorelik, O.; Arepalli, S.; Hubbs, A. F.; Mercer, R. R.; Keohavong, P.; Sussman, N.; Jin, J.; Yin, J.; Stone, S.; Chen, B. T.; Deye, G.; Maynard, A.; Castranova, V.; Baron, P. A.; Kagan, V. E.

2008-01-01

Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m3, 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5–20 μg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice. PMID:18658273

Ideal Particle Sizes for Inhaled Steroids Targeting Vocal Granulomas: Preliminary Study Using Computational Fluid Dynamics.

PubMed

Perkins, Elizabeth L; Basu, Saikat; Garcia, Guilherme J M; Buckmire, Robert A; Shah, Rupali N; Kimbell, Julia S

2018-03-01

Objectives Vocal fold granulomas are benign lesions of the larynx commonly caused by gastroesophageal reflux, intubation, and phonotrauma. Current medical therapy includes inhaled corticosteroids to target inflammation that leads to granuloma formation. Particle sizes of commonly prescribed inhalers range over 1 to 4 µm. The study objective was to use computational fluid dynamics to investigate deposition patterns over a range of particle sizes of inhaled corticosteroids targeting the larynx and vocal fold granulomas. Study Design Retrospective, case-specific computational study. Setting Tertiary academic center. Subjects/Methods A 3-dimensional anatomically realistic computational model of a normal adult airway from mouth to trachea was constructed from 3 computed tomography scans. Virtual granulomas of varying sizes and positions along the vocal fold were incorporated into the base model. Assuming steady-state, inspiratory, turbulent airflow at 30 L/min, computational fluid dynamics was used to simulate respiratory transport and deposition of inhaled corticosteroid particles ranging over 1 to 20 µm. Results Laryngeal deposition in the base model peaked for particle sizes 8 to 10 µm (2.8%-3.5%). Ideal sizes ranged over 6 to 10, 7 to 13, and 7 to 14 µm for small, medium, and large granuloma sizes, respectively. Glottic deposition was maximal at 10.8% for 9-µm-sized particles for the large posterior granuloma, 3 times the normal model (3.5%). Conclusion As the virtual granuloma size increased and the location became more posterior, glottic deposition and ideal particle size generally increased. This preliminary study suggests that inhalers with larger particle sizes, such as fluticasone propionate dry-powder inhaler, may improve laryngeal drug deposition. Most commercially available inhalers have smaller particles than suggested here.

Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

PubMed Central

2014-01-01

Background Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT. PMID:24405760

Bronchoscopy-Derived Correlates of Lung Injury Following Inhalational Injuries: A Prospective Obervational Study

EPA Science Inventory

Acute lung injury (ALI) is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studi...

Effect of Mouse Strain in a Model of Chemical-induced Respiratory Allergy

PubMed Central

Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

2014-01-01

The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical–related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical–related respiratory allergens by using a long-term sensitization–challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens. PMID:25048268

Effect of mouse strain in a model of chemical-induced respiratory allergy.

PubMed

Nishino, Risako; Fukuyama, Tomoki; Watanabe, Yuko; Kurosawa, Yoshimi; Ueda, Hideo; Kosaka, Tadashi

2014-01-01

The inhalation of many types of chemicals is a leading cause of allergic respiratory diseases, and effective protocols are needed for the detection of environmental chemical-related respiratory allergies. In our previous studies, we developed a method for detecting environmental chemical-related respiratory allergens by using a long-term sensitization-challenge protocol involving BALB/c mice. In the current study, we sought to improve our model by characterizing strain-associated differences in respiratory allergic reactions to the well-known chemical respiratory allergen glutaraldehyde (GA). According to our protocol, BALB/c, NC/Nga, C3H/HeN, C57BL/6N, and CBA/J mice were sensitized dermally with GA for 3 weeks and then challenged with intratracheal or inhaled GA at 2 weeks after the last sensitization. The day after the final challenge, all mice were euthanized, and total serum IgE levels were assayed. In addition, immunocyte counts, cytokine production, and chemokine levels in the hilar lymph nodes (LNs) and bronchoalveolar lavage fluids (BALF) were also assessed. In conclusion, BALB/c and NC/Nga mice demonstrated markedly increased IgE reactions. Inflammatory cell counts in BALF were increased in the treated groups of all strains, especially BALB/c, NC/Nga, and CBA/J strains. Cytokine levels in LNs were increased in all treated groups except for C3H/HeN and were particularly high in BALB/c and NC/Nga mice. According to our results, we suggest that BALB/c and NC/Nga are highly susceptible to respiratory allergic responses and therefore are good candidates for use in our model for detecting environmental chemical respiratory allergens.

Inhaled nitric oxide improves short term memory and reduces the inflammatory reaction in a mouse model of mild traumatic brain injury.

PubMed

Liu, Ping; Li, Yong-Sheng; Quartermain, David; Boutajangout, Allal; Ji, Yong

2013-07-19

Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24h after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8h, beginning immediately after TBI demonstrated significantly improved STM at 24h when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24h showed no improvement in STM. Mice treated with INO 10ppm for 8h exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24h after injury and persists for 2-3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

PubMed Central

Ye, Qi; Kim, Jonghan

2015-01-01

Manganese in excess promotes unstable emotional behavior. Our previous study showed that olfactory manganese uptake into the brain is altered in Hfe−/− mice, a model of iron overload hemochromatosis, suggesting that Hfe deficiency could modify the neurotoxicity of airborne manganese. We determined anxiety-related behavior and monoaminergic protein expression after repeated intranasal instillation of MnCl2 to Hfe−/− mice. Compared with manganese-instilled wild-type mice, Hfe−/− mice showed decreased manganese accumulation in the cerebellum. Hfe−/− mice also exhibited increased anxiety with decreased exploratory activity and elevated dopamine D1 receptor and norepinephrine transporter in the striatum. Moreover, Hfe deficiency attenuated manganese-associated impulsivity and modified the effect of manganese on the expression of tyrosine hydroxylase, vesicular monoamine transporter and serotonin transporter. Together, our data indicate that loss of HFE function alters manganese-associated emotional behavior and further suggest that HFE could be a potential molecular target to alleviate affective disorders induced by manganese inhalation. PMID:26189056

Early anticoagulation therapy for severe burns complicated by inhalation injury in a rabbit model

PubMed Central

Fu, Zhong-Hua; Guo, Guang-Hua; Xiong, Zhen-Fang; Liao, Xincheng; Liu, Ming-Zhuo; Luo, Jinhua

2017-01-01

The aim of the present study was to determine the effects of early anticoagulation treatment on severe burns complicated by inhalation injury in a rabbit model. Under anesthetization, an electrical burns instrument (100°C) was used to scald the backs of rabbits for 15 sec, which established a 30% III severe burns model. Treatment of the rabbits with early anticoagulation effectively improved the severe burns complicated by inhalation injury-induced lung injury, reduced PaO2, PaCO2 and SPO2 levels, suppressed the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6, and increased the activity of IL-10. In addition, it was found that early anticoagulation treatment effectively suppressed the activities of caspase-3 and caspase-9, upregulated the protein expression of vascular endothelial growth factor (VEGF) and decreased the protein expression of protease-activated receptor 1 (PAR1) in the severe burns model. It was concluded that early anticoagulation treatment affected the severe burns complicated by inhalation injury in a rabbit model through the upregulation of VEGF and downregulation of PAR1 signaling pathways. Thus, early anticoagulation is a potential therapeutic option for severe burns complicated by inhalation injury. PMID:28944866

A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays.

PubMed

Schwarz, Katharina; Pappa, Gerlinde; Miertsch, Heike; Scheel, Julia; Koch, Wolfgang

2018-04-01

Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Four typical products were sprayed onto a skin surrogate in defined rooms. For aluminium, size-related aerosol release fractions, i.e. inhalable, thoracic and respirable, were determined by a mass balance method taking droplet maturation into account. These data were included into a simple two-box exposure model, allowing calculation of the inhaled aluminium dose over 12 min. Systemic exposure doses were calculated for exposure of the deep lung and the upper respiratory tract using the Multiple Path Particle Deposition Model (MPPD) model. The total systemically available dose of aluminium was in all cases found to be less than 0.5 µg per application. With this study it could be demonstrated that refinement of the input data of the two-box exposure model with measured data of released airborne aluminium is a valuable approach to analyse the contribution of antiperspirant spray inhalation to total aluminium exposure as part of the overall risk assessment. We suggest the methodology which can also be applied to other exposure modelling approaches for spray products, and further is adapted to other similar use scenarios.

Comparison of modeled estimates of inhalation exposure to aerosols during use of consumer spray products.

PubMed

Park, Jihoon; Yoon, Chungsik; Lee, Kiyoung

2018-05-30

In the field of exposure science, various exposure assessment models have been developed to complement experimental measurements; however, few studies have been published on their validity. This study compares the estimated inhaled aerosol doses of several inhalation exposure models to experimental measurements of aerosols released from consumer spray products, and then compares deposited doses within different parts of the human respiratory tract according to deposition models. Exposure models, including the European Center for Ecotoxicology of Chemicals Targeted Risk Assessment (ECETOC TRA), the Consumer Exposure Model (CEM), SprayExpo, ConsExpo Web and ConsExpo Nano, were used to estimate the inhaled dose under various exposure scenarios, and modeled and experimental estimates were compared. The deposited dose in different respiratory regions was estimated using the International Commission on Radiological Protection model and multiple-path particle dosimetry models under the assumption of polydispersed particles. The modeled estimates of the inhaled doses were accurate in the short term, i.e., within 10 min of the initial spraying, with a differences from experimental estimates ranging from 0 to 73% among the models. However, the estimates for long-term exposure, i.e., exposure times of several hours, deviated significantly from the experimental estimates in the absence of ventilation. The differences between the experimental and modeled estimates of particle number and surface area were constant over time under ventilated conditions. ConsExpo Nano, as a nano-scale model, showed stable estimates of short-term exposure, with a difference from the experimental estimates of less than 60% for all metrics. The deposited particle estimates were similar among the deposition models, particularly in the nanoparticle range for the head airway and alveolar regions. In conclusion, the results showed that the inhalation exposure models tested in this study are suitable for estimating short-term aerosol exposure (within half an hour), but not for estimating long-term exposure. Copyright © 2018 Elsevier GmbH. All rights reserved.

Sevoflurane represses the self-renewal ability by regulating miR-7a,7b/Klf4 signalling pathway in mouse embryonic stem cells.

PubMed

Wang, Qimin; Li, Guifeng; Li, Baolin; Chen, Qiu; Lv, Dongdong; Liu, Jiaying; Ma, Jieyu; Sun, Nai; Yang, Longqiu; Fei, Xuejie; Song, Qiong

2016-10-01

Sevoflurane is a frequently-used clinical inhalational anaesthetic and can cause toxicity to embryos during foetal development. Embryonic stem cells (ESCs) are derived from the inner cell mass of blastospheres and can be used as a useful model of early development. Here, we found that sevoflurane significantly influenced self-renewal ability of mESCs on stemness maintenance and cell proliferation. The cell cycle was arrested via G1 phase delay. We further found that sevoflurane upregulated expression of miR-7a,7b to repress self-renewal. Next we performed rescue experiments and found that after adding miR-7a,7b inhibitor into mESCs treated with sevoflurane, its influence on self-renewal could be blocked. Further we identified stemness factor Klf4 as the direct target of miR-7a,7b. Overexpression of Klf4 restored self-renewal ability repressed by miR-7a,7b or sevoflurane. In this work, we determined that sevoflurane repressed self-renewal ability by regulating the miR-7a,7b/Klf4 signalling pathway in mESCs. Our study demonstrated molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on safe usage of inhalational anaesthetic during non-obstetric surgery. © 2016 John Wiley & Sons Ltd.

Role of intraglomerular circuits in shaping temporally structured responses to naturalistic inhalation-driven sensory input to the olfactory bulb

PubMed Central

Carey, Ryan M.; Sherwood, William Erik; Shipley, Michael T.; Borisyuk, Alla

2015-01-01

Olfaction in mammals is a dynamic process driven by the inhalation of air through the nasal cavity. Inhalation determines the temporal structure of sensory neuron responses and shapes the neural dynamics underlying central olfactory processing. Inhalation-linked bursts of activity among olfactory bulb (OB) output neurons [mitral/tufted cells (MCs)] are temporally transformed relative to those of sensory neurons. We investigated how OB circuits shape inhalation-driven dynamics in MCs using a modeling approach that was highly constrained by experimental results. First, we constructed models of canonical OB circuits that included mono- and disynaptic feedforward excitation, recurrent inhibition and feedforward inhibition of the MC. We then used experimental data to drive inputs to the models and to tune parameters; inputs were derived from sensory neuron responses during natural odorant sampling (sniffing) in awake rats, and model output was compared with recordings of MC responses to odorants sampled with the same sniff waveforms. This approach allowed us to identify OB circuit features underlying the temporal transformation of sensory inputs into inhalation-linked patterns of MC spike output. We found that realistic input-output transformations can be achieved independently by multiple circuits, including feedforward inhibition with slow onset and decay kinetics and parallel feedforward MC excitation mediated by external tufted cells. We also found that recurrent and feedforward inhibition had differential impacts on MC firing rates and on inhalation-linked response dynamics. These results highlight the importance of investigating neural circuits in a naturalistic context and provide a framework for further explorations of signal processing by OB networks. PMID:25717156

IL-23 secreted by bronchial epithelial cells contributes to allergic sensitization in asthma model: role of IL-23 secreted by bronchial epithelial cells.

PubMed

Lee, Hyun Seung; Park, Da-Eun; Lee, Ji-Won; Chang, Yuna; Kim, Hye Young; Song, Woo-Jung; Kang, Hye-Ryun; Park, Heung-Woo; Chang, Yoon-Seok; Cho, Sang-Heon

2017-01-01

IL-23 has been postulated to be a critical mediator contributing to various inflammatory diseases. Dermatophagoides pteronyssinus (Der p) is one of the most common inhalant allergens. However, the role of IL-23 in Der p-induced mouse asthma model is not well understood, particularly with regard to the development of allergic sensitization in the airways. The objective of this study was to evaluate roles of IL-23 in Der p sensitization and asthma development. BALB/c mice were repeatedly administered Der p intranasally to develop Der p allergic sensitization and asthma. After Der p local administration, changes in IL-23 expression were examined in lung tissues and primary epithelial cells. Anti-IL-23p19 antibody was given during the Der p sensitization period, and its effects were examined. Effects of anti-IL-23p19 antibody at bronchial epithelial levels were also examined in vitro. The expression of IL-23 at bronchial epithelial layers was increased after Der p local administration in mouse. In Der p-induced mouse models, anti-IL-23p19 antibody treatment during allergen sensitization significantly diminished Der p allergic sensitization and several features of allergic asthma including the production of Th2 cytokines and the population of type 2 innate lymphoid cells in lungs. The activation of dendritic cells in lung-draining lymph nodes was also reduced by anti-IL-23 treatment. In murine lung alveolar type II-like epithelial cell line (MLE-12) cells, IL-23 blockade prevented cytokine responses to Der p stimulation, such as IL-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-33, and also bone marrow-derived dendritic cell activation. In conclusion, IL-23 is another important bronchial epithelial cell-driven cytokine which may contribute to the development of house dust mite allergic sensitization and asthma. Copyright © 2017 the American Physiological Society.

Noncanonical Wnt5a-Ca(2+) -NFAT signaling axis in pesticide induced bone marrow aplasia mouse model: A study to explore the novel mechanism of pesticide toxicity.

PubMed

Chattopadhyay, Sukalpa; Chatterjee, Ritam; Law, Sujata

2016-10-01

According to case-control studies, long-term pesticide exposure can cause bone marrow aplasia like hematopoietic degenerative disease leading to impaired hematopoiesis and increased risk of aplastic anemia in human subjects. However, the exact mechanism of pesticide mediated hematotoxicity still remains elusive. In this study, we investigated the role of noncanonical Wnt signaling pathway, a crucial regulator of adult hematopoiesis, in pesticide induced bone marrow aplasia mouse model. Aplasia mouse model was developed following inhalation and dermal exposure of 5% aqueous mixture of common agriculturally used pesticides for 6 h/day for 5 days a week up to 90 days. After that, blood hemogram, marrow smear, cellularity, scanning electron microscopy, extramedullary hematopoiesis and flowcytometric expression analysis of noncanonical Wnt signaling components, such as Wnt 5a, fzd5, NFAT, IFN-γ, intracellular Ca(2+) level were evaluated in the bone marrow hematopoietic stem/progenitor compartment of the control and pesticide induced aplasia groups of animals. Results showed that pesticide exposed mice were anemic with peripheral blood pancytopenia, hypocellular degenerative marrow, and extramedullary hematopoiesis in the spleen. Upon pesticide exposure, Wnt 5a expression was severely downregulated with a decline in intracellular Ca(2+) level. Moreover, downstream of Wnt5a, we observed sharp downregulation of NFATc2 transcription factor expression, the major target of pesticide toxicity and its target molecule IFN-γ. Taken together, our result suggests that deregulation of Wnt5a-Ca(2+) -NFAT signaling axis in the hematopoietic stem/progenitor compartment plays a crucial role behind the pathogenesis of pesticide mediated bone marrow aplasia by limiting primitive hematopoietic stem cells' ability to maintain hematopoietic homeostasis and reconstitution mechanism in vivo during xenobiotic stress leading to ineffective hematopoiesis and evolution of bone marrow aplasia. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1163-1175, 2016. © 2015 Wiley Periodicals, Inc.

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

ANALYSIS OF FLOW THROUGH A HUMAN ORAL MODEL FOR USE IN INHALATION TOXICOLOGY AND AEROSOL THERAPY PROTOCOLS

EPA Science Inventory

RATIONALE
Understanding the transport and deposition of inhaled aerosols is of fundamental importance to inhalation toxicology and aerosol therapy. Herein, we focus on the development of a computer based oral morphology and related computational fluid dynamics (CFD) studi...

Statistical tools and control of internal lubricant content of inhalation grade HPMC capsules during manufacture.

PubMed

Ayala, Guillermo; Díez, Fernando; Gassó, María T; Jones, Brian E; Martín-Portugués, Rafael; Ramiro-Aparicio, Juan

2016-04-30

The internal lubricant content (ILC) of inhalation grade HPMC capsules is a key factor to ensure good powder release when the patient inhales a medicine from a dry powder inhaler (DPI). Powder release from capsules has been shown to be influenced by the ILC. The characteristics used to measure this are the emitted dose, fine particle fraction and mass median aerodynamic diameter. In addition the ILC level is critical for capsule shell manufacture because it is an essential part of the process that cannot work without it. An experiment has been applied to the manufacture of inhalation capsules with the required ILC. A full factorial model was used to identify the controlling factors and from this a linear model has been proposed to improve control of the process. Copyright © 2016 Elsevier B.V. All rights reserved.

Coupled in silico platform: Computational fluid dynamics (CFD) and physiologically-based pharmacokinetic (PBPK) modelling.

PubMed

Vulović, Aleksandra; Šušteršič, Tijana; Cvijić, Sandra; Ibrić, Svetlana; Filipović, Nenad

2018-02-15

One of the critical components of the respiratory drug delivery is the manner in which the inhaled aerosol is deposited in respiratory tract compartments. Depending on formulation properties, device characteristics and breathing pattern, only a certain fraction of the dose will reach the target site in the lungs, while the rest of the drug will deposit in the inhalation device or in the mouth-throat region. The aim of this study was to link the Computational fluid dynamics (CFD) with physiologically-based pharmacokinetic (PBPK) modelling in order to predict aerolisolization of different dry powder formulations, and estimate concomitant in vivo deposition and absorption of amiloride hydrochloride. Drug physicochemical properties were experimentally determined and used as inputs for the CFD simulations of particle flow in the generated 3D geometric model of Aerolizer® dry powder inhaler (DPI). CFD simulations were used to simulate air flow through Aerolizer® inhaler and Discrete Phase Method (DPM) was used to simulate aerosol particles deposition within the fluid domain. The simulated values for the percent emitted dose were comparable to the values obtained using Andersen cascade impactor (ACI). However, CFD predictions indicated that aerosolized DPI have smaller particle size and narrower size distribution than assumed based on ACI measurements. Comparison with the literature in vivo data revealed that the constructed drug-specific PBPK model was able to capture amiloride absorption pattern following oral and inhalation administration. The PBPK simulation results, based on the CFD generated particle distribution data as input, illustrated the influence of formulation properties on the expected drug plasma concentration profiles. The model also predicted the influence of potential changes in physiological parameters on the extent of inhaled amiloride absorption. Overall, this study demonstrated the potential of the combined CFD-PBPK approach to model inhaled drug bioperformance, and suggested that CFD generated results might serve as input for the prediction of drug deposition pattern in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

A small whole-body exposure chamber for laboratory use.

PubMed

O'Shaughnessy, Patrick T; Achutan, Chandran; O'Neill, Marsha E; Thorne, Peter S

2003-03-01

With the development of transgenic and specialized mouse strains, there is an increased need for inhalation exposure systems designed for smaller exposure groups. An inhalation exposure chamber, designed specifically for the exposure of up to 40 mice, was characterized. The chamber was fabricated from 0.32-cm-thick ((1)/(8)-in) aluminum sheets with outside dimensions of 61 cm long by 32 cm high by 34 cm deep, resulting in an internal volume of 65 L. Two stainless-steel open-mesh cages, separated by an absorbent barrier, can be stacked within the central portion of the chamber. Access is provided through a gasketed door with a safety-glass face. Tests were performed to determine the chamber leakage rate, degree of mixing, and spatial variation of two aerosols within the chamber. Results indicated that the fractional leakage rate was 0.0003 min(-1), well below a reported criterion for an operating chamber. Chamber operation gave similar mixing performance with, or without, use of an interior fan. For aerosols with a mass median aerodynamic diameter (MMAD) of 2.56 micro m and 3.14 micro m, the spatial variation of particulate matter concentration resulted in coefficients of variation (CVs) of 4.8% and 11.0%, respectively. These CV values are comparable to those obtained from similar studies involving other inhalation exposure chambers.

Evaluation of Cancer and Non-cancer Effects of Cumene ...

EPA Pesticide Factsheets

Cumene, also known as isopropyl benzene, is a volatile liquid. Cumene, readily absorbed via inhalation is distributed in several tissues, metabolized extensively by cytochrome P-450 isozymes within hepatic and extra-hepatic tissues and excreted through urine. No epidemiological cancer studies for humans are available, however, chronic inhalation exposure studies in rat and mouse have shown increased nasal lesions including atrophy, basal cell hyperplasia, atypical hyperplasia and hyperplasia of the olfactory epithelium glands. In addition, increased incidences of renal tubular adenoma or carcinoma that are related to a2u-globin-induced nephropathy were observed in male rats. Alveolar/bronchiolar adenomas and carcinomas of the lung are observed in male and female mice exposed to cumene. Although no multi-generational reproductive toxicity is available for cumene, cumene-exposed rats appeared to stay in estrus cycle longer than the controls. Short-term acute exposures of animals at high concentrations seem to induce transient reversible neurotoxic effects. Overall, inhalation exposure to cumene induced dose-related increased in the occurances of tumors at various sites. These cancer and non-cancer data in rats and mice as well as genotoxicity data provides consistence evidence for carcinogenic effects of cumene. This poster will be presented at the Society of Toxicology Meeting in San Diego California. The goal of this presentation is systematic evaluation of bot

Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers, Ellobius talpinus.

PubMed

Moshkin, M P; Petrovski, D V; Akulov, A E; Romashchenko, A V; Gerlinskaya, L A; Ganimedov, V L; Muchnaya, M I; Sadovsky, A S; Koptyug, I V; Savelov, A A; Troitsky, S Yu; Moshkn, Y M; Bukhtiyarov, V I; Kolchanov, N A; Sagdeev, R Z; Fomin, V M

2014-10-07

Inhalation of air-dispersed sub-micrometre and nano-sized particles presents a risk factor for animal and human health. Here, we show that nasal aerodynamics plays a pivotal role in the protection of the subterranean mole vole Ellobius talpinus from an increased exposure to nano-aerosols. Quantitative simulation of particle flow has shown that their deposition on the total surface of the nasal cavity is higher in the mole vole than in a terrestrial rodent Mus musculus (mouse), but lower on the olfactory epithelium. In agreement with simulation results, we found a reduced accumulation of manganese in olfactory bulbs of mole voles in comparison with mice after the inhalation of nano-sized MnCl2 aerosols. We ruled out the possibility that this reduction is owing to a lower transportation from epithelium to brain in the mole vole as intranasal instillations of MnCl2 solution and hydrated nanoparticles of manganese oxide MnO · (H2O)x revealed similar uptake rates for both species. Together, we conclude that nasal geometry contributes to the protection of brain and lung from accumulation of air-dispersed particles in mole voles. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Pharmacokinetic Modeling of Trivalent and Hexavalent Chromium Based on Ingestion and Inhalation of Soluble Chromium Compounds.

DTIC Science & Technology

1991-12-01

34 0-0-° AD-A256 238 - DTIC 7 ELECTE A S OCTI 6 1992 R CM S PHARMACOKINETIC MODELING OF T TRIVALENT AND HEXAVALENT CHROMIUM R BASED ON INGESTION AND...or inhalation of trivalent or hexavalent soluble chromium compounds. The research described herein began in June 1990 and was completed in December... trivalent and hexavalent chromium compounds, chromic chloride-hexahydrate and sodium dichromate, respectively (Table I). An inhalation control group was

Photoacoustic lifetime imaging for direct in vivo tissue oxygen monitoring

PubMed Central

Shao, Qi; Ashkenazi, Shai

2015-01-01

Abstract. Measuring the partial pressure of oxygen (pO2) in tissue may provide physicians with essential information about the physiological state of tissue. However, currently available methods for measuring or imaging tissue pO2 have significant limitations, preventing them from being widely used in clinics. Recently, we have reported a direct and noninvasive in vivo imaging modality based on the photoacoustic lifetime which overcomes certain drawbacks of the existing methods. The technique maps the excited triplet state of oxygen-sensitive dye, thus reflecting the spatial and temporal distributions of tissue oxygen. Here, we present two studies which apply photoacoustic lifetime imaging (PALI) to monitor changes of tissue oxygen induced by external modulations. The first study modulates tissue oxygen by controlling the percentage of oxygen a normal mouse inhales. We demonstrate that PALI is able to reflect the change in oxygen level with respect to normal, oxygen-rich, and oxygen-poor breathing conditions. The second study involves an acute ischemia model using a thin thread tied around the hindlimb of a normal mouse to reduce the blood flow. PALI images were acquired before, during, and after the restriction. The drop of tissue pO2 and recovery from hypoxia due to reperfusion were tracked and observed by PALI. PMID:25748857

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...

Pathways of inhalation exposure to manganese in children ...

EPA Pesticide Factsheets

Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source. The purpose of this study was to use a structural equations modeling approach combined with exposure estimates derived from air-dispersion modeling to assess potential inhalation exposure pathways for children to a

A Community Prevention Model to Prevent Children from Inhaling and Ingesting Harmful Legal Products

ERIC Educational Resources Information Center

Johnson, K. W.; Grube, J. W.; Ogilvie, K. A.; Collins, D.; Courser, M.; Dirks, L. G.; Ogilvie, D.; Driscoll, D.

2012-01-01

Children's misuse of harmful legal products (HLPs), including inhaling or ingesting everyday household products, prescription drugs, and over-the-counter drugs, constitutes a serious health problem for American society. This article presents a community prevention model (CPM) focusing on this problem among pre and early adolescents. The model,…

Pediatric in vitro and in silico models of deposition via oral and nasal inhalation.

PubMed

Carrigy, Nicholas B; Ruzycki, Conor A; Golshahi, Laleh; Finlay, Warren H

2014-06-01

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can be useful for estimating exposure risks to inhaled particulate matter. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, deposition in this region plays an important role in both cases. Compared to adults, much less extrathoracic deposition data are available with pediatric subjects. Recently, progress in magnetic resonance imaging and computed tomography scans to develop pediatric extrathoracic airway replicas has facilitated addressing this issue. Indeed, the use of realistic replicas for benchtop inhaler testing is now relatively common during the development and in vitro evaluation of pediatric respiratory drug delivery devices. Recently, in vitro empirical modeling studies using a moderate number of these realistic replicas have related airway geometry, particle size, fluid properties, and flow rate to extrathoracic deposition. Idealized geometries provide a standardized platform for inhaler testing and exposure risk assessment and have been designed to mimic average in vitro deposition in infants and children by replicating representative average geometrical dimensions. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Computational fluid dynamics simulations allow for the quantification of local deposition patterns and an in-depth examination of aerosol behavior in the respiratory tract. Recent studies have used both in vitro and in silico deposition measurements in realistic pediatric airway geometries to some success. This article reviews the current understanding of pediatric in vitro and in silico deposition modeling via oral and nasal inhalation.

Human dendritic cells in the severe combined immunodeficiency mouse model: their potentiating role in the allergic reaction.

PubMed

Hammad, H; Duez, C; Fahy, O; Tsicopoulos, A; André, C; Wallaert, B; Lebecque, S; Tonnel, A B; Pestel, J

2000-04-01

Dendritic cells (DCs) are present in the lungs and airways of healthy and allergic subjects where they are exposed to inhaled antigens. After the uptake of antigens, DCs migrate to lymphoid organs where T cells initiate and control the immune response. The migratory properties of DCs are an essential component of their function but remain unclear in the situation of allergic diseases. To better understand the role of DCs in response to allergens, we first investigated their presence in an original experimental model of allergic asthma: the humanized severe combined immunodeficiency (SCID) mouse reconstituted with peripheral blood mononuclear cells from patients sensitive to Dermatophagoides pteronyssinus (Dpt). Human DCs were detected in lungs of mice developing an inflammatory pulmonary infiltrate and appeared to be mainly located in the alveolar spaces. In a second step, human DCs were generated in vitro from monocytes and injected into naive SCID mice exposed or not exposed to Dpt aerosols. Their migratory behavior was explored, as well as their potential role in modulating the IgE production after exposure to Dpt. After exposure to Dpt, the number of DCs present in airways decreased, while it increased into the spleen and thymus of the mice. The IgE production increased in the presence of DCs as compared with mice not injected with DCs. These results suggest that DCs may play a role in the pulmonary allergic reaction developed in response to Dpt in SCID mice.

1′-Acetoxychavicol Acetate Isolated from Alpinia galanga Ameliorates Ovalbumin-Induced Asthma in Mice

PubMed Central

Park, Sang-Joon; Lee, Eun-Ji; Lee, Jong-Hwa; Han, Sang-Seop; Pyo, Byeong Sik; Park, Dae-Hun; Kim, Bong-Hee

2013-01-01

The World Health Organization reports that 235 million people are currently affected by asthma. This disease is associated with an imbalance of Th1 and Th2 cells, which results in the upregulation of cytokines that promote chronic inflammation of the respiratory system. The inflammatory response causes airway obstruction and can ultimately result in death. In this study we evaluated the effect of 1′-acetoxychavicol acetate (ACA) isolated from Alpinia galanga rhizomes in a mouse model of ovalbumin (OVA)-induced asthma. To generate the mouse model, BALB/c mice were sensitized by intraperitoneal injection of OVA and then challenged with OVA inhalation for 5 days. Mice in the vehicle control group were sensitized with OVA but not challenged with OVA. Treatment groups received dexamethasone, 25 mg/kg/day ACA, or 50 mg/kg/day ACA for 5 days. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. Our results showed that ACA reduced the infiltration of white blood cells (especially eosinophils) and the level of IgE in the lungs of mice challenged with OVA and suppressed histopathological changes such as airway remodeling, goblet-cell hyperplasia, eosinophil infiltration, and glycoprotein secretion. In addition, ACA inhibited expression of the Th2 cytokines interleukin (IL)-4 and IL-13, and Th1 cytokines IL-12α and interferon-γ. Because asthmatic reactions are mediated by diverse immune and inflammatory pathways, ACA shows promise as an antiasthmatic drug candidate. PMID:23451048

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

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

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and themore » volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. In conclusion, given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted.« less

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

DOE PAGES

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

2016-12-08

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and themore » volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. In conclusion, given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted.« less

Assessing Inhalation Exposures Associated with Contamination Events in Water Distribution Systems

PubMed Central

Davis, Michael J.; Janke, Robert; Taxon, Thomas N.

2016-01-01

When a water distribution system (WDS) is contaminated, short-term inhalation exposures to airborne contaminants could occur as the result of domestic water use. The most important domestic sources of such exposures are likely to be showering and the use of aerosol-producing humidifiers, i.e., ultrasonic and impeller (cool-mist) units. A framework is presented for assessing the potential effects of short-term, system-wide inhalation exposures that could result from such activities during a contamination event. This framework utilizes available statistical models for showering frequency and duration, available exposure models for showering and humidifier use, and experimental results on both aerosol generation and the volatilization of chemicals during showering. New models for the times when showering occurs are developed using time-use data for the United States. Given a lack of similar models for how humidifiers are used, or the information needed to develop them, an analysis of the sensitivity of results to assumptions concerning humidifier use is presented. The framework is applied using network models for three actual WDSs. Simple models are developed for estimating upper bounds on the potential effects of system-wide inhalation exposures associated with showering and humidifier use. From a system-wide, population perspective, showering could result in significant inhalation doses of volatile chemical contaminants, and humidifier use could result in significant inhalation doses of microbial contaminants during a contamination event. From a system-wide perspective, showering is unlikely to be associated with significant doses of microbial contaminants. Given the potential importance of humidifiers as a source of airborne contaminants during a contamination event, an improved understanding of the nature of humidifier use is warranted. PMID:27930709

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.

Inhalants as intermediate drugs between legal and illegal drugs among middle and high school students.

PubMed

Sanchez, Zila M; Ribeiro, Luciana A; Moura, Yone G; Noto, Ana R; Martins, Silvia S

2013-01-01

The aims of this study are to: (1) describe the prevalence and sociodemographic characteristics of inhalant use among middle and high school students in Brazil, and (2) test the hypothesis of inhalants being intermediate drugs between legal and illegal drug use. A representative sample of 5226 students from private schools in São Paulo, Brazil, was selected to answer a self-report questionnaire. Weighted data was analyzed through Cox proportional hazards models. In the overall sample, inhalants seems to be an intermediate drug, since prior inhalant initiation was associated with first marijuana use, adjusted for previous alcohol and tobacco initiation.

Greater involvement of neurokinins found in Guinea pig models of severe asthma compared with mild asthma.

PubMed

Mukaiyama, Osamu; Morimoto, Kiyoshi; Nosaka, Emi; Takahashi, Sakiko; Yamashita, Makoto

2004-08-01

Involvement of neurokinins in asthma has been previously pointed out by several reports. However, the relationship between neurokinins and the severity of asthma has remained unclear. We developed a model of mild asthma (model I) and severe asthma (model II) in guinea pigs, and investigated the function of neurokinins in both models. In models I and II, systemically sensitized guinea pigs were made to inhale ovalbumin once and three times, respectively. Substance P (SP) and neurokinin A (NKA) concentrations in the bronchoalveolar lavage fluid (BALF) were measured in models I and II. Then, the effects of a capsaicin pretreatment, which depletes neurokinins, in both animal models on airway narrowing induced by the last ovalbumin inhalation, airway hyperresponsiveness to inhaled methacholine, and eosinophil accumulation in BALF, were investigated. SP concentration tended to increase and the NKA concentration increased significantly in model II, but not in model I. Capsaicin pretreatment significantly inhibited the late bronchial response that was observed 2-6 h after the last ovalbumin inhalation, airway hyperresponsiveness and eosinophil accumulation in model II. On the other hand, it had no effects on the responses in model I. It is suggested that the more severe the disease, the greater the involvement of neurokinins. Copyright 2004 S. Karger AG, Basel

Modeling early events in Francisella tularensis pathogenesis.

PubMed

Gillard, Joseph J; Laws, Thomas R; Lythe, Grant; Molina-París, Carmen

2014-01-01

Computational models can provide valuable insights into the mechanisms of infection and be used as investigative tools to support development of medical treatments. We develop a stochastic, within-host, computational model of the infection process in the BALB/c mouse, following inhalational exposure to Francisella tularensis SCHU S4. The model is mechanistic and governed by a small number of experimentally verifiable parameters. Given an initial dose, the model generates bacterial load profiles corresponding to those produced experimentally, with a doubling time of approximately 5 h during the first 48 h of infection. Analytical approximations for the mean number of bacteria in phagosomes and cytosols for the first 24 h post-infection are derived and used to verify the stochastic model. In our description of the dynamics of macrophage infection, the number of bacteria released per rupturing macrophage is a geometrically-distributed random variable. When combined with doubling time, this provides a distribution for the time taken for infected macrophages to rupture and release their intracellular bacteria. The mean and variance of these distributions are determined by model parameters with a precise biological interpretation, providing new mechanistic insights into the determinants of immune and bacterial kinetics. Insights into the dynamics of macrophage suppression and activation gained by the model can be used to explore the potential benefits of interventions that stimulate macrophage activation.

The effect of smoking status on burn inhalation injury mortality.

PubMed

Knowlin, Laquanda; Stanford, Lindsay; Cairns, Bruce; Charles, Anthony

2017-05-01

Three factors that effect burn mortality are age, total body surface of burn (TBSA), and inhalation injury. Of the three, inhalation injury is the strongest predictor of mortality thus its inclusion in the revised Baux score (age+TBSA+17* (inhalation injury, 1=yes, 0=no)). However, the weighted contribution of specific comorbidities such as smoker status on mortality has traditionally not been accounted for nor studied in this subset of burn patients. We therefore sought to examine the impact of current tobacco and/or marijuana smoking in patients with inhalation injury. A retrospective analysis of patients admitted to a regional burn center from 2002 to 2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre-existing comorbidities, and smoker status. Bivariate analysis was performed and logistic regression modeling using significant variables was utilized to estimate odds of mortality. There were a total of 7640 patients over the study period. 7% (n=580) of the burn cohort with inhalation injury were included in this study. In-hospital burn mortality for inhalation injury patients was 23%. Current smokers (20%) included cigarette smokers and marijuana users, 19% and 3%, respectively. Preexisting respiratory disease (17%) was present in 36% of smokers compared to 13% of non-smokers (p<0.001). Smokers had significantly lower mortality rate (9%) compared to non-smokers (26%, p<0.01). The logistic regression model for mortality outcomes identified statistically four significant variables: age, TBSA, ethnicity, and smoker status (OR=0.41, 95% CI=0.18-0.93). Presence of comorbidities, including preexisting respiratory disease, was not significant. In the sub group of burn patients with inhalation injury, the odds of mortality significantly decreased in pre-existing smokers after adjusting for significant covariates. We postulate that an immune tolerance mechanism that modulates and diminishes the pro-inflammatory response confers a survival advantage in smokers after exposure to acute smoke inhalation injury. Future prospective studies in human and/or animal models are needed to confirm these findings. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Customizing inhaled therapy to meet the needs of COPD patients.

PubMed

Fromer, Leonard; Goodwin, Elizabeth; Walsh, John

2010-03-01

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation resulting from emphysema and chronic bronchitis. Inhaled therapy is the major therapeutic approach for treating COPD. Multiple inhaler medications are available in the United States and are delivered by a variety of different devices: metered-dose inhalers, dry powdered inhalers, and nebulizers. Each inhaler device has unique requirements for use that must be correctly performed by the patient for successful drug delivery. Patients with COPD represent a medically diverse population, with each patient having distinct characteristics, such as lung function, comorbidities, cognitive functions, hand strength, and lifestyle. These characteristics impact the patient's ability to properly use specific inhaler devices and therefore affect adherence to therapy, therapeutic outcomes, and quality of life. It is estimated that between 28% to 68% of patients do not use metered-dose inhalers or dry powder inhalers correctly. Worsening symptoms or increased frequency of exacerbations may not always indicate disease progression but may indicate a patient's inability to use their inhaler device properly. This review discusses the patient- and device-specific factors to be considered when choosing an inhaled therapy, which will be concordant with the patient's medical needs, preferences, and lifestyle. The review also considers how the ideas underlying the patient-centered medical home model can be incorporated into the choice and use of inhaler device for a given patient with COPD to improve treatment outcomes.

MATHEMATICAL MODEL FOR AEROSOL DEPOSITION IN THE RESPIRATORY TRACT OF THE GUINEA PIG

EPA Science Inventory

Laboratory animals are used as surrogates in inhalation exposure studies for: 1) risk assessments of air pollutants; and, (2) evaluations of pharmacologic drugs. erein, a mathematical model is presented which identifies factors affecting the regional distribution of inhaled aeros...

The Contributing Risk of Tobacco Use for ARDS Development in Burn-Injured Adults With Inhalation Injury.

PubMed

Afshar, Majid; Netzer, Giora; Mosier, Michael J; Cooper, Richard S; Adams, William; Burnham, Ellen L; Kovacs, Elizabeth J; Durazo-Arvizu, Ramon; Kliethermes, Stephanie

2017-11-01

This study aims to determine the relationship between tobacco use, inhalation injury, and ARDS in burn-injured adults. This study was an observational cohort of 2,485 primary burn admissions to a referral burn center between January 1, 2008 and March 15, 2015. Subjects were evaluated by methods used to account for mediation and traditional approaches (multivariable logistic regression and propensity score analysis). Mediation analysis examined both the (1) indirect effect of tobacco use via inhalation injury as the mediator on ARDS development and (2) the direct effect of tobacco use alone on ARDS development. ARDS development occurred in 6.8% ( n = 170) of the cohort. Inhalation injury occurred in 5.0% ( n = 125) of the cohort, and ARDS developed in 48.8% ( n = 83) of the subjects with inhalation injury. Tobacco use was 2-fold more common in subjects with ARDS. In the mediated model, the direct effect of tobacco use on ARDS, including interaction between tobacco use and inhalation injury, was not significant (odds ratio [OR] 1.63, 95% CI 0.91-2.92, P = .10). However, the indirect effect of tobacco use via inhalation injury as the mediator was significant (OR 1.61, 95% CI 1.25-2.07, P < .001), and the proportion of the total effect of tobacco use operating through the mediator was 55.6%. In the non-mediation models (multivariable logistic regression and propensity score analysis), which controlled for inhalation injury and other covariables, the OR for the association between tobacco use and ARDS was 1.84 (95% CI 1.22-2.81, P < .001) and 1.69 (95% CI 1.04-2.75, P = .03), respectively. In mediation analysis, inhalation injury was the overwhelming predictor for ARDS development, whereas tobacco use has its strongest effect indirectly through inhalation injury. Patients with at least moderate inhalation injury are at greatest risk for ARDS development despite baseline risk factors like tobacco use. Copyright © 2017 by Daedalus Enterprises.

Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.

PubMed

Gutting, Bradford W; Marchette, David; Sherwood, Robert; Andrews, George A; Director-Myska, Alison; Channel, Stephen R; Wolfe, Daniel; Berger, Alan E; Mackie, Ryan S; Watson, Brent J; Rukhin, Andrey

2013-07-21

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose-response data set was fitted to an exponential dose-response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40 °C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man. Published by Elsevier Ltd.

How do mice follow odor trails?

NASA Astrophysics Data System (ADS)

Zwicker, David; Trastour, Sophie; Mishra, Shruti; Mathis, Alexander; Murthy, Venkatesh; Brenner, Michael P.

2015-11-01

Mice are excellent at following odor trails e.g. to locate food or to find mates. However, it is not yet understood what navigation strategies they use. In principle, they could either evaluate temporal differences between sniffs or they could use concurrent input from the two nostrils. It is unknown to what extend these two strategies contribute to mice's performance. When mice follow trails, odors evaporate from the ground, are transported by flow in the air, and are then inhaled with the two nostrils. In order to differentiate between the two navigation strategies, we determine what information the mouse receives: first, we calculate the airflow by numerically solving the incompressible Navier-Stokes equations. We then determine the spatiotemporal odor concentration from the resulting advection-diffusion equations. Lastly, we determine the odor amount in each nostril by calculating the inhalation volumes using potential flow theory. Taken together, we determine the odor amount in each nostril during each sniff, allowing a detailed study of navigation strategies.

Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse.

PubMed

Martínez-Alfaro, Minerva; Cárabez-Trejo, Alfonso; Gallegos-Corona, Marco-Antonio; Pedraza-Aboytes, Gustavo; Hernández-Chan, Nancy Georgina; Leo-Amador, Guillermo Enrique

2010-04-01

Humans can come into contact with thinner by occupational exposure or by intentional inhalation abuse. Numerous studies of workers for genotoxic effects of thinner exposure have yielded conflicting results, perhaps because co-exposure to variable other compounds cannot be avoided in workplace exposure studies. In contrast, there is no data concerning the genotoxic effects of intentional inhalation abuse. The aim of this project was to examine the genotoxic effects of thinner inhalation in an animal model of thinner abuse (rats exposed to 3000 ppm toluene, a high solvent concentration over a very short, 15 min time period, twice a day for 6 weeks). The data presented here provides evidence that thinner inhalation in our experimental conditions is able to induce weight loss, lung abnormalities and oxidative stress. This oxidative stress induces oxidative DNA damage that is not a characteristic feature of genotoxic damage. No significant difference in DNA damage and DNA repair (biomarkers of genotoxicity) in lymphocytes from thinner-treated and control rats was found. Lead treatment was used as a positive control in these assays. Finally, bone marrow was evaluated as a biomarker of cellular alteration associated with thinner inhalation. The observed absence of hemopoietic and genetic toxicity could be explained in part by the absence of benzene, the only carcinogenic component of thinner; however, benzene is no longer a common component of thinner. In conclusion, thinner did not cause genotoxic effects in an experimental model of intentional abuse despite the fact that thinner inhalation induces oxidative stress. (c) 2009 John Wiley & Sons, Ltd.

Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease.

PubMed

Hullmann, Maja; Albrecht, Catrin; van Berlo, Damiën; Gerlofs-Nijland, Miriam E; Wahle, Tina; Boots, Agnes W; Krutmann, Jean; Cassee, Flemming R; Bayer, Thomas A; Schins, Roel P F

2017-08-30

Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m 3 , 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-β (Aβ) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aβ plaque load and higher whole brain homogenate Aβ42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer's disease.

Role of fiber dissolution in biological activity in rats.

PubMed

Eastes, W; Hadley, J G

1994-12-01

This report deals with the role of dissolution in removing long fibers from the lung and with a mathematical model that predicts chronic effects in rats following inhalation or intraperitoneal (i.p.) injection of fibers. Results of intratracheal instillation studies and inhalation studies in rats demonstrate clearly that long vitreous fibers dissolve in vivo at about the same rate measured in vitro in fluid designed to stimulate the extracellular lung fluid. For the glass, rock, and slag wool fibers tested, dissolution removed most of the fibers longer than 20 microns inhaled into the rats' lungs within 6 months after both short-term (5 days) and long-term (1 to 2 years) exposures. A mathematical model was developed that is based on fiber dissolution and allows one to predict the development of chronic lung diseases in rats. The model predicted the incidence of fibrosis and lung tumors in a series of recent inhalation studies and tumors following ip injection to within about the error of the experiments. The model suggests that all fibers, regardless of their dissolution rate in lung fluid, can produce tumors after ip injection because the dose can be unlimited by this route. After inhalation, in contrast, dissolution of many types of long vitreous fibers occurs rapidly, and disease does not ensue for these fibers.

Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension.

PubMed

Heidersbach, R S; Johengen, M J; Bekker, J M; Fineman, J R

1999-07-01

Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO induces selective, dose-dependent pulmonary vasodilation. However, its potential interactions with other simultaneously used pulmonary vasodilator therapies have not been studied. Therefore, the objective of this study was to determine the potential dose-response interactions of inhaled NO, oxygen, and alkalosis therapies. Fourteen newborn lambs (age 1-6 days) were instrumented to measure vascular pressures and left pulmonary artery blood flow. After recovery, the lambs were sedated and mechanically ventilated. During steady-state pulmonary hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B, inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and 7.60. Each condition (in randomly chosen order) was maintained for 10 min, and all variables were allowed to return to baseline between conditions. Inhaled NO, oxygen, and alkalosis produced dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At 5 ppm of inhaled NO, alkalosis and oxygen induced further dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). At inhaled NO doses > 5 ppm, alkalosis induced further dose-independent decreases in mean pulmonary arterial pressure, while oxygen did not. We conclude that in this animal model, oxygen, alkalosis, and inhaled NO induced selective, dose-dependent pulmonary vasodilation. However, when combined, a systemic arterial pH > 7.40 augmented inhaled NO-induced pulmonary vasodilation, while an FiO2 > 0.5 did not. Therefore, weaning high FiO2 during inhaled NO therapy should be considered, since it may not diminish the pulmonary vasodilating effects. Further studies are warranted to guide the clinical weaning strategies of these pulmonary vasodilator therapies.

Acute Lung Injury and Persistent Small Airway Disease in a Rabbit Model of Chlorine Inhalation

PubMed Central

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M.; Powell, Karen S.; Roberts, Andrew M.; Hoyle, Gary W.

2016-01-01

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. PMID:27913141

Substance P Antagonist CP-96345 Blocks Lung Vascular Leakage and Inflammation More Effectively than its Stereoisomer CP-96344 in a Mouse Model of Smoke Inhalation and Burn Injury

PubMed Central

Jacob, Sam; Deyo, Donald J.; Cox, Robert A.; Jacob, Reuben K; Herndon, David N.; Traber, Daniel L.; Hawkins, Hal K.

2010-01-01

The recently developed murine model of smoke inhalation and burn (SB) injury was used to study the effect of the substance-P antagonist CP96345. C57BL/6 mice were pretreated with an i.v. dose of a specific NK-1 receptor antagonist, CP9635, or its inactive enantiomer, CP96344, (10 mg/Kg) 1 hr prior to SB injury per protocol (n = 5). Mice were anesthetized and exposed to cooled cotton smoke, 2X 30 sec, followed by a 40% total body surface area flame burn per protocol. At 48 hr after SB injury Evans Blue (EB) dye and myeloperoxidase (MPO) were measured in lung after vascular perfusion. Lungs were also analyzed for hemoglobin (Hb) and wet/dry weight ratio. In the current study, CP96345 pretreatment caused a significant decrease in wet/dry weight ratio (23%, *p = 0.048), EB (31%, *p = 0.047), Hb (46%, *p = 0.002) and MPO (54%, *p = 0.037) levels following SB injury compared to animals with SB injury alone. CP-96344 pretreatment caused an insignificant decrease in wet/dry weight ratio (14%, p=0.18), EB (16%, p = 0.134), Hb (9%, p = 0.39) and an insignificant increase in MPO (4%, p =0.79) as compared to mice that received SB injury alone. As expected, levels of EB, Hb, MPO, and wet/dry weight ratios were all significantly (p < 0.05) increased 48 hr following SB injury alone compared to respective sham animals. In conclusion, the current study indicates that pretreatment with specific NK-1R antagonist CP-96345 attenuates the lung injury and inflammation induced by SB injury in mice. PMID:20201741

DOSIMETRY MODELING OF INHALED FORMALDEHYDE: BINNING NASAL FLUX PREDICTIONS FOR QUANTITATIVE RISK ASSESSMENT

EPA Science Inventory

Dosimetry Modeling of Inhaled Formaldehyde: Binning Nasal Flux Predictions for Quantitative Risk Assessment. Kimbell, J.S., Overton, J.H., Subramaniam, R.P., Schlosser, P.M., Morgan, K.T., Conolly, R.B., and Miller, F.J. (2001). Toxicol. Sci. 000, 000:000.

Interspecies e...

AEROSOL DEPOSITION EFFICIENCIES AND UPSTREAM RELEASE POSITIONS FOR DIFFERENT INHALATION MODES IN AN UPPER BRONCHIAL AIRWAY MODELS

EPA Science Inventory

Aerosol Deposition Efficiencies and Upstream Release Positions for Different Inhalation Modes in an Upper Bronchial Airway Model

Zhe Zhang, Clement Kleinstreuer, and Chong S. Kim

Center for Environmental Medicine and Lung Biology, University of North Carolina at Ch...

Use of novel inhalation kinetic studies to refine physiologically-based-pharmacokinetic models for ethanol in non-pregnant and pregnant rats

EPA Science Inventory

Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrat...

Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies

PubMed Central

Fröhlich, Eleonore; Salar-Behzadi, Sharareh

2014-01-01

The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the inhaled air and pattern of deposition in the lung). With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs. PMID:24646916

Estimating in vivo airway surface liquid concentration in trials of inhaled antibiotics.

PubMed

Hasan, M A; Lange, C F

2007-01-01

Antibiotic drugs exhibit concentration dependence in their efficacy. Therefore, ensuring appropriate concentration of these drugs in the relevant body fluid is important for obtaining the desired therapeutic and physiological action. Until recently there had been no suitable method available to measure or estimate concentration of drugs in the human airways resulting from inhaled aerosols or to determine the amount of inhaled antibiotics required to ensure minimum inhibitory concentration of a drug in the airway surface liquid (ASL). In this paper a numerical method is used for estimating local concentration of inhaled pharmaceutical aerosols in different generations of the human tracheobronchial airways. The method utilizes a mathematical lung deposition model to estimate amounts of aerosols depositing in different lung generations, and a recent ASL model along with deposition results to assess the concentration of deposited drugs immediately following inhalation. Examples of concentration estimates for two case studies: one for the antibiotic tobramycin against Pseudomonas aeruginosa, and another for taurolidine against Burkholderia cepacia are presented. The aerosol characteristics, breathing pattern and properties of nebulized solutions were adopted from two recent clinical studies on efficacy of these drugs in cystic fibrosis (CF) patients and from other sources in the literature. While the clinically effective tobramycin showed a concentration higher than the required in vivo concentration, that for the ineffective taurolidine was found to be below the speculated required in vivo concentration. Results of this study thus show that the mathematical ASL model combined with the lung deposition model can be an effective tool for helping decide the optimum dosage of inhaled antibiotic drugs delivered during human clinical trials.

Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice

PubMed Central

2011-01-01

Background Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated. Methods We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis. Results Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice. Conclusions Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation. PMID:21702963

Physical characteristics and aerosolization performance of insulin dry powders for inhalation prepared by a spray drying method.

PubMed

You, Yu; Zhao, Min; Liu, Guangli; Tang, Xing

2007-07-01

The objective of this study was to investigate the influence of formulation excipients on the physical characteristics and aerosolization performance of insulin dry powders for inhalation. Insulin dry powders were prepared by a spray drying technique using excipients such as sugars (trehalose, lactose and dextran), mannitol and amino acids (L-leucine, glycine and threonine). High performance liquid chromatography and the mouse blood glucose method were used for determination of the insulin content. The powder properties were determined and compared by scanning electron microscopy, thermo-gravimetric analysis and size distribution analysis by a time-of-flight technique. The in-vitro aerosolization behaviour of the powders was assessed with an Aerolizer inhaler using a twin-stage impinger. Powder yield and moisture absorption were also determined. Results showed that there was no noticeable change in insulin content in any of the formulations by both assay methods. All powders were highly wrinkled, with median aerodynamic diameters of 2-4 microm, and consequently suitable for pulmonary administration. The tapped density was reduced dramatically when glycine was added. The powders containing mannitol, with or without L-leucine, were less sensitive to moisture. The highest respirable fraction of 67.3 +/- 1.3% was obtained with the formulation containing L-leucine, in contrast to formulations containing glycine and threonine, which had a respirable fraction of 11.2 +/- 3.9% and 23.5 +/- 2.5%, respectively. In addition, powders with good physical properties were achieved by the combination of insulin and trehalose. This study suggests that L-leucine could be used to enhance the aerosolization behaviour of the insulin dry powders for inhalation, and trehalose could potentially be used as an excipient in the formulations.

The Oxidized Low-Density Lipoprotein Receptor Mediates Vascular Effects of Inhaled Vehicle Emissions

PubMed Central

Lucero, JoAnn; Harman, Melissa; Madden, Michael C.; McDonald, Jacob D.; Seagrave, Jean Clare; Campen, Matthew J.

2011-01-01

Rationale: To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure–induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events. Objectives: To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions. Methods: Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m3 diesel + 50 μg PM/m3 gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m3 diesel whole exhaust or high-efficiency particulate air and charcoal-filtered “clean” air (control subjects) for 2 hours, on separate occasions. Measurements and Main Results: Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1. Conclusions: These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL–LOX-1 receptor signaling, which may serve as a novel target for future therapy. PMID:21493736

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach.

PubMed

Weber, Benjamin; Hochhaus, Guenther

2015-07-01

The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.

Pathways of inhalation exposure to manganese in children living near a ferromanganese refinery: A structural equation modeling approach

EPA Science Inventory

Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation ...

DEVELOPMENT OF 3-D COMPUTER MODELS OF HUMAN LUNG MORPHOLOGY FOR IMPROOVED RISK ASSESSMENT OF INHALED PARTICULATE MATTER

EPA Science Inventory

DEVELOPMENT OF 3-D COMPUTER MODELS OF HUMAN LUNG MORPHOLOGY FOR IMPROVED RISK ASSESSMENT OF INHALED PARTICULATE MATTER

Jeffry D. Schroeter, Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599; Ted B. Martonen, ETD, NHEERL, USEPA, RTP, NC 27711; Do...

SUBCHRONIC TOXICITY OF INHALED TOLUENE IN RATS: IMMUNOLOGY, CARDIAC GENE EXPRESSION AND MARKERS OF OXIDATIVE STRESS.

EPA Science Inventory

The health effects of long-term exposure to volatile organic compounds (VOCs) are poorly understood, due primarily to insufficient human exposure data and inconsistent animal models. To develop a rodent model of long-term exposure to VOCs, a sub-chronic inhalation study with mult...

Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

PubMed

Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

2012-05-01

3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

Mathematical Modeling of Physical and Cognitive Performance Decrement from Mechanical and Inhalation Insults

DTIC Science & Technology

2006-12-01

on specific short term problems. 1.1.1 Dynamic Physiological Modeling The oxygenation of the blood by the lung through respiration is a critical...tests as apnea , reduced arterial saturation, and may even be linked to long term CNS deficits. Inhalation of toxic gases can dramatically affect the...of TGAS model the respiration , circulation, and metabolic processes and include models of the ventilation and cardiac output control due to 3

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation.

PubMed Central

Luu, H M; Hutter, J C

2001-01-01

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D(4)) after intravenous (IV), inhalation, or implantation exposures. The model used (14)C-D(4) IV disposition data in rats to estimate tissue distribution coefficients, metabolism, and excretion parameters. We validated the model by comparing the predicted blood and tissues concentrations of D(4) after inhalation to experimental results in both rats and humans. We then used the model to simulate D(4) kinetics after single and/or repeated D(4) exposures in rats and humans. The model predicted bioaccumulation of D(4) in fatty tissues (e.g., breast), especially in women. Because of its high lipid solubility (Log P(oct/water) = 5.1), D(4) persisted in fat with a half life of 11.1 days after inhalation and 18.2 days after breast implant exposure. Metabolism and excretion remained constant with repeated exposures, larger doses, and/or different routes of exposure. The accumulation of D(4) in fatty tissues should play an important role in the risk assessment of D(4) especially in women exposed daily to multiple personal care products and silicone breast implants. PMID:11712992

Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

PubMed

Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

2008-12-01

Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

Chronic Intermittent Ethanol Inhalation Increases Ethanol Self-administration in both C57BL/6J and DBA/2J Mice

PubMed Central

McCool, Brian A.; Chappell, Ann M.

2015-01-01

Inbred mouse strains provide significant opportunities to understand the genetic mechanisms controlling ethanol-directed behaviors and neurobiology. They have been specifically employed to understand cellular mechanisms contributing to ethanol consumption, acute intoxication, and sensitivities to chronic effects. However, limited ethanol consumption by some strains has restricted our understanding of clinically relevant endpoints such as dependence-related ethanol intake. Previous work with a novel tastant-substitution procedure using monosodium glutamate (MSG or umami flavor) has shown that the procedure greatly enhances ethanol consumption by mouse strains that express limited drinking phenotypes using other methods. In the current study, we employ this MSG-substitution procedure to examine how ethanol dependence, induced with passive vapor inhalation, modifies ethanol drinking in C57BL/6J and DBA/2J mice. These strains represent ‘high’ and ‘low’ drinking phenotypes, respectively. We found that the MSG substitution greatly facilitates ethanol drinking in both strains, and likewise, ethanol dependence increased ethanol consumption regardless of strain. However, DBA/2J mice exhibited greater sensitivity dependence-enhanced drinking, as represented by consumption behaviors directed at lower ethanol concentrations and relative to baseline intake levels. DBA/2J mice also exhibited significant withdrawal-associated anxiety-like behavior while C57BL/6J mice did not. These findings suggest that the MSG-substitution procedure can be employed to examine dependence-enhanced ethanol consumption across a range of drinking phenotypes, and that C57BL/6J and DBA/2J mice may represent unique neurobehavioral pathways for developing dependence-enhanced ethanol consumption. PMID:25659650

Health risk represented by inhaling polycyclic aromatic hydrocarbons (PAH) during daily commuting involving using a high traffic flow route in Bogotá.

PubMed

Pachón, Jorge E; Sarmiento, Hugo; Hoshiko, Tomomi

2013-01-01

Assessing the risk to health by inhaling particles and particle-bound PAH during daily commuting along a high traffic flow route/corridor in Bogotá. A van was equipped with a PAS2000 photo-electric sensor for real-time measurement of particle-bound PAH and a Dust Trakfor monitoring PM10 concentration; it drove along typical commuting routes in the city. Exposure to particles and particle-bound PAH was assessed by using an inhalation intake model. A similar trend was observed for both PM10 and PAH concentration, indicating that traffic was the same source for both contaminants. Extreme PM10 and PAH inhalation concentrations were recorded every time direct bus and microbus emissions were measured by the van. Inhalation model results indicated that exposure was significantly greater when using a venues having mixed traffic use (i.e. buses, microbuses, passenger vehicles, motorcycles) compared to using roads where the TransMilenio system (articulated buses) had been implemented. The results may support evaluating bus drivers, commuters and bike users' exposure to toxic compounds in the city.

Quail egg homogenate alleviates food allergy induced eosinophilic esophagitis like disease through modulating PAR-2 transduction pathway in peanut sensitized mice.

PubMed

Lianto, Priscilia; Han, Shiwen; Li, Xinrui; Ogutu, Fredrick Onyango; Zhang, Yani; Fan, Zhuoyan; Che, Huilian

2018-01-18

The present pharmacotherapy for eosinophilic esophagitis (EoE) fundamentally depend on inhaled corticosteroids. Despite the fact that oral intake of topical steroids can be successful in restricting EoE-related inflammation, there are concerns with respect to the long term utilization of steroids, especially in kids. In the current research, we assess the effect of quail egg, which is reportedly a known serine protease inhibitor, on symptomatology and immune responses in a peanut-sensitized mouse model of food allergy induced EoE. Daily oral treatment with quail egg attenuated mice symptomatology and immune response. Treatment with quail egg inhibited antigen-prompted increments in mouse tryptase and eosinophil cationic protein (ECP) in serum and eosinophil in inflamed tissues like oesophagus, lung, and digestive system. Quail egg treatment resulted in decreased antibody specific IgE and IgG1 and a variety of inflammatory genes that were abnormally expressed in EoE. Other effects included increased IL-10, decreased PAR-2 activation and NF-kB p65 in inflamed tissues. Our results suggest that quail egg treatment may have therapeutic potential in attenuating the symptoms of food allergy induced EoE like disease through regulating PAR-2 downstream pathway by blocking the activation of the transcription factor NF-kB p65 activity.

Analgesic Effect of Xenon in Rat Model of Inflammatory Pain.

PubMed

Kukushkin, M L; Igon'kina, S I; Potapov, S V; Potapov, A V

2017-02-01

The analgesic effects of inert gas xenon were examined on rats. The formalin model of inflammatory pain, tail-flick test, and hot-plate test revealed the antinociceptive effects of subanesthetizing doses of inhalation anesthetic xenon. Inhalation of 50/50 xenon/oxygen mixture moderated the nociceptive responses during acute and tonic phases of inflammatory pain.

Pharmacokinetic-Pharmacodynamic Assessment of Faropenem in a Lethal Murine Bacillus anthracis Inhalation Postexposure Prophylaxis Model

DTIC Science & Technology

2010-05-01

Inhalation Postexposure Prophylaxis Model Stanley C. Gill,1* Christopher M. Rubino,2 Jennifer Bassett,3 Lynda Miller,3 Paul G. Ambrose,2 Sujata M. Bhavnani,2...tandem repeat analysis reveals genetic relationships within Bacillus anthracis. J. Bacteriol. 182:2928–2936. 14. Mohammed, M. J., C. K. Marston , T

Antibiotic Treatment of Experimental Pneumonic Plague in Mice

PubMed Central

Byrne, William R.; Welkos, Susan L.; Pitt, M. Louise; Davis, Kelly J.; Brueckner, Ralf P.; Ezzell, John W.; Nelson, Gene O.; Vaccaro, Joseph R.; Battersby, Luann C.; Friedlander, Arthur M.

1998-01-01

A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized Yersinia pestis organisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia. PMID:9517950

Deterministic Models of Inhalational Anthrax in New Zealand White Rabbits

PubMed Central

2014-01-01

Computational models describing bacterial kinetics were developed for inhalational anthrax in New Zealand white (NZW) rabbits following inhalation of Ames strain B. anthracis. The data used to parameterize the models included bacterial numbers in the airways, lung tissue, draining lymph nodes, and blood. Initial bacterial numbers were deposited spore dose. The first model was a single exponential ordinary differential equation (ODE) with 3 rate parameters that described mucociliated (physical) clearance, immune clearance (bacterial killing), and bacterial growth. At 36 hours postexposure, the ODE model predicted 1.7×107 bacteria in the rabbit, which agreed well with data from actual experiments (4.0×107 bacteria at 36 hours). Next, building on the single ODE model, a physiological-based biokinetic (PBBK) compartmentalized model was developed in which 1 physiological compartment was the lumen of the airways and the other was the rabbit body (lung tissue, lymph nodes, blood). The 2 compartments were connected with a parameter describing transport of bacteria from the airways into the body. The PBBK model predicted 4.9×107 bacteria in the body at 36 hours, and by 45 hours the model showed all clearance mechanisms were saturated, suggesting the rabbit would quickly succumb to the infection. As with the ODE model, the PBBK model results agreed well with laboratory observations. These data are discussed along with the need for and potential application of the models in risk assessment, drug development, and as a general aid to the experimentalist studying inhalational anthrax. PMID:24527843

Impact of non-constant concentration exposure on lethality of inhaled hydrogen cyanide.

PubMed

Sweeney, Lisa M; Sommerville, Douglas R; Channel, Stephen R

2014-03-01

The ten Berge model, also known as the toxic load model, is an empirical approach in hazard assessment modeling for estimating the relationship between the inhalation toxicity of a chemical and the exposure duration. The toxic load (TL) is normally expressed as a function of vapor concentration (C) and duration (t), with TL equaling C(n) × t being a typical form. Hypothetically, any combination of concentration and time that yields the same "toxic load" will give a constant biological response. These formulas have been developed and tested using controlled, constant concentration animal studies, but the validity of applying these assumptions to time-varying concentration profiles has not been tested. Experiments were designed to test the validity of the model under conditions of non-constant acute exposure. Male Sprague-Dawley rats inhaled constant or pulsed concentrations of hydrogen cyanide (HCN) generated in a nose-only exposure system for 5, 15, or 30 min. The observed lethality of HCN for the 11 different C versus t profiles was used to evaluate the ability of the model to adequately describe the lethality of HCN under the conditions of non-constant inhalation exposure. The model was found to be applicable under the tested conditions, with the exception of the median lethality of very brief, high concentration, discontinuous exposures.

Towards the optimisation and adaptation of dry powder inhalers.

PubMed

Cui, Y; Schmalfuß, S; Zellnitz, S; Sommerfeld, M; Urbanetz, N

2014-08-15

Pulmonary drug delivery by dry powder inhalers is becoming more and more popular. Such an inhalation device must insure that during the inhalation process the drug powder is detached from the carrier due to fluid flow stresses. The goal of the project is the development of a drug powder detachment model to be used in numerical computations (CFD, computational fluid dynamics) of fluid flow and carrier particle motion through the inhaler and the resulting efficiency of drug delivery. This programme will be the basis for the optimisation of inhaler geometry and dry powder inhaler formulation. For this purpose a multi-scale approach is adopted. First the flow field through the inhaler is numerically calculated with OpenFOAM(®) and the flow stresses experienced by the carrier particles are recorded. This information is used for micro-scale simulations using the Lattice-Boltzmann method where only one carrier particle covered with drug powder is placed in cubic flow domain and exposed to the relevant flow situations, e.g. plug and shear flow with different Reynolds numbers. Therefrom the fluid forces on the drug particles are obtained. In order to allow the determination of the drug particle detachment possibility by lift-off, sliding or rolling, also measurements by AFM (atomic force microscope) were conducted for different carrier particle surface structures. The contact properties, such as van der Waals force, friction coefficient and adhesion surface energy were used to determine, from a force or moment balance (fluid forces versus contact forces), the detachment probability by the three mechanisms as a function of carrier particle Reynolds number. These results will be used for deriving the drug powder detachment model. Copyright © 2014 Elsevier B.V. All rights reserved.

Does dental undergraduate education and postgraduate training enable intention to provide inhalation sedation in primary dental care? A path analytical exploration.

PubMed

Yuan, S; J Carson, S; Rooksby, M; McKerrow, J; Lush, C; Humphris, G; Freeman, R

2017-08-01

To examine how quality standards of dental undergraduate education, postgraduate training and qualifications together with confidence and barriers could be utilised to predict intention to provide inhalation sedation. All 202 dentists working within primary dental care in NHS Highland were invited to participate. The measures in the questionnaire survey included demographic information, undergraduate education and postgraduate qualifications, current provision and access to sedation service, attitudes towards confidence, barriers and intention to provide inhalation sedation. A path analytical approach was employed to investigate the fit of collected data to the proposed mediational model. One hundred and nine dentists who completed the entire questionnaire participated (response rate of 54%). Seventy-six per cent of dentists reported receiving lectures in conscious sedation during their undergraduate education. Statistically significantly more Public Dental Service dentists compared with General Dental Service (GDS) dentists had postgraduate qualification and Continuing Professional Development training experience in conscious sedation. Only twenty-four per cent of the participants stated that they provided inhalation sedation to their patients. The findings indicated that PDS dentists had higher attitudinal scores towards inhalation sedation than GDS practitioners. The proposed model showed an excellent level of fit. A multigroup comparison test confirmed that the level of association between confidence in providing inhalation sedation and intention varied by group (GDS vs. PDS respondents). Public Dental Service respondents who showed extensive postgraduate training experience in inhalation sedation were more confident and likely to provide this service. The quality standards of dental undergraduate education, postgraduate qualifications and training together with improved confidence predicted primary care dentists' intention to provide inhalation sedation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management.

PubMed

Hayashida, Kei; Sano, Motoaki; Kamimura, Naomi; Yokota, Takashi; Suzuki, Masaru; Ohta, Shigeo; Fukuda, Keiichi; Hori, Shingo

2014-12-09

We have previously shown that hydrogen (H2) inhalation, begun at the start of hyperoxic cardiopulmonary resuscitation, significantly improves brain and cardiac function in a rat model of cardiac arrest. Here, we examine the effectiveness of this therapeutic approach when H2 inhalation is begun on the return of spontaneous circulation (ROSC) under normoxic conditions, either alone or in combination with targeted temperature management (TTM). Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O2 and normothermia (control); mechanically ventilated with 26% O2, 1.3% H2, and normothermia (H2); mechanically ventilated with 26% O2 and TTM (TTM); and mechanically ventilated with 26% O2, 1.3% H2, and TTM (TTM+H2). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H2 and TTM groups, and 85.7% in the TTM+H2 group. Combined therapy of TTM and H2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H2 inhalation alone, with the combined therapy of TTM and H2 inhalation being most effective. H2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia. Combined TTM and H2 inhalation was more effective than TTM alone. © 2014 American Heart Association, Inc.

Mathematical Modeling of Physical and Cognitive Performance Decrement from Mechanical and Inhalation Insults

DTIC Science & Technology

2009-12-01

INHALATION TOXICOLOGY RESEARCH 2.1.1 Development of a Fatigue Model & Blood Oxygen-based Parameter Corre- lates Liu et al. (2002) introduced a muscle ...and Stuhmiller, J.H. “Generalization of a ‘phenomenological’ muscle fatigue model.” Technical report J0287-10-382 (in preparation). Product 3. Sih...physiologic response to exercise and a model of muscle fatigue which have been developed and validated separately are integrated. Integration occurs through

Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products.

PubMed

Velaga, Sitaram P; Djuris, Jelena; Cvijic, Sandra; Rozou, Stavroula; Russo, Paola; Colombo, Gaia; Rossi, Alessandra

2018-02-15

In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated. This review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhalers, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent biorelevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined. Copyright © 2017 Elsevier B.V. All rights reserved.

Budesonide + formoterol delivered via Spiromax® for the management of asthma and COPD: The potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler®.

PubMed

Lewis, A; Torvinen, S; Dekhuijzen, P N R; Chrystyn, H; Melani, A; Zöllner, Y; Kolbe, K; Watson, A T; Blackney, M; Plich, A

2017-08-01

Fixed-dose combinations of inhaled corticosteroids and long-acting β 2 agonists are commonly used for the treatment of asthma and COPD. However, the most frequently prescribed dry powder inhaler delivering this medicine - Symbicort ® (budesonide and formoterol, BF) Turbuhaler ® - is associated with poor inhalation technique, which can lead to poor disease control and high disease management costs. A recent study showed that patients make fewer inhaler errors when using the novel DuoResp ® (BF) Spiromax ® inhaler, compared with BF Turbuhaler ® . Therefore switching patients from BF Turbuhaler ® to BF Spiromax ® could improve inhalation technique, and potentially lead to better disease control and healthcare cost savings. A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler ® to BF Spiromax ® over three years in Germany, Italy, Sweden and the UK. The model estimated changes to the number, and associated cost, of unscheduled healthcare events. The model considered two scenarios: in Scenario 1, all patients were immediately switched from BF Turbuhaler ® to BF Spiromax ® ; in Scenario 2, 4%, 8% and 12% of patients were switched in years 1, 2 and 3 of the model, respectively. In Scenario 1, per patient cost savings amounted to €60.10, €49.67, €94.14 and €38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were €100.86 million, €19.42 million, €36.65 million and €15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled €8.07 million, €1.55 million, €2.93 million and €1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were €4.81, €3.97, €7.53 and €3.06. We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler ® to BF Spiromax ® are likely to improve patients' disease control and generate considerable cost savings through healthcare events avoided. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Anthrax Vaccine Powder Formulations for Nasal Mucosal Delivery

DTIC Science & Technology

2005-08-04

inhalational anthrax can be achieved in a rabbit model, by intranasal delivery of a powder rPA formulation. Here we describe the preformulation and...fluorescence. Based on these stability profiles, spray freeze-dried (SFD) formulations were prepared at pH 7–8 using trehalose as stabilizer and a CpG...gas- trointestinal, and pulmonary routes. The inhaled form is of particular concern considering its de- monstrated use as a bioweapon.1–4 Inhalational

Numerical study of dynamic glottis and tidal breathing on respiratory sounds in a human upper airway model

PubMed Central

Wang, Zhaoxuan; Talaat, Khaled; Glide-Hurst, Carri; Dong, Haibo

2018-01-01

Background Human snores are caused by vibrating anatomical structures in the upper airway. The glottis is a highly variable structure and a critical organ regulating inhaled flows. However, the effects of the glottis motion on airflow and breathing sound are not well understood, while static glottises have been implemented in most previous in silico studies. The objective of this study is to develop a computational acoustic model of human airways with a dynamic glottis and quantify the effects of glottis motion and tidal breathing on airflow and sound generation. Methods Large eddy simulation and FW-H models were adopted to compute airflows and respiratory sounds in an image-based mouth-lung model. User-defined functions were developed that governed the glottis kinematics. Varying breathing scenarios (static vs. dynamic glottis; constant vs. sinusoidal inhalations) were simulated to understand the effects of glottis motion and inhalation pattern on sound generation. Pressure distributions were measured in airway casts with different glottal openings for model validation purpose. Results Significant flow fluctuations were predicted in the upper airways at peak inhalation rates or during glottal constriction. The inhalation speed through the glottis was the predominating factor in the sound generation while the transient effects were less important. For all frequencies considered (20–2500 Hz), the static glottis substantially underestimated the intensity of the generated sounds, which was most pronounced in the range of 100–500 Hz. Adopting an equivalent steady flow rather than a tidal breathing further underestimated the sound intensity. An increase of 25 dB in average was observed for the life condition (sine-dynamic) compared to the idealized condition (constant-rigid) for the broadband frequencies, with the largest increase of approximately 40 dB at the frequency around 250 Hz. Conclusion Results show that a severely narrowing glottis during inhalation, as well as flow fluctuations in the downstream trachea, can generate audible sound levels. PMID:29101633

Numerical study of dynamic glottis and tidal breathing on respiratory sounds in a human upper airway model.

PubMed

Xi, Jinxiang; Wang, Zhaoxuan; Talaat, Khaled; Glide-Hurst, Carri; Dong, Haibo

2018-05-01

Human snores are caused by vibrating anatomical structures in the upper airway. The glottis is a highly variable structure and a critical organ regulating inhaled flows. However, the effects of the glottis motion on airflow and breathing sound are not well understood, while static glottises have been implemented in most previous in silico studies. The objective of this study is to develop a computational acoustic model of human airways with a dynamic glottis and quantify the effects of glottis motion and tidal breathing on airflow and sound generation. Large eddy simulation and FW-H models were adopted to compute airflows and respiratory sounds in an image-based mouth-lung model. User-defined functions were developed that governed the glottis kinematics. Varying breathing scenarios (static vs. dynamic glottis; constant vs. sinusoidal inhalations) were simulated to understand the effects of glottis motion and inhalation pattern on sound generation. Pressure distributions were measured in airway casts with different glottal openings for model validation purpose. Significant flow fluctuations were predicted in the upper airways at peak inhalation rates or during glottal constriction. The inhalation speed through the glottis was the predominating factor in the sound generation while the transient effects were less important. For all frequencies considered (20-2500 Hz), the static glottis substantially underestimated the intensity of the generated sounds, which was most pronounced in the range of 100-500 Hz. Adopting an equivalent steady flow rather than a tidal breathing further underestimated the sound intensity. An increase of 25 dB in average was observed for the life condition (sine-dynamic) compared to the idealized condition (constant-rigid) for the broadband frequencies, with the largest increase of approximately 40 dB at the frequency around 250 Hz. Results show that a severely narrowing glottis during inhalation, as well as flow fluctuations in the downstream trachea, can generate audible sound levels.

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation.

PubMed

Musah, Sadiatu; Schlueter, Connie F; Humphrey, David M; Powell, Karen S; Roberts, Andrew M; Hoyle, Gary W

2017-01-15

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24h after exposure to 800ppm chlorine for 4min to study acute effects or up to 7days after exposure to 400ppm for 8min to study longer term effects. Acute effects observed 6 or 24h after inhalation of 800ppm chlorine for 4min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400ppm chlorine for 8min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

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

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, Da

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbitsmore » were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. • Acute effects of chlorine were pulmonary edema, hypoxemia and impaired lung function. • Persistent small airway disease developed following recovery from acute injury. • Small airway disease included inflammation and bronchiolitis obliterans lesions. • The model should be useful for studying chlorine lung injury and testing treatments.« less

RODENT MODELS OF SUSCEPTIBILITY: WHAT IS THEIR PLACE IN INHALATION TOXICOLOGY

EPA Science Inventory

Abstract: There is renewed interest in inhalation toxicology regarding "susceptibility" as associated with host variables, including genetics, age, diet, and disease. This interest derives from epidemiology that shows air pollution-related human mortality/morbidity, especially a...

Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats

PubMed Central

Watanabe, Sadahiro; Fujita, Masanori; Ishihara, Masayuki; Tachibana, Shoichi; Yamamoto, Yoritsuna; Kaji, Tatsumi; Kawauchi, Toshio; Kanatani, Yasuhiro

2014-01-01

The effect of inhalation of hydrogen-containing gas (1.3% hydrogen + 20.8% oxygen + 77.9% nitrogen) (HCG) on radiation-induced dermatitis and on the healing of healing-impaired skin wounds in rats was examined using a rat model of radiation-induced skin injury. An X-ray dose of 20 Gy was irradiated onto the lower part of the back through two holes in a lead shield. Irradiation was performed before or after inhalation of HCG for 2 h. Inhalation of HCG significantly reduced the severity of radiodermatitis and accelerated healing-impaired wound repair. Staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) showed that the proportion of apoptotic keratinocytes and the level of staining in the X-irradiated skin of rats that pre-inhaled HCG were significantly lower than that of rats which did not pre-inhale HCG. Cutaneous full-thickness wounds were then created in the X-irradiated area to examine the time-course of wound healing. X-irradiation significantly increased the time required for wound healing, but the inhalation of HCG prior to the irradiation significantly decreased the delay in wound healing compared with the control and post-inhalation of HCG groups. Therefore, radiation-induced skin injury can potentially be alleviated by the pre-inhalation of HCG. PMID:25034733

Pathology and pathophysiology of inhalational anthrax in a guinea pig model.

PubMed

Savransky, Vladimir; Sanford, Daniel C; Syar, Emily; Austin, Jamie L; Tordoff, Kevin P; Anderson, Michael S; Stark, Gregory V; Barnewall, Roy E; Briscoe, Crystal M; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris; Skiadopoulos, Mario H

2013-04-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

PubMed Central

Savransky, Vladimir; Sanford, Daniel C.; Syar, Emily; Austin, Jamie L.; Tordoff, Kevin P.; Anderson, Michael S.; Stark, Gregory V.; Barnewall, Roy E.; Briscoe, Crystal M.; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris

2013-01-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104 spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans. PMID:23357384

Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model.

PubMed

Smither, Sophie J; Eastaugh, Lin S; Steward, Jackie A; Nelson, Michelle; Lenk, Robert P; Lever, Mark S

2014-04-01

Filoviruses cause disease with high case fatality rates and are considered biological threat agents. Licensed post-exposure therapies that can be administered by the oral route are desired for safe and rapid distribution and uptake in the event of exposure or outbreaks. Favipiravir or T-705 has broad antiviral activity and has already undergone phase II and is undergoing phase III clinical trials for influenza. Here we report the first use of T-705 against Ebola virus. T-705 gave 100% protection against aerosol Ebola virus E718 infection; protection was shown in immune-deficient mice after 14 days of twice-daily dosing. T-705 was also shown to inhibit Ebola virus infection in cell culture. T-705 is likely to be licensed for use against influenza in the near future and could also be used with a new indication for filovirus infection. Copyright © 2014. Published by Elsevier B.V.

Mass-spectrometric analysis of hydroperoxy- and hydroxy-derivatives of cardiolipin and phosphatidylserine in cells and tissues induced by pro-apoptotic and pro-inflammatory stimuli

PubMed Central

Tyurin, Vladimir A.; Tyurina, Yulia Y.; Jung, Mi-Yeon; Tungekar, Muhammad A.; Wasserloos, Karla J.; Bayir, Hülya; Greenberger, Joel S.; Kochanek, Patrick M.; Shvedova, Anna A.; Pitt, Bruce; Kagan, Valerian E.

2009-01-01

Oxidation of two anionic phospholipids - cardiolipin (CL) in mitochondria and phosphatidylserine (PS) in extramitochondrial compartments - are important signaling events, particularly during the execution of programmed cell death and clearance of apoptotic cells. Quantitative analysis of CL and PS oxidation products is central to understanding their molecular mechanisms of action. We combined the identification of diverse phospholipid molecular species by ESI-MS with quantitative assessments of lipid hydroperoxides using a fluorescence HPLC-based protocol. We characterized CL and PS oxidation products formed in a model system (cyt c/H2O2), in apoptotic cells (neurons, pulmonary artery endothelial cells) and mouse lung under inflammatory/oxidative stress conditions (hyperoxia, inhalation of single walled carbon nanotubes). Our results demonstrate the usefulness of this approach for quantitative assessments, identification of individual molecular species and structural characterization of anionic phospholipids that are involved in oxidative modification in cells and tissues. PMID:19328050

Functional genomics of chlorine-induced acute lung injury in mice.

PubMed

Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J; Liu, Pengyuan; Bein, Kiflai; Brant, Kelly A; Dopico, Richard A; Di, Y Peter; Jang, An-Soo; Dietsch, Maggie; Medvedovic, Mario; Li, Qian; Vuga, Louis J; Kaminski, Naftali; You, Ming; Prows, Daniel R

2010-07-01

Acute lung injury can be induced indirectly (e.g., sepsis) or directly (e.g., chlorine inhalation). Because treatment is still limited to supportive measures, mortality remains high ( approximately 74,500 deaths/yr). In the past, accidental (railroad derailments) and intentional (Iraq terrorism) chlorine exposures have led to deaths and hospitalizations from acute lung injury. To better understand the molecular events controlling chlorine-induced acute lung injury, we have developed a functional genomics approach using inbred mice strains. Various mouse strains were exposed to chlorine (45 ppm x 24 h) and survival was monitored. The most divergent strains varied by more than threefold in mean survival time, supporting the likelihood of an underlying genetic basis of susceptibility. These divergent strains are excellent models for additional genetic analysis to identify critical candidate genes controlling chlorine-induced acute lung injury. Gene-targeted mice then could be used to test the functional significance of susceptibility candidate genes, which could be valuable in revealing novel insights into the biology of acute lung injury.

Development of a design space and predictive statistical model for capsule filling of low-fill-weight inhalation products.

PubMed

Faulhammer, E; Llusa, M; Wahl, P R; Paudel, A; Lawrence, S; Biserni, S; Calzolari, V; Khinast, J G

2016-01-01

The objectives of this study were to develop a predictive statistical model for low-fill-weight capsule filling of inhalation products with dosator nozzles via the quality by design (QbD) approach and based on that to create refined models that include quadratic terms for significant parameters. Various controllable process parameters and uncontrolled material attributes of 12 powders were initially screened using a linear model with partial least square (PLS) regression to determine their effect on the critical quality attributes (CQA; fill weight and weight variability). After identifying critical material attributes (CMAs) and critical process parameters (CPPs) that influenced the CQA, model refinement was performed to study if interactions or quadratic terms influence the model. Based on the assessment of the effects of the CPPs and CMAs on fill weight and weight variability for low-fill-weight inhalation products, we developed an excellent linear predictive model for fill weight (R(2 )= 0.96, Q(2 )= 0.96 for powders with good flow properties and R(2 )= 0.94, Q(2 )= 0.93 for cohesive powders) and a model that provides a good approximation of the fill weight variability for each powder group. We validated the model, established a design space for the performance of different types of inhalation grade lactose on low-fill weight capsule filling and successfully used the CMAs and CPPs to predict fill weight of powders that were not included in the development set.

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

Chen, Jing; Mo, Yiqun; Schlueter, Connie F.

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-inducedmore » neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.« less

Decision Support Model to Optimize Site Characterization Activities Taken in Compliance with the Comprehensive Environmental Response Compensation and Liability Act

DTIC Science & Technology

1995-12-01

Contingency Plan ............................... 10 Table 2: Summary of Inhalation Emission Factors (K) for Equation ( 1 ...surveys for exposure factors commonly used in risk assessment (EPA, 1989a: 1 - 1 ). Exposure can take place via three possible routes, the inhalation ...Equation ( 1 ) calculates the dose for the inhalation route (USEPA, 1991 a:51-52; USEPA, 1989b:6-44). Dose - (C)(IRXETXEFXED) (K)(BWXAT) where C

Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

PubMed Central

Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W.

2013-01-01

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. PMID:23800689

Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide.

PubMed

Chen, Jing; Mo, Yiqun; Schlueter, Connie F; Hoyle, Gary W

2013-10-15

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. © 2013.

Adolescent inhalant abuse leads to other drug use and impaired growth; implications for diagnosis.

PubMed

Crossin, Rose; Cairney, Sheree; Lawrence, Andrew J; Duncan, Jhodie R

2017-02-01

Abuse of inhalants containing the volatile solvent toluene is a significant public health issue, especially for adolescent and Indigenous communities. Adolescent inhalant abuse can lead to chronic health issues and may initiate a trajectory towards further drug use. Identification of at-risk individuals is difficult and diagnostic tools are limited primarily to measurement of serum toluene. Our objective was to identify the effects of adolescent inhalant abuse on subsequent drug use and growth parameters, and to test the predictive power of growth parameters as a diagnostic measure for inhalant abuse. We retrospectively analysed drug use and growth data from 118 Indigenous males; 86 chronically sniffed petrol as adolescents. Petrol sniffing was the earliest drug used (mean 13 years) and increased the likelihood and earlier use of other drugs. Petrol sniffing significantly impaired height and weight and was associated with meeting 'failure to thrive' criteria; growth diagnostically out-performed serum toluene. Adolescent inhalant abuse increases the risk for subsequent and earlier drug use. It also impairs growth such that individuals meet 'failure to thrive' criteria, representing an improved diagnostic model for inhalant abuse. Implications for Public Health: Improved diagnosis of adolescent inhalant abuse may lead to earlier detection and enhanced health outcomes. © 2016 The Authors.

Pulmonary Response to Surface-Coated Nanotitanium Dioxide Particles Includes Induction of Acute Phase Response Genes, Inflammatory Cascades, and Changes in MicroRNAs: A Toxicogenomic Study

PubMed Central

Halappanavar, Sabina; Jackson, Petra; Williams, Andrew; Jensen, Keld A; Hougaard, Karin S; Vogel, Ulla; Yauk, Carole L; Wallin, Håkan

2011-01-01

Titanium dioxide nanoparticles (nanoTiO2) are used in various applications including in paints. NanoTiO2 inhalation may induce pulmonary toxicity and systemic effects. However, the underlying molecular mechanisms are poorly understood. In this study, the effects of inhaled surface-coated nanoTiO2 on pulmonary global messenger RNA (mRNA) and microRNA (miRNA) expression in mouse were characterized to provide insight into the molecular response. Female C57BL/6BomTac mice were exposed for 1 hr daily to 42.4 ± 2.9 (SEM) mg surface-coated nanoTiO2/m3 for 11 consecutive days by inhalation and were sacrificed 5 days following the last exposure. Physicochemical properties of the particles were determined. Pulmonary response to nanoTiO2 was characterized using DNA microarrays and pathway-specific PCR arrays and related to data on pulmonary inflammation from bronchial lavages. NanoTiO2 exposure resulted in increased levels of mRNA for acute phase markers serum amyloid A-1 (Saa1) and serum amyloid A-3 (Saa3), several C-X-C and C-C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more than 1.2-fold (adjusted P-value < 0.05) following exposure. Real time polymerase chain reaction confirmed the upregulation of miR-1, miR-449a and revealed dramatic induction of miR-135b (60-fold). Thus, inhalation of surface-coated nanoTiO2 results in changes in the expression of genes associated with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.† PMID:21259345

Inhalation of Photochemically Altered Urban Mixtures Depresses Cardiac Function in Mice

EPA Science Inventory

Rationale: Epidemiological studies have indicated an association between urban air pollution exposure and cardiovascular morbidity and mortality. The present study was designed to evaluate the cardiac effects of inhaled photochemical products in urban mixtures in a murine model. ...

FACTORS AFFECTING THE DEPOSITION OF INHALED POROUS DRUG PARTICLES

EPA Science Inventory

Abstract
Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol ...

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates.

PubMed

Longest, P Worth; Tian, Geng; Khajeh-Hosseini-Dalasm, Navvab; Hindle, Michael

2016-12-01

The objective of this study was to compare aerosol deposition predictions of a new whole-airway CFD model with available in vivo data for a dry powder inhaler (DPI) considered across multiple inhalation waveforms, which affect both the particle size distribution (PSD) and particle deposition. The Novolizer DPI with a budesonide formulation was selected based on the availability of 2D gamma scintigraphy data in humans for three different well-defined inhalation waveforms. Initial in vitro cascade impaction experiments were conducted at multiple constant (square-wave) particle sizing flow rates to characterize PSDs. The whole-airway CFD modeling approach implemented the experimentally determined PSDs at the point of aerosol formation in the inhaler. Complete characteristic airway geometries for an adult were evaluated through the lobar bronchi, followed by stochastic individual pathway (SIP) approximations through the tracheobronchial region and new acinar moving wall models of the alveolar region. It was determined that the PSD used for each inhalation waveform should be based on a constant particle sizing flow rate equal to the average of the inhalation waveform's peak inspiratory flow rate (PIFR) and mean flow rate [i.e., AVG(PIFR, Mean)]. Using this technique, agreement with the in vivo data was acceptable with <15% relative differences averaged across the three regions considered for all inhalation waveforms. Defining a peripheral to central deposition ratio (P/C) based on alveolar and tracheobronchial compartments, respectively, large flow-rate-dependent differences were observed, which were not evident in the original 2D in vivo data. The agreement between the CFD predictions and in vivo data was dependent on accurate initial estimates of the PSD, emphasizing the need for a combination in vitro-in silico approach. Furthermore, use of the AVG(PIFR, Mean) value was identified as a potentially useful method for characterizing a DPI aerosol at a constant flow rate.

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

PubMed Central

Tian, Geng; Khajeh-Hosseini-Dalasm, Navvab; Hindle, Michael

2016-01-01

Abstract Background: The objective of this study was to compare aerosol deposition predictions of a new whole-airway CFD model with available in vivo data for a dry powder inhaler (DPI) considered across multiple inhalation waveforms, which affect both the particle size distribution (PSD) and particle deposition. Methods: The Novolizer DPI with a budesonide formulation was selected based on the availability of 2D gamma scintigraphy data in humans for three different well-defined inhalation waveforms. Initial in vitro cascade impaction experiments were conducted at multiple constant (square-wave) particle sizing flow rates to characterize PSDs. The whole-airway CFD modeling approach implemented the experimentally determined PSDs at the point of aerosol formation in the inhaler. Complete characteristic airway geometries for an adult were evaluated through the lobar bronchi, followed by stochastic individual pathway (SIP) approximations through the tracheobronchial region and new acinar moving wall models of the alveolar region. Results: It was determined that the PSD used for each inhalation waveform should be based on a constant particle sizing flow rate equal to the average of the inhalation waveform's peak inspiratory flow rate (PIFR) and mean flow rate [i.e., AVG(PIFR, Mean)]. Using this technique, agreement with the in vivo data was acceptable with <15% relative differences averaged across the three regions considered for all inhalation waveforms. Defining a peripheral to central deposition ratio (P/C) based on alveolar and tracheobronchial compartments, respectively, large flow-rate-dependent differences were observed, which were not evident in the original 2D in vivo data. Conclusions: The agreement between the CFD predictions and in vivo data was dependent on accurate initial estimates of the PSD, emphasizing the need for a combination in vitro–in silico approach. Furthermore, use of the AVG(PIFR, Mean) value was identified as a potentially useful method for characterizing a DPI aerosol at a constant flow rate. PMID:27082824

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

Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation.

PubMed

Salar-Behzadi, Sharareh; Wu, Shengqian; Mercuri, Annalisa; Meindl, Claudia; Stranzinger, Sandra; Fröhlich, Eleonore

2017-10-30

The growing interest in the inhalable pharmaceutical products requires advanced approaches to safe and fast product development, such as in silico tools that can be used for estimating the bioavailability and toxicity of developed formulation. GastroPlus™ is one of the few available software packages for in silico simulation of PBPK profile of inhalable products. It contains a complementary module for calculating the lung deposition, the permeability and the systemic absorption of inhalable products. Experimental values of lung deposition and permeability can also be used. This study aims to assess the efficiency of simulation by applying experimental permeability and deposition values, using budesonide as a model substance. The lung deposition values were obtained from the literature, the lung permeability data were experimentally determined by culturing Calu-3 cells under air-liquid interface and submersed conditions to morphologically resemble bronchial and alveolar epithelial cells, respectively. A two-compartment PK model was created for i.v. administration and used as a background for the in silico simulation of the plasma profile of budesonide after inhalation. The predicted plasma profile was compared with the in vivo data from the literature and the effects of experimental lung deposition and permeability on prediction were assessed. The developed model was significantly improved by using realistic lung deposition data combined with experimental data for peripheral permeability. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice.

PubMed

Tanaka, Ken-Ichiro; Sato, Keizo; Aoshiba, Kazutetsu; Azuma, Arata; Mizushima, Tohru

2012-06-15

Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

PubMed Central

Mo, Yiqun; Chen, Jing; Schlueter, Connie F.

2013-01-01

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated. PMID:23171502

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis.

PubMed

Mo, Yiqun; Chen, Jing; Schlueter, Connie F; Hoyle, Gary W

2013-01-15

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated.

Inhaler technique maintenance: gaining an understanding from the patient's perspective.

PubMed

Ovchinikova, Ludmila; Smith, Lorraine; Bosnic-Anticevich, Sinthia

2011-08-01

The aim of this study was to determine the patient-, education-, and device-related factors that predict inhaler technique maintenance. Thirty-one community pharmacists were trained to deliver inhaler technique education to people with asthma. Pharmacists evaluated (based on published checklists), and where appropriate, delivered inhaler technique education to patients (participants) in the community pharmacy at baseline (Visit 1) and 1 month later (Visit 2). Data were collected on participant demographics, asthma history, current asthma control, history of inhaler technique education, and a range of psychosocial aspects of disease management (including adherence to medication, motivation for correct technique, beliefs regarding the importance of maintaining correct technique, and necessity and concern beliefs regarding preventer therapy). Stepwise backward logistic regression was used to identify the predictors of inhaler technique maintenance at 1 month. In total 145 and 127 participants completed Visits 1 and 2, respectively. At baseline, 17% of patients (n = 24) demonstrated correct technique (score 11/11) which increased to 100% (n = 139) after remedial education by pharmacists. At follow-up, 61% (n = 77) of patients demonstrated correct technique. The predictors of inhaler technique maintenance based on the logistic regression model (X(2) (3, N = 125) = 16.22, p = .001) were use of a dry powder inhaler over a pressurized metered-dose inhaler (OR 2.6), having better asthma control at baseline (OR 2.3), and being more motivated to practice correct inhaler technique (OR 1.2). Contrary to what is typically recommended in previous research, correct inhaler technique maintenance may involve more than repetition of instructions. This study found that past technique education factors had no bearing on technique maintenance, whereas patient psychosocial factors (motivation) did.

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

NASA Astrophysics Data System (ADS)

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-06-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening.

Simulation of the Velocity and Temperature Distribution of Inhalation Thermal Injury in a Human Upper Airway Model by Application of Computational Fluid Dynamics.

PubMed

Chang, Yang; Zhao, Xiao-zhuo; Wang, Cheng; Ning, Fang-gang; Zhang, Guo-an

2015-01-01

Inhalation injury is an important cause of death after thermal burns. This study was designed to simulate the velocity and temperature distribution of inhalation thermal injury in the upper airway in humans using computational fluid dynamics. Cervical computed tomography images of three Chinese adults were imported to Mimics software to produce three-dimensional models. After grids were established and boundary conditions were defined, the simulation time was set at 1 minute and the gas temperature was set to 80 to 320°C using ANSYS software (ANSYS, Canonsburg, PA) to simulate the velocity and temperature distribution of inhalation thermal injury. Cross-sections were cut at 2-mm intervals, and maximum airway temperature and velocity were recorded for each cross-section. The maximum velocity peaked in the lower part of the nasal cavity and then decreased with air flow. The velocities in the epiglottis and glottis were higher than those in the surrounding areas. Further, the maximum airway temperature decreased from the nasal cavity to the trachea. Computational fluid dynamics technology can be used to simulate the velocity and temperature distribution of inhaled heated air.

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

PubMed Central

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-01-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening. PMID:28621308

Identification of cigarette smoke inhalations from wearable sensor data using a Support Vector Machine classifier.

PubMed

Lopez-Meyer, Paulo; Tiffany, Stephen; Sazonov, Edward

2012-01-01

This study presents a subject-independent model for detection of smoke inhalations from wearable sensors capturing characteristic hand-to-mouth gestures and changes in breathing patterns during cigarette smoking. Wearable sensors were used to detect the proximity of the hand to the mouth and to acquire the respiratory patterns. The waveforms of sensor signals were used as features to build a Support Vector Machine classification model. Across a data set of 20 enrolled participants, precision of correct identification of smoke inhalations was found to be >87%, and a resulting recall >80%. These results suggest that it is possible to analyze smoking behavior by means of a wearable and non-invasive sensor system.

THREE-DIMENSIONAL COMPUTER MODELING OF THE HUMAN UPPER RESPIRATORY TRACT

EPA Science Inventory

ABSTRACT
Computer simulations of airflow and particle transport phenomena within the human respiratory system have important applications to aerosol therapy (e.g., the targeted delivery of inhaled drugs) and inhalation toxicology (e.g., the risk assessment of air pollutants). ...

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.

Ethanol toxicokinetics resulting from inhalation exposure in human volunteers and toxicokinetic modeling.

PubMed

Dumas-Campagna, Josée; Tardif, Robert; Charest-Tardif, Ginette; Haddad, Sami

2014-02-01

Uncertainty exists regarding the validity of a previously developed physiologically-based pharmacokinetic model (PBPK) for inhaled ethanol in humans to predict the blood levels of ethanol (BLE) at low level exposures (<1000 ppm). Thus, the objective of this study is to document the BLE resulting from low levels exposures in order to refine/validate this PBPK model. Human volunteers were exposed to ethanol vapors during 4 h at 5 different concentrations (125-1000 ppm), at rest, in an inhalation chamber. Blood and exhaled air were sampled. Also, the impact of light exercise (50 W) on the BLE was investigated. There is a linear relationship between the ethanol concentrations in inhaled air and (i) BLE (women: r²= 0.98/men: r²= 0.99), as well as (ii) ethanol concentrations in the exhaled air at end of exposure period (men: r²= 0.99/women: r²= 0.99). Furthermore, the exercise resulted in a net and significant increase of BLE (2-3 fold). Overall, the original model predictions overestimated the BLE for all low exposures performed in this study. To properly simulate the toxicokinetic data, the model was refined by adding a description of an extra-hepatic biotransformation of high affinity and low capacity in the richly perfused tissues compartment. This is based on the observation that total clearance observed at low exposure levels was much greater than liver blood flow. The results of this study will facilitate the refinement of the risk assessment associated with chronic inhalation of low levels of ethanol in the general population and especially among workers.

Long-Term Prevalence and Demographic Trends in U.S. Adolescent Inhalant Use: Implications for Clinicians and Prevention Scientists.

PubMed

Halliburton, Amanda Elizabeth; Bray, Bethany Cara

2016-01-01

Inhalant use by adolescents is cause for concern due to the early age of inhalant use initiation and the many short- and long-term health consequences that can occur concurrently with and subsequent to use. However, inhalant use research has been limited relative to the literature available on other drug use. The present research examined long-term trends in inhalant use prevalence, demographic risk factors of inhalant use, and median grade level of first use. Monitoring the Future data from 1991 to 2011, which includes information drawn from United States eighth, tenth, and twelfth graders, were examined. The total sample comprised more than one million participants. Results were examined descriptively with figures and quantitatively with mixed-effects regression models of the effect of time on use rates. Inhalant use prevalence rates generally declined over the selected period. Though rates of use by males and females decreased significantly, the proportion of females among lifetime users increased significantly. Whites, Hispanics, and members of uncategorized "other" ethnicities showed the highest prevalence rates. Although the proportion of Whites among lifetime users decreased significantly, the proportion of Hispanics and "other" ethnicities increased significantly. The median first use was between sixth and ninth grade. Results suggest a need to tailor inhalant use treatment and prevention programs to the needs of specific demographic groups and to target interventions early to prevent youth inhalant use. Strengths, limitations, and directions for future research are discussed.

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.

Chronic intermittent ethanol inhalation increases ethanol self-administration in both C57BL/6J and DBA/2J mice.

PubMed

McCool, Brian A; Chappell, Ann M

2015-03-01

Inbred mouse strains provide significant opportunities to understand the genetic mechanisms controlling ethanol-directed behaviors and neurobiology. They have been specifically employed to understand cellular mechanisms contributing to ethanol consumption, acute intoxication, and sensitivities to chronic effects. However, limited ethanol consumption by some strains has restricted our understanding of clinically relevant endpoints such as dependence-related ethanol intake. Previous work with a novel tastant-substitution procedure using monosodium glutamate (MSG or umami flavor) has shown that the procedure greatly enhances ethanol consumption by mouse strains that express limited drinking phenotypes using other methods. In the current study, we employ this MSG-substitution procedure to examine how ethanol dependence, induced with passive vapor inhalation, modifies ethanol drinking in C57BL/6J and DBA/2J mice. These strains represent 'high' and 'low' drinking phenotypes, respectively. We found that the MSG substitution greatly facilitates ethanol drinking in both strains, and likewise, ethanol dependence increased ethanol consumption regardless of strain. However, DBA/2J mice exhibited greater sensitivity dependence-enhanced drinking, as represented by consumption behaviors directed at lower ethanol concentrations and relative to baseline intake levels. DBA/2J mice also exhibited significant withdrawal-associated anxiety-like behavior while C57BL/6J mice did not. These findings suggest that the MSG-substitution procedure can be employed to examine dependence-enhanced ethanol consumption across a range of drinking phenotypes, and that C57BL/6J and DBA/2J mice may represent unique neurobehavioral pathways for developing dependence-enhanced ethanol consumption. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Smoke inhalation increases intensive care requirements and morbidity in paediatric burns.

PubMed

Tan, Alethea; Smailes, Sarah; Friebel, Thessa; Magdum, Ashish; Frew, Quentin; El-Muttardi, Naguib; Dziewulski, Peter

2016-08-01

Burn survival has improved with advancements in fluid resuscitation, surgical wound management, wound dressings, access to antibiotics and nutritional support for burn patients. Despite these advancements, the presence of smoke inhalation injury in addition to a cutaneous burn still significantly increases morbidity and mortality. The pathophysiology of smoke inhalation has been well studied in animal models. Translation of this knowledge into effectiveness of clinical management and correlation with patient outcomes including the paediatric population, is still limited. We retrospectively reviewed our experience of 13 years of paediatric burns admitted to a regional burn's intensive care unit. We compared critical care requirements and patient outcomes between those with cutaneous burns only and those with concurrent smoke inhalation injury. Smoke inhalation increases critical care requirements and mortality in the paediatric burn population. Therefore, early critical care input in the management of these patients is advised. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

SUBCHRONIC INHALATION EXPOSURE OF RATS TO LIBBY AMPHIBOLE AND AMOSITE ASBESTOS

EPA Science Inventory

Exposure to Libby amphibole (LA) is associated with significant increases in asbestosis, lung cancer, and mesothelioma. To support biological potency assessment and dosimetry model development, a subchronic nose-only inhalation exposure study (6 hr/d, 5 d/wk, 13 wk) was conducted...

Results of examination of the nasal mucosa. [in Apollo 17 BIOCORE pocket mice

NASA Technical Reports Server (NTRS)

Kraft, L. M.; Vogel, F. S.; Lloyd, B.; Benton, E. V.; Cruty, M. R.; Haymaker, W.; Leon, H. A.; Billingham, J.; Turnbill, C. E.; Teas, V.

1975-01-01

The olfactory epithelium, but not the nasal respiratory epithelium, of the four pocket mice (Perognathus longimembris) that survived their flight on Apollo XVII showed both diffuse alterations and numerous disseminated focal lesions. The olfactory mucosa of the mouse that died during flight was also affected, but to a minor degree insofar as could be determined. All this was in contrast to the normal appearance of the olfactory mucosa of the numerous control animals. A number of possible causes were considered: systemic or regional infection; inhaled particulate material (seed dust); by-products from the KO2 bed in aerosol or particulate form; gas contaminants originating in the flight package; volatile substances from the dead mouse; weightlessness; and cosmic ray particle radiation. Where feasible, studies were conducted in an effort to rule in or rule out some of these potentially causative factors. No definitive conclusions were reached as to the cause of the lesions in the flight mice.

Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema.

PubMed

You, Ran; Lu, Wen; Shan, Ming; Berlin, Jacob M; Samuel, Errol Lg; Marcano, Daniela C; Sun, Zhengzong; Sikkema, William Ka; Yuan, Xiaoyi; Song, Lizhen; Hendrix, Amanda Y; Tour, James M; Corry, David B; Kheradmand, Farrah

2015-10-05

Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c(+) lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

Internal dosimetry of inhaled iodine-131.

PubMed

Kiani Nasab, Mitra; Rafat Motavalli, Laleh; Miri Hakimabad, Hashem

2018-01-01

In this paper, the dose assessment for the iodine inhalation exposure in 19 aerosol sizes and three gas/vapor forms at three levels of thyroid uptake, was performed. Two different modes of work (light vs. heavy) and breathing (nose vs. mouth) for aerosol inhalation were investigated. In order to calculate the cumulated activities per unit of inhaled activity, a combined model which included the latest models of both human respiratory and alimentary tract was developed. The S values for 131 I were computed based on the ICRP adult male and female reference voxel phantoms by the Monte Carlo method. Then, the committed equivalent and committed effective dose coefficients were obtained (The data are available at http://www.um.ac.ir/∼mirihakim). In general, for the nonzero thyroid uptakes, the maximum cumulated activity was found in the thyroid. When the thyroid is blocked, however, the maximum depends on the work and breathing mode and radioisotope form. Overall, the maximum CED coefficient was evaluated for the inhalation of elemental iodine at thyroid uptake of ∼27% (2.8 × 10 -8 Sv/Bq). As for the particle inhalation per se, mouth breathing of 0.6 nm and 0.2 μm AMTD particles showed to have the maximum (2.8 × 10 -8 Sv/Bq) and minimum (6.4 × 10 -9 Sv/Bq) CED coefficients, respectively. Compared to the reference CED coefficients, the authors found an increase of about 58% for inhalation of the aerosols with AMAD of 1 μm and 70% for 5 μm. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

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

Jonasson, Sofia, E-mail: sofia.jonasson@foi.se; Wigenstam, Elisabeth; Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of themore » corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in Cl{sub 2}-induced lung injury. • Early medical intervention of corticosteroids is of importance. • Treatment with corticosteroids alone is insufficient to counteract acute lung injury.« less

The Dynamic Characteristics of Silver Nanoparticles in Physiological Fluids: Toxicological Implications

DTIC Science & Technology

2014-11-19

and polysaccharide (Ag-PS) coated silver NM. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages... polysaccharide -coated (Ag− PS) silver NMs. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages...bioeffects, we evaluated fluid-specific influences on 25 nm Ag NPs with either a hydrocarbon or polysaccharide coating. Our data demonstrated that

Comparison of dermal and inhalation routes of entry for organic chemicals

NASA Technical Reports Server (NTRS)

Jepson, Gary W.; Mcdougal, James N.; Clewell, Harvey J., III

1992-01-01

The quantitative comparison of the chemical concentration inside the body as the result of a dermal exposure versus an inhalation exposure is useful for assessing human health risks and deciding on an appropriate protective posture. In order to describe the relationship between dermal and inhalation routes of exposure, a variety of organic chemicals were evaluated. The types of chemicals chosen for the study were halogenated hydrocarbons, aromatic compounds, non-polar hydrocarbons and inhalation anesthetics. Both dermal and inhalation exposures were conducted in rats and the chemicals were in the form of vapors. Prior to the dermal exposure, rat fur was closely clipped and during the exposure rats were provided fresh breathing air through latex masks. Blood samples were taken during 4-hour exposures and analyzed for the chemical of interest. A physiologically based pharmacokinetic model was used to predict permeability constants (cm/hr) consistent with the observed blood concentrations of the chemical. The ratio of dermal exposure to inhalation exposure required to achieve the same internal dose of chemical was calculated for each test chemical. The calculated ratio in humans ranged from 18 for styrene to 1180 for isoflurane. This methodology can be used to estimate the dermal exposure required to reach the internal dose achieved by a specific inhalation exposure. Such extrapolation is important since allowable exposure standards are often set for inhalation exposures, but occupational exposures may be dermal.

Ferrets develop fatal influenza after inhaling small particle aerosols of highly pathogenic avian influenza virus A/Vietnam/1203/2004 (H5N1)

PubMed Central

2010-01-01

Background There is limited knowledge about the potential routes for H5N1 influenza virus transmission to and between humans, and it is not clear whether humans can be infected through inhalation of aerosolized H5N1 virus particles. Ferrets are often used as a animal model for humans in influenza pathogenicity and transmissibility studies. In this manuscript, a nose-only bioaerosol inhalation exposure system that was recently developed and validated was used in an inhalation exposure study of aerosolized A/Vietnam/1203/2004 (H5N1) virus in ferrets. The clinical spectrum of influenza resulting from exposure to A/Vietnam/1203/2004 (H5N1) through intranasal verses inhalation routes was analyzed. Results Ferrets were successfully infected through intranasal instillation or through inhalation of small particle aerosols with four different doses of Influenza virus A/Vietnam/1203/2004 (H5N1). The animals developed severe influenza encephalomyelitis following intranasal or inhalation exposure to 101, 102, 103, or 104 infectious virus particles per ferret. Conclusions Aerosolized Influenza virus A/Vietnam/1203/2004 (H5N1) is highly infectious and lethal in ferrets. Clinical signs appeared earlier in animals infected through inhalation of aerosolized virus compared to those infected through intranasal instillation. PMID:20843329

Airway Obstruction Due to Bronchial Vascular Injury after Sulfur Mustard Analog Inhalation

PubMed Central

Veress, Livia A.; O'Neill, Heidi C.; Hendry-Hofer, Tara B.; Loader, Joan E.; Rancourt, Raymond C.; White, Carl W.

2010-01-01

Rationale: Sulfur mustard (SM) is a frequently used chemical warfare agent, even in modern history. SM inhalation causes significant respiratory tract injury, with early complications due to airway obstructive bronchial casts, akin to those seen after smoke inhalation and in single-ventricle physiology. This process with SM is poorly understood because animal models are unavailable. Objectives: To develop a rat inhalation model for airway obstruction with the SM analog 2-chloroethyl ethyl sulfide (CEES), and to investigate the pathogenesis of bronchial cast formation. Methods: Adult rats were exposed to 0, 5, or 7.5% CEES in ethanol via nose-only aerosol inhalation (15 min). Airway microdissection and confocal microscopy were used to assess cast formation (4 and 18 h after exposure). Bronchoalveolar lavage fluid (BALF) retrieval and intravascular dye injection were done to evaluate vascular permeability. Measurements and Main Results: Bronchial casts, composed of abundant fibrin and lacking mucus, occluded dependent lobar bronchi within 18 hours of CEES exposure. BALF contained elevated concentrations of IgM, protein, and fibrin. Accumulation of fibrin-rich fluid in peribronchovascular regions (4 h) preceded cast formation. Monastral blue dye leakage identified bronchial vessels as the site of leakage. Conclusions: After CEES inhalation, increased permeability from damaged bronchial vessels underlying damaged airway epithelium leads to the appearance of plasma proteins in both peribronchovascular regions and BALF. The subsequent formation of fibrin-rich casts within the airways then leads to airways obstruction, causing significant morbidity and mortality acutely after exposure. PMID:20639443

Respiratory carcinogenicity assessment of soluble nickel compounds.

PubMed Central

Oller, Adriana R

2002-01-01

The many chemical forms of nickel differ in physicochemical properties and biological effects. Health assessments for each main category of nickel species are needed. The carcinogenicity assessment of water-soluble nickel compounds has proven particularly difficult. Epidemiologic evidence indicates an association between inhalation exposures to nickel refinery dust containing soluble nickel compounds and increased risk of respiratory cancers. However, the nature of this association is unclear because of limitations of the exposure data, inconsistent results across cohorts, and the presence of mixed exposures to water-insoluble nickel compounds and other confounders that are known or suspected carcinogens. Moreover, well-conducted animal inhalation studies, where exposures were solely to soluble nickel, failed to demonstrate a carcinogenic potential. Similar negative results were seen in animal oral studies. A model exists that relates respiratory carcinogenic potential to the bioavailability of nickel ion at nuclear sites within respiratory target cells. This model helps reconcile human, animal, and mechanistic data for soluble nickel compounds. For inhalation exposures, the predicted lack of bioavailability of nickel ion at target sites suggests that water-soluble nickel compounds, by themselves, will not be complete human carcinogens. However, if inhaled at concentrations high enough to induce chronic lung inflammation, these compounds may enhance carcinogenic risks associated with inhalation exposure to other substances. Overall, the weight of evidence indicates that inhalation exposure to soluble nickel alone will not cause cancer; moreover, if exposures are kept below levels that cause chronic respiratory toxicity, any possible tumor-enhancing effects (particularly in smokers) would be avoided. PMID:12426143

Exposure versus internal dose: Respiratory tract deposition modeling of inhaled asbestos fibers in rats and humans (Presentation Poster)

EPA Science Inventory

Exposure to asbestos is associated with respiratory diseases, including asbestosis, lung cancer and mesothelioma. Internal fiber dose depends on fiber inhalability and orientation, fiber density, length and width, and various deposition mechanisms (DM). Species-specific param...

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

PubMed

Javadi-Paydar, Mehrak; Nguyen, Jacques D; Kerr, Tony M; Grant, Yanabel; Vandewater, Sophia A; Cole, Maury; Taffe, Michael A

2018-06-16

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. To compare thermoregulatory and locomotor responses to inhaled ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

NIR studies of cholesterol-dependent structural modification of the model lipid bilayer doped with inhalation anesthetics

NASA Astrophysics Data System (ADS)

Kuć, Marta; Cieślik-Boczula, Katarzyna; Rospenk, Maria

2018-06-01

The influence of cholesterol on the structure of the model lipid bilayers treated with inhalation anesthetics (enflurane, isoflurane, sevoflurane and halothane) was investigated employing near-infrared (NIR) spectroscopy combined with the Principal Component Analysis (PCA). The conformational changes occurring in the hydrophobic area of the lipid bilayers were analyzed using the first overtones of symmetric (2νs) and antisymmetric (2νas) stretching vibrations of the CH2 groups of lipid aliphatic chains. The temperature values of chain-melting phase transition (Tm) of anesthetic-mixed dipalmitoylphosphatidylcholine (DPPC)/cholesterol and dipalmitoylphosphatidylglycerol (DPPG)/cholesterol membranes, which were obtained from the PCA analysis, were compared with cholesterol-free DPPC and DPPG bilayers mixed with inhalation anesthetics.

Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

PubMed

Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

2017-09-01

Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

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

Shankaran, Harish, E-mail: harish.shankaran@pnnl.gov; Adeshina, Femi; Teeguarden, Justin G.

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the modelmore » using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available pharmacokinetic data. • The model can be used for extrapolating across routes, doses and exposure durations. • We illustrate how the model can be used for developing Provisional Advisory Levels.« less

Direct tissue oxygen monitoring by in vivo photoacoustic lifetime imaging (PALI)

NASA Astrophysics Data System (ADS)

Shao, Qi; Morgounova, Ekaterina; Ashkenazi, Shai

2014-03-01

Tissue oxygen plays a critical role in maintaining tissue viability and in various diseases, including response to therapy. Images of oxygen distribution provide the history of tissue hypoxia and evidence of oxygen availability in the circulatory system. Currently available methods of direct measuring or imaging tissue oxygen all have significant limitations. Previously, we have reported a non-invasive in vivo imaging modality based on photoacoustic lifetime. The technique maps the excited triplet state of oxygen-sensitive dye, thus reflects the spatial and temporal distribution of tissue oxygen. We have applied PALI on tumor hypoxia in small animals, and the hypoxic region imaged by PALI is consistent with the site of the tumor imaged by ultrasound. Here, we present two studies of applying PALI to monitor changes of tissue oxygen by modulations. The first study involves an acute ischemia model using a thin thread tied around the hind limb of a normal mouse to reduce the blood flow. PALI images were acquired before, during, and after the restriction. The drop of muscle pO2 and recovery from hypoxia due to reperfusion were observed by PALI tracking the same region. The second study modulates tissue oxygen by controlling the percentage of oxygen the mouse inhales. We demonstrate that PALI is able to reflect the change of oxygen level with respect to both hyperbaric and hypobaric conditions. We expect this technique to be very attractive for a range of clinical applications in which tissue oxygen mapping would improve therapy decision making and treatment planning.

Simultaneous and Noninvasive Imaging of Cerebral Oxygen Metabolic Rate, Blood Flow and Oxygen Extraction Fraction in Stroke Mice

PubMed Central

Zhu, Xiao-Hong; Chen, James; Tu, Tsang-Wei; Chen, Wei; Song, Sheng-Kwei

2012-01-01

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO2 and CBF. This study employed the recently developed in vivo 17O MR spectroscopic imaging to simultaneously assess CMRO2, CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of 17O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive 17O-MR approach for rapidly imaging CMRO2, CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO2 and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising 17O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This 17O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy. PMID:23000789

Simultaneous and noninvasive imaging of cerebral oxygen metabolic rate, blood flow and oxygen extraction fraction in stroke mice.

PubMed

Zhu, Xiao-Hong; Chen, James M; Tu, Tsang-Wei; Chen, Wei; Song, Sheng-Kwei

2013-01-01

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO(2)) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO(2) and CBF. This study employed the recently developed in vivo (17)O MR spectroscopic imaging to simultaneously assess CMRO(2), CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of (17)O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive (17)O-MR approach for rapidly imaging CMRO(2), CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO(2) and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising (17)O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This (17)O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy. Copyright © 2012 Elsevier Inc. All rights reserved.

Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

PubMed Central

Blake, Linda C.; Roy, Anuradha; Neul, David; Schoenen, Frank J.; Aubé, Jeffrey; Scott, Emily E.

2013-01-01

Purpose 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Methods Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. Results A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Conclusions Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure. PMID:23756756

Development of a simultaneous optical/PET imaging system for awake mice

NASA Astrophysics Data System (ADS)

Takuwa, Hiroyuki; Ikoma, Yoko; Yoshida, Eiji; Tashima, Hideaki; Wakizaka, Hidekatsu; Shinaji, Tetsuya; Yamaya, Taiga

2016-09-01

Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [11C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [11C]raclopride radioactivity concentration simultaneously. Accumulation of [11C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models.

Does Inhalation of Virgin Coconut Oil Accelerate Reversal of Airway Remodelling in an Allergic Model of Asthma?

PubMed

Kamalaldin, N A; Sulaiman, S A; Yusop, M R; Yahaya, B

2017-01-01

Many studies have been done to evaluate the effect of various natural products in controlling asthma symptoms. Virgin coconut oil (VCO) is known to contain active compounds that have beneficial effects on human health and diseases. The objective of this study was to evaluate the effect of VCO inhalation on airway remodelling in a rabbit model of allergic asthma. The effects of VCO inhalation on infiltration of airway inflammatory cells, airway structures, goblet cell hyperplasia, and cell proliferation following ovalbumin induction were evaluated. Allergic asthma was induced by a combination of ovalbumin and alum injection and/or followed by ovalbumin inhalation. The effect of VCO inhalation was then evaluated via the rescue or the preventive route. Percentage of inflammatory cells infiltration, thickness of epithelium and mucosa regions, and the numbers of goblet and proliferative cells were reduced in the rescue group but not in preventive group. Analysis using a gas chromatography-mass spectrometry found that lauric acid and capric acid were among the most abundant fatty acids present in the sample. Significant improvement was observed in rescue route in alleviating the asthma symptoms, which indicates the VCO was able to relieve asthma-related symptoms more than preventing the onset of asthma.

Does Inhalation of Virgin Coconut Oil Accelerate Reversal of Airway Remodelling in an Allergic Model of Asthma?

PubMed Central

Sulaiman, S. A.

2017-01-01

Many studies have been done to evaluate the effect of various natural products in controlling asthma symptoms. Virgin coconut oil (VCO) is known to contain active compounds that have beneficial effects on human health and diseases. The objective of this study was to evaluate the effect of VCO inhalation on airway remodelling in a rabbit model of allergic asthma. The effects of VCO inhalation on infiltration of airway inflammatory cells, airway structures, goblet cell hyperplasia, and cell proliferation following ovalbumin induction were evaluated. Allergic asthma was induced by a combination of ovalbumin and alum injection and/or followed by ovalbumin inhalation. The effect of VCO inhalation was then evaluated via the rescue or the preventive route. Percentage of inflammatory cells infiltration, thickness of epithelium and mucosa regions, and the numbers of goblet and proliferative cells were reduced in the rescue group but not in preventive group. Analysis using a gas chromatography-mass spectrometry found that lauric acid and capric acid were among the most abundant fatty acids present in the sample. Significant improvement was observed in rescue route in alleviating the asthma symptoms, which indicates the VCO was able to relieve asthma-related symptoms more than preventing the onset of asthma. PMID:28660089

An empirical model of human aspiration in low-velocity air using CFD investigations.

PubMed

Anthony, T Renée; Anderson, Kimberly R

2015-01-01

Computational fluid dynamics (CFD) modeling was performed to investigate the aspiration efficiency of the human head in low velocities to examine whether the current inhaled particulate mass (IPM) sampling criterion matches the aspiration efficiency of an inhaling human in airflows common to worker exposures. Data from both mouth and nose inhalation, averaged to assess omnidirectional aspiration efficiencies, were compiled and used to generate a unifying model to relate particle size to aspiration efficiency of the human head. Multiple linear regression was used to generate an empirical model to estimate human aspiration efficiency and included particle size as well as breathing and freestream velocities as dependent variables. A new set of simulated mouth and nose breathing aspiration efficiencies was generated and used to test the fit of empirical models. Further, empirical relationships between test conditions and CFD estimates of aspiration were compared to experimental data from mannequin studies, including both calm-air and ultra-low velocity experiments. While a linear relationship between particle size and aspiration is reported in calm air studies, the CFD simulations identified a more reasonable fit using the square of particle aerodynamic diameter, which better addressed the shape of the efficiency curve's decline toward zero for large particles. The ultimate goal of this work was to develop an empirical model that incorporates real-world variations in critical factors associated with particle aspiration to inform low-velocity modifications to the inhalable particle sampling criterion.

MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF CONDITIONING AND PHYSICAL ACTIVITY

EPA Science Inventory

Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals whether exposure duration is acute or...

MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF FEEDING STATUS, PHYSICAL ACTIVITY AND STRAIN

EPA Science Inventory

Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals whether exposure duration is acute or...

MODULAR APPLICATION OF COMPUTATIONAL MODELS OF INHALED REACTIVE GAS DOSIMETRY FOR RISK ASSESSMENT OF RESPIRATORY TRACT TOXICITY: CHLORINE

EPA Science Inventory

Inhaled reactive gases typically cause respiratory tract toxicity with a prominent proximal to distal lesion pattern. This pattern is largely driven by airflow and interspecies differences between rodents and humans result from factors such as airway architecture, ventilation ra...

AMMONIA ABATEMENT SYSTEM FOR WHOLE-BODY SMALL ANIMAL INHALATION EXPOSURES TO ACID MODELS

EPA Science Inventory

Conducting whole-body acid aerosol inhalation exposures of laboratory animals is complicated by ammonia arising from the excrement of the test animals which is sufficient to completely neutralize much of the acid aerosol. he neutralization of acid by ammonia con only be controlle...

Predicting the acute behavioral effects in rats inhaling toluene (or up to 24 hrs: Inhaled vs. internal dose metrics.

EPA Science Inventory

The acute toxicity oftoluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) ofexposure, and guidelines for acute exposures have traditionally used ext relationships to extrapolate protective and/or effective concentrations across durat...

SPECIFYING PHYSIOLOGICAL PARAMETERS FOR THE KINETICS OF INHALED TOLUENE IN RATS PERFORMING THE VISUAL SIGNAL DETECTION TASK (SDT).

EPA Science Inventory

A physiologically-based pharmacokinetic (PBPK) model is being developed to estimate the dosimetry of toluene in rats inhaling the VOC under various experimental conditions. The effects of physical activity are currently being estimated utilizing a three-step process. First, we d...

Smoke Inhalation Injury and the Effect of Carbon Monoxide in the Sheep Model

DTIC Science & Technology

1990-01-01

there is a great discrepancy in the terized by progressive inflammatory changes resulting in relationship between peak carboxyhemoglobin (CO-Hb...al- smoke inhalation injury; in one animal model a 20% peak though no single substance appears to be responsible for carboxyhemoglobin (CO-Hb) level...venous carboxyhemoglobin (CO-Hb) levels im- of the smoke group at 1 hour after exposure was not mediately after smoke and CO exposure were 57.0

Chlorpyrifos PBPK/PD model for multiple routes of exposure.

PubMed

Poet, Torka S; Timchalk, Charles; Hotchkiss, Jon A; Bartels, Michael J

2014-10-01

1. Chlorpyrifos (CPF) is an important pesticide used to control crop insects. Human Exposures to CPF will occur primarily through oral exposure to residues on foods. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been developed that describes the relationship between oral, dermal and inhalation doses of CPF and key events in the pathway for cholinergic effects. The model was built on a prior oral model that addressed age-related changes in metabolism and physiology. This multi-route model was developed in rats and humans to validate all scenarios in a parallelogram design. 2. Critical biological effects from CPF exposure require metabolic activation to CPF oxon, and small amounts of metabolism in tissues will potentially have a great effect on pharmacokinetics and pharmacodynamic outcomes. Metabolism (bioactivation and detoxification) was therefore added in diaphragm, brain, lung and skin compartments. Pharmacokinetic data are available for controlled human exposures via the oral and dermal routes and from oral and inhalation studies in rats. The validated model was then used to determine relative dermal versus inhalation uptake from human volunteers exposed to CPF in an indoor scenario.

An Acoustic-Based Method to Detect and Quantify the Effect of Exhalation into a Dry Powder Inhaler.

PubMed

Holmes, Martin S; Seheult, Jansen N; O'Connell, Peter; D'Arcy, Shona; Ehrhardt, Carsten; Healy, Anne Marie; Costello, Richard W; Reilly, Richard B

2015-08-01

Dry powder inhaler (DPI) users frequently exhale into their inhaler mouthpiece before the inhalation step. This error in technique compromises the integrity of the drug and results in poor bronchodilation. This study investigated the effect of four exhalation factors (exhalation flow rate, distance from mouth to inhaler, exhalation duration, and relative air humidity) on dry powder dose delivery. Given that acoustic energy can be related to the factors associated with exhalation sounds, we then aimed to develop a method of identifying and quantifying this critical inhaler technique error using acoustic based methods. An in vitro test rig was developed to simulate this critical error. The effect of the four factors on subsequent drug delivery were investigated using multivariate regression models. In a further study we then used an acoustic monitoring device to unobtrusively record the sounds 22 asthmatic patients made whilst using a Diskus(™) DPI. Acoustic energy was employed to automatically detect and analyze exhalation events in the audio files. All exhalation factors had a statistically significant effect on drug delivery (p<0.05); distance from the inhaler mouthpiece had the largest effect size. Humid air exhalations were found to reduce the fine particle fraction (FPF) compared to dry air. In a dataset of 110 audio files from 22 asthmatic patients, the acoustic method detected exhalations with an accuracy of 89.1%. We were able to classify exhalations occurring 5 cm or less in the direction of the inhaler mouthpiece or recording device with a sensitivity of 72.2% and specificity of 85.7%. Exhaling into a DPI has a significant detrimental effect. Acoustic based methods can be employed to objectively detect and analyze exhalations during inhaler use, thus providing a method of remotely monitoring inhaler technique and providing personalized inhaler technique feedback.

Method Development for Clinical Comprehensive Evaluation of Pediatric Drugs Based on Multi-Criteria Decision Analysis: Application to Inhaled Corticosteroids for Children with Asthma.

PubMed

Yu, Yuncui; Jia, Lulu; Meng, Yao; Hu, Lihua; Liu, Yiwei; Nie, Xiaolu; Zhang, Meng; Zhang, Xuan; Han, Sheng; Peng, Xiaoxia; Wang, Xiaoling

2018-04-01

Establishing a comprehensive clinical evaluation system is critical in enacting national drug policy and promoting rational drug use. In China, the 'Clinical Comprehensive Evaluation System for Pediatric Drugs' (CCES-P) project, which aims to compare drugs based on clinical efficacy and cost effectiveness to help decision makers, was recently proposed; therefore, a systematic and objective method is required to guide the process. An evidence-based multi-criteria decision analysis model that involved an analytic hierarchy process (AHP) was developed, consisting of nine steps: (1) select the drugs to be reviewed; (2) establish the evaluation criterion system; (3) determine the criterion weight based on the AHP; (4) construct the evidence body for each drug under evaluation; (5) select comparative measures and calculate the original utility score; (6) place a common utility scale and calculate the standardized utility score; (7) calculate the comprehensive utility score; (8) rank the drugs; and (9) perform a sensitivity analysis. The model was applied to the evaluation of three different inhaled corticosteroids (ICSs) used for asthma management in children (a total of 16 drugs with different dosage forms and strengths or different manufacturers). By applying the drug analysis model, the 16 ICSs under review were successfully scored and evaluated. Budesonide suspension for inhalation (drug ID number: 7) ranked the highest, with comprehensive utility score of 80.23, followed by fluticasone propionate inhaled aerosol (drug ID number: 16), with a score of 79.59, and budesonide inhalation powder (drug ID number: 6), with a score of 78.98. In the sensitivity analysis, the ranking of the top five and lowest five drugs remains unchanged, suggesting this model is generally robust. An evidence-based drug evaluation model based on AHP was successfully developed. The model incorporates sufficient utility and flexibility for aiding the decision-making process, and can be a useful tool for the CCES-P.

In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy.

PubMed

Ciciliani, Anna-Maria; Langguth, Peter; Wachtel, Herbert

2017-01-01

Combining in vitro mouth-throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment. The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups - moderate and very severe COPD - were applied. Theoretical lung deposition patterns were assessed by an individual path model. For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%-63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth-throat model and the highest amount reaching all regions of the simulation lung model.

In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy

PubMed Central

Ciciliani, Anna-Maria; Langguth, Peter; Wachtel, Herbert

2017-01-01

Background Combining in vitro mouth–throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment. Methods The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups – moderate and very severe COPD – were applied. Theoretical lung deposition patterns were assessed by an individual path model. Results and conclusion For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%–63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth–throat model and the highest amount reaching all regions of the simulation lung model. PMID:28603412

Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid

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

Teeguarden, Justin G.; Deisinger, P. J.; Poet, Torka S.

2005-05-01

The metabolic series (family) approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. An initial physiologically-based pharmacokinetic (PBPK) model was developed to support the implementation of the metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol, and n-butyric acid (the butyl series) (Barton et al. 2000). In conjunction with pilot pharmacokinetic studies, the model was used to design the definitive intravenous (i.v.) PK studies. Rats were implanted with dual indwelling cannulae and administered testmore » compounds by i.v. bolus dose, i.v. infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate and n-butanol was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following i.v. administration, and inhalation exposure to n-butyl acetate and n-butanol. A fully scaled human version of the model successfully reproduces arterial blood n-butanol kinetics following inhalation exposure to n-butanol. These validated i.v (rat) and inhalation route models (rat, butyl acetate, n-butanol; human, butanol only) can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Further, this work demonstrates the usefulness of i.v. kinetic data for parameterization of systemic metabolism and the value of collaboration between experimentalists and kineticists in the development of PBPK models. The product of this effort, validated rat and human PBPK models for the butyl series compounds, illustrates the effectiveness of broad multi-institutional public/private collaborations in the pursuit of developing state of the art tools for risk assessment.« less

A mathematical model of transport and regional uptake of radioactive gases in the human respiratory system

NASA Astrophysics Data System (ADS)

Baek, Inseok

The purpose of this research is to describe the development of a mathematical model of diffusion, convection, and lateral transport into the airway wall and alveolar absorption for inhaled radioactive gases in the human conductive and respiratory airways based on a Single Path Trumpet-bell model (SPM). Mathematical simulation models have been used successfully to study transport, absorption into the blood through alveoli, and lung tissue uptake of soluble and nonreactive radioactive gases. Results from such simulations also show clearly that inhaled radioactive gases are absorbed into the lung tissues as well as into the blood through the alveoli. In contrast to previous reports in the literature, the present study found that blood uptake through alveoli is much greater than that calculated previously. Regional depositions in the lung from inhaled radioactive gases are presented as the result of this simulation. The committed effective dose to lung tissue due to submersion in radioactive clouds has been newly defined using the results of this simulation.

Computational Fluid Dynamics Modeling of Bacillus anthracis Spore Deposition in Rabbit and Human Respiratory Airways

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

Kabilan, Senthil; Suffield, Sarah R.; Recknagle, Kurtis P.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived from computed tomography (CT) or µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditionsmore » using average species-specific minute volumes. The highest exposure concentration was modeled in the rabbit based upon prior acute inhalation studies. For comparison, human simulation was also conducted at the same concentration. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the upper conducting airways compared to the human at the same air concentration of anthrax spores. As a result, higher particle deposition was predicted in the conducting airways and deep lung of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology.« less

NATIONAL-SCALE ASSESSMENT OF AIR TOXICS RISKS ...

EPA Pesticide Factsheets

The national-scale assessment of air toxics risks is a modeling assessment which combines emission inventory development, atmospheric fate and transport modeling, exposure modeling, and risk assessment to characterize the risk associated with inhaling air toxics from outdoor sources. This national-scale effort will be initiated for the base year 1996 and repeated every three years thereafter to track trends and inform program development. Provide broad-scale understanding of inhalation risks for a subset of atmospherically-emitted air toxics to inform further data-gathering efforts and priority-setting for the EPA's Air Toxics Programs.

Evaluating environmental modeling and sampling data with biomarker data to identify sources and routes of exposure

NASA Astrophysics Data System (ADS)

Shin, Hyeong-Moo; McKone, Thomas E.; Bennett, Deborah H.

2013-04-01

Exposure to environmental chemicals results from multiple sources, environmental media, and exposure routes. Ideally, modeled exposures should be compared to biomonitoring data. This study compares the magnitude and variation of modeled polycyclic aromatic hydrocarbons (PAHs) exposures resulting from emissions to outdoor and indoor air and estimated exposure inferred from biomarker levels. Outdoor emissions result in both inhalation and food-based exposures. We modeled PAH intake doses using U.S. EPA's 2002 National Air Toxics Assessment (NATA) county-level emissions data for outdoor inhalation, the CalTOX model for food ingestion (based on NATA emissions), and indoor air concentrations from field studies for indoor inhalation. We then compared the modeled intake with the measured urine levels of hydroxy-PAH metabolites from the 2001-2002 National Health and Nutrition Examination Survey (NHANES) survey as quantifiable human intake of PAH parent-compounds. Lognormal probability plots of modeled intakes and estimated intakes inferred from biomarkers suggest that a primary route of exposure to naphthalene, fluorene, and phenanthrene for the U.S. population is likely inhalation from indoor sources. For benzo(a)pyrene, the predominant exposure route is likely from food ingestion resulting from multi-pathway transport and bioaccumulation due to outdoor emissions. Multiple routes of exposure are important for pyrene. We also considered the sensitivity of the predicted exposure to the proportion of the total naphthalene production volume emitted to the indoor environment. The comparison of PAH biomarkers with exposure variability estimated from models and sample data for various exposure pathways supports that both indoor and outdoor models are needed to capture the sources and routes of exposure to environmental contaminants.

Feasibility of Deploying Inhaler Sensors to Identify the Impacts of Environmental Triggers and Built Environment Factors on Asthma Short-Acting Bronchodilator Use.

PubMed

Su, Jason G; Barrett, Meredith A; Henderson, Kelly; Humblet, Olivier; Smith, Ted; Sublett, James W; Nesbitt, LaQuandra; Hogg, Chris; Van Sickle, David; Sublett, James L

2017-02-01

Epidemiological asthma research has relied upon self-reported symptoms or healthcare utilization data, and used the residential address as the primary location for exposure. These data sources can be temporally limited, spatially aggregated, subjective, and burdensome for the patient to collect. First, we aimed to test the feasibility of collecting rescue inhaler use data in space-time using electronic sensors. Second, we aimed to evaluate whether these data have the potential to identify environmental triggers and built environment factors associated with rescue inhaler use and to determine whether these findings would be consistent with the existing literature. We utilized zero-truncated negative binomial models to identify triggers associated with inhaler use, and implemented three sensitivity analyses to validate our findings. Electronic sensors fitted on metered dose inhalers tracked 5,660 rescue inhaler use events in space and time for 140 participants from 13 June 2012 to 28 February 2014. We found that the inhaler sensors were feasible in passively collecting objective rescue inhaler use data. We identified several environmental triggers with a positive and significant association with inhaler use, including: AQI, PM10, weed pollen, and mold. Conversely, the spatial distribution of tree cover demonstrated a negative and significant association with inhaler use. Utilizing a sensor to capture the signal of rescue inhaler use in space-time offered a passive and objective signal of asthma activity. This approach enabled detailed analyses to identify environmental triggers and built environment factors that are associated with asthma symptoms beyond the residential address. The application of these new technologies has the potential to improve our surveillance and understanding of asthma. Citation: Su JG, Barrett MA, Henderson K, Humblet O, Smith T, Sublett JW, Nesbitt L, Hogg C, Van Sickle D, Sublett JL. 2017. Feasibility of deploying inhaler sensors to identify the impacts of environmental triggers and built environment factors on asthma short-acting bronchodilator use. Environ Health Perspect 125:254-261; http://dx.doi.org/10.1289/EHP266.

Effect of pulmonary irradiation from inhaled /sup 90/Y on immunity to Listeria monocytogenes in mice

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

Sanchez, A.; Lundgren, D.L.; McClellan, R.O.

1976-01-01

The immunological response of mice subjected to irradiation from particles deposited in the lungs and challenged with Listeria monocytogenes was investigated. Mice, exposed by inhalation to /sup 90/Y (a beta-emitting radionuclide) in relatively insoluble fused aluminosilicate particles, were immunized with L. monocytogenes either before or after exposure. Two additional groups of mice were either immunized or irradiated only. A group of control mice received no irradiation or immunization. The beta radiation dose absorbed by the lungs of each mouse at time of challenge averaged 10,000 rads. Fourteen days after immunization, all mice were challenged with 2 LD/sub 50/ doses ofmore » L. monocytogenes via the respiratory route. Survival of all immunized mice either with or without exposure to /sup 90/Y varied from 90 to 100% as compared to 10 to 20% for the mice irradiated only and for control mice through 14 days after challenge. Pulmonary clearance of inhaled L. monocytogenes during the first 4 hr after challenge was suppressed in the mice irradiated only but not in those immunized only, or in the immunized and irradiated groups, and control mice. There appeared to be a suppression of proliferation of L. monocytogenes in lungs and spleen in the immunized groups 72 hr after challenge, whereas the lungs and spleens of the mice irradiated only and the control mice had extensive bacterial invasion. It was concluded that the 10,000 rads of beta radiation absorbed by the lungs did not suppress the immune mechanisms of the immunized mice.« less

Inhalation of Carbon Black Nanoparticles Aggravates Pulmonary Inflammation in Mice

PubMed Central

Saputra, Devina; Yoon, Jin-ha; Park, Hyunju; Heo, Yongju; Yang, Hyoseon; Lee, Eun Ji; Lee, Sangjin; Song, Chang-Woo; Lee, Kyuhong

2014-01-01

An increasing number of recent studies have focused on the impact of particulate matter on human health. As a model for atmospheric particulate inhalation, we investigated the effects of inhaled carbon black nanoparticles (CBNP) on mice with bleomycin-induced pulmonary fibrosis. The CNBPs were generated by a novel aerosolization process, and the mice were exposed to the aerosol for 4 hours. We found that CBNP inhalation exacerbated lung inflammation, as evidenced by histopathology analysis and by the expression levels of interleukin-6 protein, fibronectin, and interferon-γ mRNAs in lung tissues. Notably, fibronectin mRNA expression showed a statistically significant increase in expression after CBNP exposure. These data suggest that the concentration of CBNPs delivered (calculated to be 12.5 μg/m3) can aggravate lung inflammation in mice. Our results also suggest that the inhalation of ultrafine particles like PM 2.5 is an impactful environmental risk factor for humans, particularly in susceptible populations with predisposing lung conditions. PMID:25071917

Computational Fluid Dynamics Simulations of Inhaled Nano-and Micro-Particle Deposition in the Rhesus Monkey Nasal Passages

DTIC Science & Technology

2016-12-01

reconstruction of the adult model was originally developed by Kepler et al. (1998) from serial Magnetic Resonance Imaging ( MRI ) sections of the right...upper airways and MRI imaging of a lung cast to form a contiguous reconstruction from the nostrils through 19 airway generations of the lung. For this...and Musante, C. J. (2001). A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies. Inhal. Toxicol. 13:307-324

Computational Fluid Dynamics Simulations of Inhaled Nano- and Micro-Particle Deposition in the Rhesus Monkey Nasal Passages

DTIC Science & Technology

2016-12-01

reconstruction of the adult model was originally developed by Kepler et al. (1998) from serial Magnetic Resonance Imaging ( MRI ) sections of the right...upper airways and MRI imaging of a lung cast to form a contiguous reconstruction from the nostrils through 19 airway generations of the lung. For this...and Musante, C. J. (2001). A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies. Inhal. Toxicol. 13:307-324

Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity.

PubMed

Clippinger, Amy J; Allen, David; Behrsing, Holger; BéruBé, Kelly A; Bolger, Michael B; Casey, Warren; DeLorme, Michael; Gaça, Marianna; Gehen, Sean C; Glover, Kyle; Hayden, Patrick; Hinderliter, Paul; Hotchkiss, Jon A; Iskandar, Anita; Keyser, Brian; Luettich, Karsta; Ma-Hock, Lan; Maione, Anna G; Makena, Patrudu; Melbourne, Jodie; Milchak, Lawrence; Ng, Sheung P; Paini, Alicia; Page, Kathryn; Patlewicz, Grace; Prieto, Pilar; Raabe, Hans; Reinke, Emily N; Roper, Clive; Rose, Jane; Sharma, Monita; Spoo, Wayne; Thorne, Peter S; Wilson, Daniel M; Jarabek, Annie M

2018-06-20

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Predicting the acute behavioral effects in rats inhaling toluene for up to 24 hrs: Inhaled vs, internal dose metrics and tolerance.

EPA Science Inventory

The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used extrelationships to extrapolate protective and/or effective concentrations across dura...

Turbulence in the trachea and its effect on micro-particle deposition

NASA Astrophysics Data System (ADS)

Geisler, Taylor; Shaqfeh, Eric; Iaccarino, Gianluca

2017-11-01

The health effects of inhaled aerosols are often predicted by extrapolating experimental data taken using nonhuman primate animal studies to humans. While the existence of a laminar-to-turbulent flow transition in the human larynx is widely reported in the literature, it was previously unknown, to our knowledge, whether a similar flow behavior exists in the airways of rhesus monkeys. By using Large Eddy Simulation (LES) in the CT-based airway models of rhesus monkeys we demonstrate the existence of such a flow transition at elevated inspiratory flow rates. The geometries comprise the nasal cavity, larynx, and trachea. We observe turbulence intensity values that peak after the larynx and decay throughout the trachea similar to that of humans. Deposition of inhaled micro-particles is also computed and validated using experiments in 3D-printed model airways with excellent agreement. Deposition in the turbulent regions of the airway (larynx and trachea) is shown to be substantial at elevated flow rates and to depend on the flow unsteadiness. These results provide insight into the fate of inhaled particles in rhesus monkey animal experiments and their connection to human inhalation.

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids.

PubMed

Jonasson, Sofia; Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders

2013-09-01

Chlorine (Cl2) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl2-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200ppm Cl2 during 15min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24h or 14days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100mg/kg) was administered intraperitoneally 1, 3, 6, or 12h following Cl2 exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1h was dose-dependent; high-dose significantly reduced acute airway inflammation (100mg/kg) but not treatment with the relatively low-dose (10mg/kg). Both doses reduced AHR 14days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl2 exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl2 exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

Ntp report on the toxicity studies of ethylbenzene in f344/n rats and b6c3f1 mice (inhalation studies). Report for 29 March-30 June 1988

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

Chan, P.

1992-03-01

Inhalation toxicology studies of ethylbenzene (99% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to ethylbenzene vapor at chamber concentrations of 0 to 1000 ppm, 6 hours per day, 5 days per week for 13 weeks. No rats or mice died during the 13-week exposure. Body weight gains were slightly lower in the high dose groups of male and female rats, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were increased in the exposed rats, while weight increases occurred only in the livers of exposed mice.more » No changes were observed in the evaluation of sperm or vaginal cytology in rats or mice. Ethylbenzene was not mutagenic in Salmonella and did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary (CHO) cells in vitro, though it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested. Micronuclei assays in peripheral blood of mice were negative.« less

Establishment of an in vitro cell line experimental system for the study of inhalational anesthetic mechanisms.

PubMed

Nagamoto, Seiji; Iijima, Norio; Ishii, Hirotaka; Takumi, Ken; Higo, Shimpei; Aikawa, Satoko; Anzai, Megumi; Matsuo, Izumi; Nakagawa, Shinji; Takashima, Naoyuki; Shigeyoshi, Yasufumi; Sakamoto, Atsuhiro; Ozawa, Hitoshi

2016-05-04

General anesthesia affects the expression of clock genes in various organs. Expression of Per2, a core component of the circadian clock, is markedly and reversibly suppressed by sevoflurane in the suprachiasmatic nucleus (SCN), and is considered to be a biochemical marker of anesthetic effect in the brain. The SCN contains various types of neurons, and this complexity makes it difficult to investigate the molecular mechanisms of anesthesia. Here, we established an in vitro experimental system using a cell line to investigate the mechanisms underlying anesthetic action. Development of the system comprised two steps: first, we developed a system for application of inhalational anesthetics and incubation; next, we established cultures of anesthetic-responsive cells expressing mPer2 promoter-dLuc. GT1-7 cells, derived from the mouse hypothalamus, responded to sevoflurane by reversibly decreasing mPer2-promoter-driven bioluminescence. Interestingly, the suppression of bioluminescence was found only in the serum-starved GT1-7 cells, which showed neuron-like morphology, but not in growing cells, suggesting that neuron-like characteristics are required for anesthetic effects in GT1-7 cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

PubMed

Nguyen, Jacques D; Aarde, Shawn M; Vandewater, Sophia A; Grant, Yanabel; Stouffer, David G; Parsons, Loren H; Cole, Maury; Taffe, Michael A

2016-10-01

Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preventive and curative effects of radon inhalation on chronic constriction injury-induced neuropathic pain in mice.

PubMed

Yamato, K; Kataoka, T; Nishiyama, Y; Taguchi, T; Yamaoka, K

2013-04-01

Radon therapy is clinically useful for the treatment of pain-related diseases. However, there have been no studies regarding the effects of radon inhalation on neuropathic pain. In this study, we aimed to determine whether radon inhalation actually induced a remission of neuropathic pain and improved the quality of life. First, we investigated the antinociceptive effects of radon inhalation in the chronic constriction injury (CCI) model of neuropathic pain. We evaluated pain behaviour in mice before and after CCI surgery, using von Frey test. Pretreated mice received CCI surgery immediately after 24-h inhalation of radon at background (BG) concentration (c. 19 Bq/m(3) ), or at a concentration of 1000 or 2000 Bq/m(3) , and post-treated mice inhaled similar levels of radon 2 days after CCI surgery. CCI surgery induced mechanical allodynia and hyperalgesia on a plantar surface of mice, as assessed using von Frey test, and 2000 Bq/m(3) radon inhalation alleviated hyperalgesic conditions 22-37% compared to BG level concentration. Concurrently, CCI surgery increased norepinephrine (NE), tumour necrosis factor-alpha (TNF-α) and nitric oxide (NO) concentrations in plasma, and leukocyte migration in paws. Furthermore, CCI-induced neuropathy reduced superoxide dismutase (SOD) activity. Treatment with radon inhalation, specifically at a concentration of 2000 Bq/m(3) , produced antinociceptive effects, i.e., lowered plasma TNF-α, NE and NO levels and restored SOD activity, as well as pain-related behaviour. This study showed that inhalation of 2000 Bq/m(3) radon prevented and alleviated CCI-induced neuropathic pain in mice. © 2012 European Federation of International Association for the Study of Pain Chapters.

History of aerosol therapy: liquid nebulization to MDIs to DPIs.

PubMed

Anderson, Paula J

2005-09-01

Inhaled therapies have been used since ancient times and may have had their origins with the smoking of datura preparations in India 4,000 years ago. In the late 18th and in the 19th century, earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and other ingredients. Atomizers and nebulizers were developed in the mid-1800s in France and were thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling thermal waters at spas. Around the turn of the 20th century, combustible powders and cigarettes containing stramonium were popular for asthma and other lung complaints. Following the discovery of the utility of epinephrine for treating asthma, hand-bulb nebulizers were developed, as well as early compressor nebulizers. The marketing of the first pressurized metered-dose inhaler for epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development of inhaled drugs. There have been remarkable advances in the technology of devices and formulations for inhaled drugs in the past 50 years. These have been influenced greatly by scientific developments in several areas: theoretical modeling and indirect measures of lung deposition, particle sizing techniques and in vitro deposition studies, scintigraphic deposition studies, pharmacokinetics and pharmacodynamics, and the 1987 Montreal Protocol, which banned chlorofluorocarbon propellants. We are now in an era of rapid technologic progress in inhaled drug delivery and applications of aerosol science, with the use of the aerosolized route for drugs for systemic therapy and for gene replacement therapy, use of aerosolized antimicrobials and immunosuppressants, and interest in specific targeting of inhaled drugs.

Assessing the Risk of Primary Amoebic Meningoencephalitis from Swimming in the Presence of Environmental Naegleria fowleri

PubMed Central

Cabanes, Pierre-André; Wallet, France; Pringuez, Emmanuelle; Pernin, Pierre

2001-01-01

Free-living Naegleria fowleri amoebae cause primary amoebic meningoencephalitis (PAM). Because of the apparent conflict between their ubiquity and the rarity of cases observed, we sought to develop a model characterizing the risk of PAM after swimming as a function of the concentration of N. fowleri. The probability of death from PAM as a function of the number of amoebae inhaled is modeled according to results obtained from animals infected with amoeba strains. The calculation of the probability of inhaling one or more amoebae while swimming is based on a double hypothesis: that the distribution of amoebae in the water follows a Poisson distribution and that the mean quantity of water inhaled while swimming is 10 ml. The risk of PAM for a given concentration of amoebae is then obtained by summing the following products: the probability of inhaling n amoebae × the probability of PAM associated with inhaling these n amoebae. We chose the lognormal model to assess the risk of PAM because it yielded the best analysis of the studentized residuals. Nonetheless, the levels of risk thereby obtained cannot be applied to humans without correction, because they are substantially greater than those indicated by available epidemiologic data. The curve was thus adjusted by a factor calculated with the least-squares method. This provides the PAM risk in humans as a function of the N. fowleri concentration in the river. For example, the risk is 8.5 × 10−8 at a concentration of 10 N. fowleri amoebae per liter. PMID:11425704

Inhalational and dermal exposures during spray application of biocides.

PubMed

Berger-Preiss, Edith; Boehncke, Andrea; Könnecker, Gustav; Mangelsdorf, Inge; Holthenrich, Dagmar; Koch, Wolfgang

2005-01-01

Data on inhalational and potential dermal exposures during spray application of liquid biocidal products were generated. On the one hand, model experiments with different spraying devices using fluorescent tracers were carried out to investigate the influence of parameters relevant to the exposure (e.g. spraying equipment, nozzle size, direction of application). On the other hand, measurements were performed at selected workplaces (during disinfection operations in food and feed areas; pest control operations for private, public and veterinary hygiene; wood protection and antifouling applications) after application of biocidal products such as Empire 20, Responsar SC, Omexan-forte, Actellic, Perma-forte; Fendona SC, Pyrethrum mist; CBM 8, Aldekol Des 03, TAD CID, Basileum, Basilit. The measurements taken in the model rooms demonstrated dependence of the inhalation exposure on the type of spraying device used, in the following order: "spraying with low pressure" < "airless spraying" < "fogging" indicating that the particle diameter of the released spray droplets is the most important parameter. In addition inhalation exposure was lowest when the spraying direction was downward. Also for the potential dermal exposure, the spraying direction was of particular importance: overhead spraying caused the highest contamination of body surfaces. The data of inhalational and potential dermal exposures gained through workplace measurements showed considerable variation. During spraying procedures with low-pressure equipments, dose rates of active substances inhaled by the operators ranged from 7 to 230 microg active substance (a.s.)/h. An increase in inhaled dose rates (6-33 mg a.s./h) was observed after use of high application volumes/time unit during wood protection applications indoors. Spraying in the veterinary sector using medium-pressure sprayers led to inhaled dose rates between 2 and 24mga.s./h. The highest inhaled dose rates were measured during fogging (114 mg a.s./h) and after-high-pressure applications in the antifouling sector (110-300 mg a.s./h). The potential dermal exposure of spray operators was lowest (dose rates from 0.2 to 7 mg a.s./h) in the areas of food and feed disinfection and private and public hygiene during spraying with low-pressure devices. During fogging, wood protection and antifouling applications, high-potential dermal exposures of the operators were determined. Dermal dose rates varied between 100 and 34,000 mg a.s./h.

Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data.

PubMed

Tian, Geng; Hindle, Michael; Lee, Sau; Longest, P Worth

2015-10-01

CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data. The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways. For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7 μm. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error <10% for each inhaler. CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods.

Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data

PubMed Central

Tian, Geng; Hindle, Michael; Lee, Sau; Longest, P. Worth

2015-01-01

Purpose CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data. Methods The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways. Results For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7μm. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error <10% for each inhaler. Conclusions CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods. PMID:25944585

A personalized medicine approach to the design of dry powder inhalers: Selecting the optimal amount of bypass.

PubMed

Kopsch, Thomas; Murnane, Darragh; Symons, Digby

2017-08-30

In dry powder inhalers (DPIs) the patient's inhalation manoeuvre strongly influences the release of drug. Drug release from a DPI may also be influenced by the size of any air bypass incorporated in the device. If the amount of bypass is high less air flows through the entrainment geometry and the release rate is lower. In this study we propose to reduce the intra- and inter-patient variations of drug release by controlling the amount of air bypass in a DPI. A fast computational method is proposed that can predict how much bypass is needed for a specified drug delivery rate for a particular patient. This method uses a meta-model which was constructed using multiphase computational fluid dynamic (CFD) simulations. The meta-model is applied in an optimization framework to predict the required amount of bypass needed for drug delivery that is similar to a desired target release behaviour. The meta-model was successfully validated by comparing its predictions to results from additional CFD simulations. The optimization framework has been applied to identify the optimal amount of bypass needed for fictitious sample inhalation manoeuvres in order to deliver a target powder release profile for two patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Deposition and clearance of inhaled particles.

PubMed Central

Stuart, B O

1984-01-01

Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as governed principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of approximations of the respiratory tract to predict fractional deposition caused by fundamental physical processes of particle impaction, sedimentation, and diffusion. These models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with early and recent experimental studies. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior in the respiratory tract of very fine (less than 0.1 micron) particles requires further investigation. Properties of particle shape, charge and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns; definitive experimental work is needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of differing ventilation techniques with selected inhaled particle sizes holds promise in diagnosis of respiratory tract diseases. Mechanisms of conducting airway and alveolar clearance processes involving the pulmonary macrophage, mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic vessels are discussed. PMID:6376108

Decreased Hippocampal Neuroplasticity and Behavioral Impairment in an Animal Model of Inhalant Abuse

PubMed Central

Malloul, Hanaa; Bennis, Mohammed; Bonzano, Sara; Gambarotta, Giovanna; Perroteau, Isabelle; De Marchis, Silvia; Ba-M'hamed, Saadia

2018-01-01

Thinners are highly toxic chemicals widely employed as organic solvents in industrial and domestic use. They have psychoactive properties when inhaled, and their chronic abuse as inhalants is associated with severe long-term health effects, including brain damage and cognitive-behavioral alterations. Yet, the sites and mechanisms of action of these compounds on the brain are far from being fully understood. Here, we investigated the consequences of paint thinner inhalation in adult male mice. Depression-like behaviors and an anxiolytic effect were found following repeated exposure in chronic treatments lasting 12 weeks. Both subchronic (6 weeks) and chronic treatments impaired learning and memory functions, while no changes were observed after acute treatment. To investigate possible molecular/structural alterations underlying such behavioral changes, we focused on the hippocampus. Notably, prolonged, but not acute thinner inhalation strongly affected adult neurogenesis in the dentate gyrus (DG), reducing progenitor cell proliferation after chronic treatments and impairing the survival of newborn neurons following both chronic and subchronic treatments. Furthermore, a down-regulation in the expression of BDNF and NMDA receptor subunits as well as a reduction in CREB expression/phosphorylation were found in the hippocampi of chronically treated mice. Our findings demonstrate for the first time significant structural and molecular changes in the adult hippocampus after prolonged paint thinner inhalation, indicating reduced hippocampal neuroplasticity and strongly supporting its implication in the behavioral dysfunctions associated to inhalant abuse. PMID:29472835

Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI)

PubMed Central

Pauluhn, Jürgen

2015-01-01

Abstract This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose–response curve of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) × variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C × t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m3 × min (75 mg/m3 for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m3 × min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C × t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat “asthma” model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general. PMID:25924102

Commentary on Inhaled 239PuO 2 in Dogs — A Prophylaxis against Lung Cancer?

DOE PAGES

Cuttler, Jerry M.; Feinendegen, Ludwig E.

2015-01-01

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from 239PuO 2 inhalation, as a prophylaxis against lung cancer.

Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer’s Disease

PubMed Central

McClure, Richard; Ong, Henry; Janve, Vaibhab; Barton, Shawn; Zhu, Meiying; Li, Bo; Dawes, Mary; Jerome, W. Gray; Anderson, Adam; Massion, Pierre; Gore, John C.; Pham, Wellington

2018-01-01

We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer’s disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work. PMID:27802223

Commentary on Inhaled 239PuO 2 in Dogs — A Prophylaxis against Lung Cancer?

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

Cuttler, Jerry M.; Feinendegen, Ludwig E.

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from 239PuO 2 inhalation, as a prophylaxis against lung cancer.

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

PubMed Central

Nguyen, Jacques D; Aarde, Shawn M; Cole, Maury; Vandewater, Sophia A; Grant, Yanabel; Taffe, Michael A

2016-01-01

Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 μg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5–1.0 mg/kg), or MDPV (0.5–1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine. PMID:27277119

Olfactory deposition of inhaled nanoparticles in humans

PubMed Central

Garcia, Guilherme J. M.; Schroeter, Jeffry D.; Kimbell, Julia S.

2016-01-01

Context Inhaled nanoparticles can migrate to the brain via the olfactory bulb, as demonstrated in experiments in several animal species. This route of exposure may be the mechanism behind the correlation between air pollution and human neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Objectives This manuscript aims to (1) estimate the dose of inhaled nanoparticles that deposit in the human olfactory epithelium during nasal breathing at rest and (2) compare the olfactory dose in humans with our earlier dose estimates for rats. Materials and methods An anatomically-accurate model of the human nasal cavity was developed based on computed tomography scans. The deposition of 1–100 nm particles in the whole nasal cavity and its olfactory region were estimated via computational fluid dynamics (CFD) simulations. Our CFD methods were validated by comparing our numerical predictions for whole-nose deposition with experimental data and previous CFD studies in the literature. Results In humans, olfactory dose of inhaled nanoparticles is highest for 1–2 nm particles with approximately 1% of inhaled particles depositing in the olfactory region. As particle size grows to 100 nm, olfactory deposition decreases to 0.01% of inhaled particles. Discussion and conclusion Our results suggest that the percentage of inhaled particles that deposit in the olfactory region is lower in humans than in rats. However, olfactory dose per unit surface area is estimated to be higher in humans due to their larger minute volume. These dose estimates are important for risk assessment and dose-response studies investigating the neurotoxicity of inhaled nanoparticles. PMID:26194036

Modeling vascular inflammation and atherogenicity after inhalation of ambient levels of ozone: exploratory lessons from transcriptomics.

PubMed

Tham, Andrea; Lullo, Dominic; Dalton, Sarah; Zeng, Siyang; van Koeverden, Ian; Arjomandi, Mehrdad

2017-02-01

Epidemiologic studies have linked inhalation of air pollutants such as ozone to cardiovascular mortality. Human exposure studies have shown that inhalation of ambient levels of ozone causes airway and systemic inflammation and an imbalance in sympathetic/parasympathetic tone. To explore molecular mechanisms through which ozone inhalation contributes to cardiovascular mortality, we compared transcriptomics data previously obtained from bronchoalveolar lavage (BAL) cells obtained from healthy subjects after inhalational exposure to ozone (200 ppb for 4 h) to those of various cell samples from 11 published studies of patients with atherosclerotic disease using the Nextbio genomic data platform. Overlapping gene ontologies that may be involved in the transition from pulmonary to systemic vascular inflammation after ozone inhalation were explored. Local and systemic enzymatic activity of an overlapping upregulated gene, matrix metalloproteinase-9 (MMP-9), was measured by zymography after ozone exposure. A set of differentially expressed genes involved in response to stimulus, stress, and wounding were in common between the ozone and most of the atherosclerosis studies. Many of these genes contribute to biological processes such as cholesterol metabolism dysfunction, increased monocyte adherence, endothelial cell lesions, and matrix remodeling, and to diseases such as heart failure, ischemia, and atherosclerotic occlusive disease. Inhalation of ozone increased MMP-9 enzymatic activity in both BAL fluid and serum. Comparison of transcriptomics between BAL cells after ozone exposure and various cell types from patients with atherosclerotic disease reveals commonly regulated processes and potential mechanisms by which ozone inhalation may contribute to progression of pre-existent atherosclerotic lesions.

Subchronic inhalation exposure of rats to Libby amphibole and amosite asbestos: Effects at 1 and 3 months post exposure#

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident in humans after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Ra...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 18 Months Post Exposure###

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rats were ex...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 18 Months Post Exposure

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rats were ex...

Subchronic Inhalation Exposure of Rats to Libby Amphibole and Amosite Asbestos: Effects at 1 and 3 Months Post Exposure**

EPA Science Inventory

Increased asbestosis, lung cancer, and mesothelioma rates are evident after exposures to Libby amphibole (LA). To support dosimetry model development and compare potency, a subchronic nose-only inhalation exposure study (6 hr/d, 5 d/wk, 13 wk) was conducted in male F344 rats. Rat...

Pulmonary exposure to carbonaceous nanomaterials and sperm quality.

PubMed

Skovmand, Astrid; Jacobsen Lauvås, Anna; Christensen, Preben; Vogel, Ulla; Sørig Hougaard, Karin; Goericke-Pesch, Sandra

2018-01-31

Semen quality parameters are potentially affected by nanomaterials in several ways: Inhaled nanosized particles are potent inducers of pulmonary inflammation, leading to the release of inflammatory mediators. Small amounts of particles may translocate from the lungs into the lung capillaries, enter the systemic circulation and ultimately reach the testes. Both the inflammatory response and the particles may induce oxidative stress which can directly affect spermatogenesis. Furthermore, spermatogenesis may be indirectly affected by changes in the hormonal milieu as systemic inflammation is a potential modulator of endocrine function. The aim of this study was to investigate the effects of pulmonary exposure to carbonaceous nanomaterials on sperm quality parameters in an experimental mouse model. Effects on sperm quality after pulmonary inflammation induced by carbonaceous nanomaterials were investigated by intratracheally instilling sexually mature male NMRI mice with four different carbonaceous nanomaterials dispersed in nanopure water: graphene oxide (18 μg/mouse/i.t.), Flammruss 101, Printex 90 and SRM1650b (0.1 mg/mouse/i.t. each) weekly for seven consecutive weeks. Pulmonary inflammation was determined by differential cell count in bronchoalveolar lavage fluid. Epididymal sperm concentration and motility were measured by computer-assisted sperm analysis. Epididymal sperm viability and morphological abnormalities were assessed manually using Hoechst 33,342/PI flourescent and Spermac staining, respectively. Epididymal sperm were assessed with regard to sperm DNA integrity (damage). Daily sperm production was measured in the testis, and testosterone levels were measured in blood plasma by ELISA. Neutrophil numbers in the bronchoalveolar fluid showed sustained inflammatory response in the nanoparticle-exposed groups one week after the last instillation. No significant changes in epididymal sperm parameters, daily sperm production or plasma testosterone levels were found. Despite the sustained pulmonary inflammatory response, an eight week exposure to graphene oxide, Flammruss 101, Printex 90 and the diesel particle SRM1650b in the present study did not appear to affect semen parameters, daily sperm production or testosterone concentration in male NMRI mice.

[Pollution characteristics and health risk assessment of atmospheric volatile organic compounds (VOCs) in pesticide factory].

PubMed

Tan, Bing; Wang, Tie-Yu; Pang, Bo; Zhu, Zhao-Yun; Wang, Dao-Han; Lü, Yong-Long

2013-12-01

A method for determining volatile organic compounds (VOCs) in air by summa canister collecting and gas chromatography/ mass spectroscopy detecting was adopted. Pollution condition and characteristics of VOCs were discussed in three representative pesticide factories in Zhangjiakou City, Hebei Province. Meanwhile, an internationally recognized four-step evaluation model of health risk assessment was applied to preliminarily assess the health risk caused by atmospheric VOCs in different exposure ways, inhalation and dermal exposure. Results showed that serious total VOCs pollution existed in all factories. Concentrations of n-hexane (6161.90-6910.00 microg x m(-3)), benzene (126.00-179.30 microg x m(-3)) and 1,3-butadiene (115.00-177.30 microg x m(-3)) exceeded the Chronic Inhalation Reference Concentrations recommended by USEPA, corresponding to 700, 30 and 2 microg x m(-3), respectively. Concentration of dichloromethane (724.00 microg x m(-3)) in factory B was also higher than the reference concentration (600 microg x m(-3)). Results of health risk assessment indicated that non-carcinogenic risk indexes of VOCs ranged from 1.00E-04 to 1.00E + 00 by inhalation exposure, and 1.00E-09 to 1.00E-05 by dermal exposure. Risk indexes of n-hexane and dichloromethane by inhalation exposure in all factories exceeded 1, and risk index of benzene by inhalation in factory B was also higher than 1. Carcinogenic risk indexes exposed to VOCs ranged from 1.00E-08 to 1.00E-03 by inhalation exposure and 1. oo00E -13 to 1.00E-08 by dermal exposure. Cancer risk of 1,3-butadiene by inhalation exceeded 1.0E-04, which lead to definite risk, and those of benzene by inhalation also exceeded the maximum allowable level recommended by International Commission on Radiological Protection (5.0E-05). The risks of dermal exposure presented the same trend as inhalation exposure, but the level was much lower than that of inhalation exposure. Thus, inhalation exposure of atmospheric VOCs was the dominant way of health risk in these factories.

H2 Gas Improves Functional Outcome After Cardiac Arrest to an Extent Comparable to Therapeutic Hypothermia in a Rat Model

PubMed Central

Hayashida, Kei; Sano, Motoaki; Kamimura, Naomi; Yokota, Takashi; Suzuki, Masaru; Maekawa, Yuichiro; Kawamura, Akio; Abe, Takayuki; Ohta, Shigeo; Fukuda, Keiichi; Hori, Shingo

2012-01-01

Background All clinical and biological manifestations related to postcardiac arrest (CA) syndrome are attributed to ischemia–reperfusion injury in various organs including brain and heart. Molecular hydrogen (H2) has potential as a novel antioxidant. This study tested the hypothesis that inhalation of H2 gas starting at the beginning of cardiopulmonary resuscitation (CPR) could improve the outcome of CA. Methods and Results Ventricular fibrillation was induced by transcutaneous electrical epicardial stimulation in rats. After 5 minutes of the subsequent CA, rats were randomly assigned to 1 of 4 experimental groups at the beginning of CPR: mechanical ventilation (MV) with 2% N2 and 98% O2 under normothermia (37°C), the control group; MV with 2% H2 and 98% O2 under normothermia; MV with 2% N2 and 98% O2 under therapeutic hypothermia (TH), 33°C; and MV with 2% H2 and 98% O2 under TH. Mixed gas inhalation and TH continued until 2 hours after the return of spontaneous circulation (ROSC). H2 gas inhalation yielded better improvement in survival and neurological deficit score (NDS) after ROSC to an extent comparable to TH. H2 gas inhalation, but not TH, prevented a rise in left ventricular end-diastolic pressure and increase in serum IL-6 level after ROSC. The salutary impact of H2 gas was at least partially attributed to the radical-scavenging effects of H2 gas, because both 8-OHdG- and 4-HNE-positive cardiomyocytes were markedly suppressed by H2 gas inhalation after ROSC. Conclusions Inhalation of H2 gas is a favorable strategy to mitigate mortality and functional outcome of post-CA syndrome in a rat model, either alone or in combination with TH. PMID:23316300

Estimating diesel fuel exposure for a plumber repairing an underground pipe.

PubMed

Finn, Mary; Stenzel, Mark; Ramachandran, Gurumurthy

2017-04-01

We estimated the diesel fuel exposure of a plumber repairing an underground water line leak at a truck stop. The repair work was performed over three days during which the plumber spent most of his time in a pit filled with a mixture of water and diesel fuel. Thus, the plumber was exposed via both the inhalation and dermal routes. While previously asymptomatic, he was diagnosed with acute renal failure 35 days after working at this site. No measurements were available for estimating either inhalation or dermal exposures or the cumulative dose and, therefore, two different approaches were used that were based on simple models of the exposure scenario. The first approach used the ideal gas law with the vapor pressure of the diesel fuel mixture to estimate a saturation vapor concentration, while the second one used a mass balance of the petroleum hydrocarbon component of diesel fuel in conjunction with the Henry's Law constant for this mixture. These inhalation exposure estimates were then adjusted to account for the limited ventilation in a confined space. The inhalation exposure concentrations predicted when handling the water layer alone is much lower than that expected from the organic layer. This case study illustrates the large differences in inhalation exposure associated with volatile organic layers and aqueous solution containing these chemicals. The estimate of dermal exposure was negligible compared to the inhalation exposure because the skin presents a much smaller surface area of exposure to the contaminant compared to the lungs. The methodology presented here is useful for situations where little information is available for more formal mathematical exposure modeling, but where adjustments to the worst-case exposures, estimated simply, can provide reasonable exposure estimates.

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.

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.

PubMed

Andreae, Michael H; Carter, George M; Shaparin, Naum; Suslov, Kathryn; Ellis, Ronald J; Ware, Mark A; Abrams, Donald I; Prasad, Hannah; Wilsey, Barth; Indyk, Debbie; Johnson, Matthew; Sacks, Henry S

2015-12-01

Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Special aspects of pharmacokinetics of inhalation anesthesia.

PubMed

Hendrickx, J F A; De Wolf, A

2008-01-01

Recent interest in the use of low-flow or closed circuit anesthesia has rekindled interest in the pharmacokinetics of inhaled anesthetics. The kinetic properties of inhaled anesthetics are most often modeled by physiologic models because of the abundant information that is available on tissue solubilities and organ perfusion. These models are intuitively attractive because they can be easily understood in terms of the underlying anatomy and physiology. The use of classical compartment modeling, on the other hand, allows modeling of data that are routinely available to the anesthesiologist, and eliminates the need to account for every possible confounding factor at each step of the partial pressure cascade of potent inhaled agents. Concepts used to describe IV kinetics can readily be applied to inhaled agents (e.g., context-sensitive half-time and effect site concentrations). The interpretation of the F(A)/F(I) vs time curve is expanded by reintroducing the concept of the general anesthetic equation-the focus is shifted from "how F(A) approaches F(I)" to "what combination of delivered concentration and fresh gas flow (FGF) can be used to attain the desired F(A)." When the desired F(A) is maintained with a FGF that is lower than minute ventilation, rebreathing causes a discrepancy between the concentration delivered by the anesthesia machine (=selected by the anesthesiologist on the vaporizer, F(D)) and that inspired by the patient. This F(D)-F(I) discrepancy may be perceived as "lack of control" and has been the rationale to use a high FGF to ensure the delivered matched the inspired concentration. Also, with low FGF there is larger variability in F(D) because of interpatient variability in uptake. The F(D)-F(I) discrepancy increases with lower FGF because of more rebreathing, and as a consequence the uptake pattern seems to be more reflected in the F(D) required to keep F(A) constant. The clinical implication for the anesthesiologist is that with high FGF few F(D) adjustments have to be made, while with a low FGF F(D) has to be adjusted according to a pattern that follows the decreasing uptake pattern in the body. The ability to model and predict the uptake pattern of the individual patient and the resulting kinetics in a circle system could therefore help guide the anesthesiologist in the use of low-flow anesthesia with conventional anesthesia machines. Several authors have developed model-based low FGF administration schedules, but biologic variability limits the performance of any model, and therefore end-expired gas analysis is obligatory. Because some fine-tuning based on end-expired gas analysis will always be needed, some clinicians may not be inclined to use very low FGF in a busy operating room, considering the perceived increase in complexity. This practice may be facilitated by the development of anesthesia machines that use closed circuit anesthesia (CCA) with end-expired feedback control--they "black box" these issues (see Chapter 21). In this chapter, we first explore how and why the kinetic properties of intravenous and inhaled anesthetics have been modeled differently. Next, we will review the method most commonly used to describe the kinetics of inhaled agents, the F(A)/F(I) vs time curve that describes how the alveolar (F(A)) approaches the inspired (F(I)) fraction (in the gas phase, either "fraction," "concentration," or "partial pressure" can be used). Finally, we will reintroduce the concept of the general anesthetic equation to explain why the use of low-flow or closed circuit anesthesia has rekindled interest in the modeling of pharmacokinetics of inhaled anesthetics. Clinical applications of some of these models are reviewed. A basic understanding of the circle system is required, and will be provided in the introduction.

Numerical simulation of humidification and heating during inspiration in nose models with three different located septal perforations.

PubMed

Lindemann, Jörg; Reichert, Michael; Kröger, Ralf; Schuler, Patrick; Hoffmann, Thomas; Sommer, Fabian

2016-07-01

Nasal septum perforations (SP) are characterized by nasal obstruction, bleeding and crusting. The disturbed heating and humidification of the inhaled air are important factors, which cause these symptoms due to a disturbed airflow. Numerical simulations offer a great potential to avoid these limitations and to provide valid data. The aim of the study was to simulate the humidification and heating of the inhaled air in digital nose models with three different SPs and without SP. Four realistic bilateral nose models based on a multi-slice CT scan were created. The SP were located anterior caudal, anterior cranial and posterior caudal. One model was without SP. A numerical simulation was performed. Boundary conditions were based on previous in vivo measurements. Heating and humidification of the inhaled air were displayed, analyzed in each model and compared to each other. Anterior caudal SPs cause a disturbed decrease of temperature and humidity of the inhaled air. The reduced temperature and humidity values can still be shown in the posterior nose. The anterior cranial and the posterior caudal perforation have only a minor influence on heating and humidification. A reduced humidification and heating of the air can be shown by numerical simulations due to SP depending on their localization. The anterior caudal SP representing a typical localization after previous surgery has the biggest influence on heating and humidification. The results explain the typical symptoms such as crusting by drying-out the nasal mucosa. The size and the localization of the SP are essential for the symptoms.

Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema

PubMed Central

You, Ran; Lu, Wen; Shan, Ming; Berlin, Jacob M; Samuel, Errol LG; Marcano, Daniela C; Sun, Zhengzong; Sikkema, William KA; Yuan, Xiaoyi; Song, Lizhen; Hendrix, Amanda Y; Tour, James M; Corry, David B; Kheradmand, Farrah

2015-01-01

Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c+ lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers. DOI: http://dx.doi.org/10.7554/eLife.09623.001 PMID:26437452

An overview of animal models for assessing synthetic vitreous fibers (SVFs) safety.

PubMed

Johnson, N F

1994-12-01

Synthetic vitreous fibers (SVFs) are materials with many important commercial applications. The fibrous nature of the SVFs raises concerns about their potential human health hazards. However, sufficient epidemiological data do not exist to establish the hazardous nature of all SVFs. In addition, the cellular and molecular mechanisms underlying the induction of pulmonary lesions are only partially understood. Without sufficient evidence to associate fiber exposure and lung disease, animal bioassays have been used to identify specific hazardous fibers. These bioassays include inhalation exposures, intratracheal instillation, and intracavitary injection (intrapleural and intraperitoneal). Inhalation exposures of animals most closely represent the human experience, but these exposures are costly and time-consuming to conduct. Intratracheal and intracavitary administrations of fiber are alternatives to inhalation exposures; however, they do not represent human exposures and can give false positive results. The limitations of the noninhalation approaches must be considered when addressing the potential for a respirable fiber to induce human lung disease. In addition, when the results from inhalation exposures do not agree with the alternative animal assays, most weight should be given to the animal inhalation assays because of the limitations of the alternative approaches. To determine the safety of SVFs, both the inhalation and noninhalation approaches are suggested.

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.

A HYBRID CFD-PBPK MODEL OF INHALED CHLORINE GAS UPTAKE AND TISSUE DOSIMETRY IN THE ISOLATED UPPER RESPIRATORY TRACT (URT) OF F344 RATS

EPA Science Inventory

Chlorine (Cl₂), an important commercial gas, is highly reactive in water, causing irritant effects in the respiratory tract on inhalation. Nasal extraction of Cl₂ is high and resultant lesions in the respiratory tract show a proximal to distal distribution ...

Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: Evidence from a novel translational in vitro model**

EPA Science Inventory

The vascular toxicity of inhaled agents may be caused by soluble factors that are released into the systemic circulation. To confirm this in a straightforward manner, we obtained plasma from healthy human volunteers before and after exposure to diesel exhaust (DE) and nitrogen di...

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

PubMed Central

Kuempel, Eileen D.; Sweeney, Lisa M.; Morris, John B.; Jarabek, Annie M.

2015-01-01

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates. PMID:26551218

[Application of three risk assessment models in occupational health risk assessment of dimethylformamide].

PubMed

Wu, Z J; Xu, B; Jiang, H; Zheng, M; Zhang, M; Zhao, W J; Cheng, J

2016-08-20

Objective: To investigate the application of United States Environmental Protection Agency (EPA) inhalation risk assessment model, Singapore semi-quantitative risk assessment model, and occupational hazards risk assessment index method in occupational health risk in enterprises using dimethylformamide (DMF) in a certain area in Jiangsu, China, and to put forward related risk control measures. Methods: The industries involving DMF exposure in Jiangsu province were chosen as the evaluation objects in 2013 and three risk assessment models were used in the evaluation. EPA inhalation risk assessment model: HQ=EC/RfC; Singapore semi-quantitative risk assessment model: Risk= (HR×ER) 1/2 ; Occupational hazards risk assessment index=2 Health effect level ×2 exposure ratio ×Operation condition level. Results: The results of hazard quotient (HQ>1) from EPA inhalation risk assessment model suggested that all the workshops (dry method, wet method and printing) and work positions (pasting, burdening, unreeling, rolling, assisting) were high risk. The results of Singapore semi-quantitative risk assessment model indicated that the workshop risk level of dry method, wet method and printing were 3.5 (high) , 3.5 (high) and 2.8 (general) , and position risk level of pasting, burdening, unreeling, rolling, assisting were 4 (high) , 4 (high) , 2.8 (general) , 2.8 (general) and 2.8 (general) . The results of occupational hazards risk assessment index method demonstrated that the position risk index of pasting, burdening, unreeling, rolling, assisting were 42 (high) , 33 (high) , 23 (middle) , 21 (middle) and 22 (middle) . The results of Singapore semi-quantitative risk assessment model and occupational hazards risk assessment index method were similar, while EPA inhalation risk assessment model indicated all the workshops and positions were high risk. Conclusion: The occupational hazards risk assessment index method fully considers health effects, exposure, and operating conditions and can comprehensively and accurately evaluate occupational health risk caused by DMF.

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins

PubMed Central

Zeki, Amir A; Bratt, Jennifer M; Chang, Kevin Y; Franzi, Lisa M; Ott, Sean; Silveria, Mark; Fiehn, Oliver; Last, Jerold A; Kenyon, Nicholas J

2015-01-01

Systemic treatment with statins mitigates allergic airway inflammation, TH2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks. Mice received intratracheal instillations of pravastatin before and after each OVA exposure (30 mg/kg). Ultra performance liquid chromatography – mass spectrometry was used to quantify plasma, lung, and bronchoalveolar lavage fluid (BALF) pravastatin concentration. Pravastatin was quantifiable in mouse plasma, lung tissue, and BALF (BALF > lung > plasma for OVA and FA groups). At these concentrations pravastatin inhibited airway goblet cell hyperplasia/metaplasia, and reduced BALF levels of cytokines TNFα and KC, but did not reduce BALF total leukocyte or eosinophil cell counts. While pravastatin did not mitigate AHR, it did inhibit airway hypersensitivity (AHS). In this proof-of-principle study, using novel mass spectrometry methods we show that pravastatin is quantifiable in tissues, achieves high levels in mouse lungs with minimal systemic absorption, and mitigates some pathological features of allergic asthma. Inhaled pravastatin may be beneficial for the treatment of asthma by having direct airway effects independent of a potent anti-inflammatory effect. Statins with greater lipophilicity may achieve better anti-inflammatory effects warranting further research. PMID:25969462

Use of Immunohistochemistry to Demonstrate In Vivo Expression of the Burkholderia mallei Virulence Factor BpaB During Experimental Glanders.

PubMed

Zimmerman, Shawn M; Long, Mackenzie E; Dyke, Jeremy S; Jelesijevic, Tomislav P; Michel, Frank; Lafontaine, Eric R; Hogan, Robert J

2018-03-01

Burkholderia mallei causes the highly contagious and debilitating zoonosis glanders, which infects via inhalation or percutaneous inoculation and often culminates in life-threatening pneumonia and sepsis. In humans, glanders is difficult to diagnose and requires prolonged antibiotic therapy with low success rates. No vaccine exists to protect against B. mallei, and there is concern regarding its use as a bioweapon. The authors previously identified the protein BpaB as a potential target for devising therapies due to its role in adherence to host cells and the formation of biofilms in vitro and its contribution to pathogenicity in a mouse model of glanders. In the present study, the authors developed an immunostaining approach to probe tissues of experimentally infected animals and demonstrated that BpaB is produced exclusively in vivo by wild-type B. mallei in target organs from mice and marmosets. They detected the expression of BpaB by B. mallei both extracellularly and within macrophages, neutrophils, and epithelial cells in respiratory tissues (7/10 marmoset; 2/2 mouse). The authors also noted the intracellular expression of BpaB by B. mallei in macrophages in the regional lymph nodes of mice (2/2 tissues) and MALT of marmosets (4/5 tissues). It is interesting that B. mallei bacteria infecting distal organs did not express BpaB (2/2 mice; 3/3 marmosets), suggesting that the protein is not necessary for bacterial fitness in these anatomic locations. These findings underscore the value of BpaB as a target for developing medical countermeasures and provide insight into its role in pathogenesis.

Age-specific absolute and relative organ weight distributions for B6C3F1 mice.

PubMed

Marino, Dale J

2012-01-01

The B6C3F1 mouse is the standard mouse strain used in toxicology studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). While numerous reports have been published on growth, survival, and tumor incidence, no overall compilation of organ weight data is available. Importantly, organ weight change is an endpoint used by regulatory agencies to develop toxicity reference values (TRVs) for use in human health risk assessments. Furthermore, physiologically based pharmacokinetic (PBPK) models, which utilize relative organ weights, are increasingly being used to develop TRVs. Therefore, all available absolute and relative organ weight data for untreated control B6C3F1 mice were collected from NCI/NTP studies in order to develop age-specific distributions. Results show that organ weights were collected more frequently in NCI/NTP studies at 2-wk (60 studies), 3-mo (147 studies), and 15-mo (40 studies) intervals than at other intervals, and more frequently from feeding and inhalation than drinking water studies. Liver, right kidney, lung, heart, thymus, and brain weights were most frequently collected. From the collected data, the mean and standard deviation for absolute and relative organ weights were calculated. Results show age-related increases in absolute liver, right kidney, lung, and heart weights and relatively stable brain and right testis weights. The results suggest a general variability trend in absolute organ weights of brain < right testis < right kidney < heart < liver < lung < spleen < thymus. This report describes the results of this effort.

In vivo epigenetic effects induced by engineered nanomaterials: A case study of copper oxide and laser printer-emitted engineered nanoparticles

PubMed Central

Lu, Xiaoyan; Miousse, Isabelle R.; Pirela, Sandra V.; Moore, Jodene K.; Melnyk, Stepan; Koturbash, Igor; Demokritou, Philip

2016-01-01

Evidence continues to grow on potential environmental health hazards associated with engineered nanomaterials (ENMs). While the geno- and cytotoxic effects of ENMs have been investigated, their potential to target the epigenome remains largely unknown. The aim of this study is twofold: 1) determining whether or not industry relevant ENMs can affect the epigenome in vivo; and 2) validating a recently developed in vitro epigenetic screening platform for inhaled ENMs. Laser printer-emitted engineered nanoparticles (PEPs) released from nano-enabled toners during consumer use and copper oxide (CuO) were chosen since these particles induced significant epigenetic changes in a recent in vitro companion study. In this study, the epigenetic alterations in lung tissue, alveolar macrophages, and peripheral blood from intratracheally instilled mice were evaluated. The methylation of global DNA and transposable elements (TEs), the expression of the DNA methylation machinery and TEs, in addition to general toxicological effects in the lung were assessed. CuO exhibited higher cell-damaging potential to the lung, while PEPs showed a greater ability to target the epigenome. Alterations in the methylation status of global DNA and TEs, and expression of TEs and DNA machinery in mouse lung were observed after exposure to CuO and PEPs. Additionally, epigenetic changes were detected in the peripheral blood after PEPs exposure. Altogether, CuO and PEPs can induce epigenetic alterations in a mouse experimental model, which in turn confirms that the recently developed in vitro epigenetic platform using macrophage and epithelial cell lines can be successfully utilized in the epigenetic screening of ENMs. PMID:26559097

Reducing the cytotoxicity of inhalable engineered nanoparticles via in situ passivation with biocompatible materials.

PubMed

Byeon, Jeong Hoon; Park, Jae Hong; Peters, Thomas M; Roberts, Jeffrey T

2015-07-15

The cytotoxicity of model welding nanoparticles was modulated through in situ passivation with soluble biocompatible materials. A passivation process consisting of a spark discharge particle generator coupled to a collison atomizer as a co-flow or counter-flow configuration was used to incorporate the model nanoparticles with chitosan. The tested model welding nanoparticles are inhaled and that A549 cells are a human lung epithelial cell line. Measurements of in vitro cytotoxicity in A549 cells revealed that the passivated nanoparticles had a lower cytotoxicity (>65% in average cell viability, counter-flow) than the untreated model nanoparticles. Moreover, the co-flow incorporation between the nanoparticles and chitosan induced passivation of the nanoparticles, and the average cell viability increased by >80% compared to the model welding nanoparticles. As a more convenient way (additional chitosan generation and incorporation devices may not be required), other passivation strategies through a modification of the welding rod with chitosan adhesive and graphite paste did also enhance average cell viability (>58%). The approach outlined in this work is potentially generalizable as a new platform, using only biocompatible materials in situ, to treat nanoparticles before they are inhaled. Copyright © 2015 Elsevier B.V. All rights reserved.

In Silico Models of Aerosol Delivery to the Respiratory Tract – Development and Applications

PubMed Central

Longest, P. Worth; Holbrook, Landon T.

2011-01-01

This review discusses the application of computational models to simulate the transport and deposition of inhaled pharmaceutical aerosols from the site of particle or droplet formation to deposition within the respiratory tract. Traditional one-dimensional (1-D) whole-lung models are discussed briefly followed by a more in-depth review of three-dimensional (3-D) computational fluid dynamics (CFD) simulations. The review of CFD models is organized into sections covering transport and deposition within the inhaler device, the extrathoracic (oral and nasal) region, conducting airways, and alveolar space. For each section, a general review of significant contributions and advancements in the area of simulating pharmaceutical aerosols is provided followed by a more in-depth application or case study that highlights the challenges, utility, and benefits of in silico models. Specific applications presented include the optimization of an existing spray inhaler, development of charge-targeted delivery, specification of conditions for optimal nasal delivery, analysis of a new condensational delivery approach, and an evaluation of targeted delivery using magnetic aerosols. The review concludes with recommendations on the need for more refined model validations, use of a concurrent experimental and CFD approach for developing aerosol delivery systems, and development of a stochastic individual path (SIP) model of aerosol transport and deposition throughout the respiratory tract. PMID:21640772

The Relationship Between the Permeability and the Performance of Carrier-Based Dry Powder Inhalation Mixtures: New Insights and Practical Guidance.

PubMed

Shalash, Ahmed O; Khalafallah, Nawal M; Molokhia, Abdulla M; Elsayed, Mustafa M A

2018-02-01

The permeability of a powder bed reflects its particle size distribution, shape, packing, porosity, cohesivity, and tensile strength in a manner relevant to powder fluidization. The relationship between the permeability and the performance of carrier-based dry powder inhalation (DPI) mixtures has, however, aroused controversy. The current study sought to gain new insights into the relationship and to explore its potential applications. We studied eight lactose materials as DPI carriers. The carriers covered a broad permeability range of 0.42-13.53 D and moreover differed in particle size distribution, particle shape, crystal form, and/or porosity. We evaluated the performance of inhalation mixtures of each of these carriers and fluticasone propionate after aerosolization from an Aerolizer®, a model turbulent-shear inhaler, at a flow rate of 60 L/min. Starting from the high permeability side, the inhalation mixture performance increased as the carrier permeability decreased until optimum performance was reached at permeability of ~ 3.2 D. Increased resistance to air flow strengthens aerodynamic dispersion forces. The inhalation mixture performance then decreased as the carrier permeability further decreased. Very high resistance to air flow restricts powder dispersion. The permeability accounted for effects of carrier size, shape, and macroporosity on the performance. We confirmed the relationship by analysis of two literature permeability-performance datasets, representing measurements that differ from ours in terms of carrier grades, drug, technique used to determine permeability, turbulent-shear inhaler, and/or aerosolization flow rate. Permeability provides useful information that can aid development of DPI mixtures for turbulent-shear inhalers. A practical guidance is provided.

Analysis of intervention strategies for inhalation exposure to polycyclic aromatic hydrocarbons and associated lung cancer risk based on a Monte Carlo population exposure assessment model.

PubMed

Zhou, Bin; Zhao, Bin

2014-01-01

It is difficult to evaluate and compare interventions for reducing exposure to air pollutants, including polycyclic aromatic hydrocarbons (PAHs), a widely found air pollutant in both indoor and outdoor air. This study presents the first application of the Monte Carlo population exposure assessment model to quantify the effects of different intervention strategies on inhalation exposure to PAHs and the associated lung cancer risk. The method was applied to the population in Beijing, China, in the year 2006. Several intervention strategies were designed and studied, including atmospheric cleaning, smoking prohibition indoors, use of clean fuel for cooking, enhancing ventilation while cooking and use of indoor cleaners. Their performances were quantified by population attributable fraction (PAF) and potential impact fraction (PIF) of lung cancer risk, and the changes in indoor PAH concentrations and annual inhalation doses were also calculated and compared. The results showed that atmospheric cleaning and use of indoor cleaners were the two most effective interventions. The sensitivity analysis showed that several input parameters had major influence on the modeled PAH inhalation exposure and the rankings of different interventions. The ranking was reasonably robust for the remaining majority of parameters. The method itself can be extended to other pollutants and in different places. It enables the quantitative comparison of different intervention strategies and would benefit intervention design and relevant policy making.

Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

PubMed

Prah, James; Ashley, David; Blount, Benjamin; Case, Martin; Leavens, Teresa; Pleil, Joachim; Cardinali, Frederick

2004-02-01

Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.

Sevoflurane anesthesia during acute right ventricular ischemia in pigs preserves cardiac function better than propofol anesthesia.

PubMed

Haraldsen, Pernille; Metzsch, Carsten; Lindstedt, Sandra; Algotsson, Lars; Ingemansson, Richard

2016-09-01

The intention of the present study was to evaluate possible cardioprotective properties of inhalation anesthesia with sevoflurane. A porcine, open-chest model of right ventricular ischemia was used in 7 pigs receiving inhalation anesthesia with sevoflurane. The model was earlier developed and published by our group, using pigs receiving intravenous anesthesia with propofol. They served as controls. The animals were observed for three hours after the induction of right ventricular ischemia by ligation of the main branches supplying the right ventricular free wall. In the sevoflurane group, the cardiac output recovered 2 hours after the induction of ischemia and intact right ventricular stroke work was observed. In the propofol group, no such recovery occurred. The release of troponin T was significantly lower than in the sevoflurane group. Inhalation anesthesia with sevoflurane seems superior to intravenous anesthesia with propofol in acute right ventricular ischemic dysfunction. © The Author(s) 2016.

Sugar administration is an effective adjunctive therapy in the treatment of Pseudomonas aeruginosa pneumonia

PubMed Central

Bucior, Iwona; Abbott, Jason; Song, Yuanlin; Matthay, Michael A.

2013-01-01

Treatment of acute and chronic pulmonary infections caused by opportunistic pathogen Pseudomonas aeruginosa is limited by the increasing frequency of multidrug bacterial resistance. Here, we describe a novel adjunctive therapy in which administration of a mix of simple sugars—mannose, fucose, and galactose—inhibits bacterial attachment, limits lung damage, and potentiates conventional antibiotic therapy. The sugar mixture inhibits adhesion of nonmucoid and mucoid P. aeruginosa strains to bronchial epithelial cells in vitro. In a murine model of acute pneumonia, treatment with the sugar mixture alone diminishes lung damage, bacterial dissemination to the subpleural alveoli, and neutrophil- and IL-8-driven inflammatory responses. Remarkably, the sugars act synergistically with anti-Pseudomonas antibiotics, including β-lactams and quinolones, to further reduce bacterial lung colonization and damage. To probe the mechanism, we examined the effects of sugars in the presence or absence of antibiotics during growth in liquid culture and in an ex vivo infection model utilizing freshly dissected mouse tracheas and lungs. We demonstrate that the sugar mixture induces rapid but reversible formation of bacterial clusters that exhibited enhanced susceptibility to antibiotics compared with individual bacteria. Our findings reveal that sugar inhalation, an inexpensive and safe therapeutic, could be used in combination with conventional antibiotic therapy to more effectively treat P. aeruginosa lung infections. PMID:23792737

Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

PubMed

Begley, Dale A; Sundberg, John P; Krupke, Debra M; Neuhauser, Steven B; Bult, Carol J; Eppig, Janan T; Morse, Herbert C; Ward, Jerrold M

2015-12-01

Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. Copyright © 2015 Elsevier Inc. All rights reserved.

Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

PubMed

Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

2015-07-15

Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Disposition of Cannabichromene, Cannabidiol, and Δ9-Tetrahydrocannabinol and its Metabolites in Mouse Brain following Marijuana Inhalation Determined by High-Performance Liquid Chromatography–Tandem Mass Spectrometry

PubMed Central

Poklis, Justin L.; Thompson, Candace C.; Long, Kelly A.; Lichtman, Aron H.; Poklis, Alphonse

2011-01-01

A liquid chromatography–tandem mass spectrometry (LC–MS–MS) method was developed for the analysis of marijuana cannabinoids in mouse brain tissue using an Applied Biosystems 3200 Q trap with a turbo V source for TurbolonSpray attached to a Shimadzu SCL HPLC system. The method included cannabichromene (CBC), cannabidiol (CBD), D9-tetrahydrocannabinol (THC), 11-hydroxytetrahydrocannabinol (11-OH-THC), and 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). These compounds were isolated by liquid-liquid extraction using cold acetonitrile. The following transition ions were monitored by multiple reaction monitoring (MRM): m/z 315>193, 315>259 for THC/CBD/CBC; m/z 331>193, 331>105 for 11-OH-THC; m/z 345>299, 345>193 for THC-COOH;c m/z 318>196 for THC-d3; m/z 334>196 for 11-OH-THC-d3, and m/z 348>302 for THCCOOH-d3. Linearity for THC, 1-OH-THC, and THC-COOH was 1-200 ng/g; for CBC and CBD, it was 0.5–20 ng/g. Within-run and between-run precisions for all the analytes yielded coefficients of variation of < 20%. Four C57BL6 mice were sacrificed 20 min after nose-only exposure to the smoke of 200 mg of marijuana containing 0.44 mg CBC, 0.93 mg CBD, and 8.81 mg THC. The mean brain concentrations were 3.9 ± 1.5 ng/g CBC, 21 ± 3.9 ng/g CBD, 364 ± 74 ng/g THC, and 28 ± 5.9 ng/g 11-OH-THC. THCCOOH was not detected. The relative mean brain cannabinoid concentrations correlated to the amounts of the cannabinoids in the inhaled marijuana. PMID:21258613

Circulating factors induce coronary endothelial ceIl activation foIlowing exposure to inhaled diesel exhaust and nitrogen dioxide in humans :Evidence from a novel translational in vitro model

EPA Science Inventory

The vascular toxicity of inhaled agents may be caused by soluble factors that are released into the systemic circulation. To confirm this in a straightforward manner, we obtained plasma from healthy human volunteers before and after exposure to diesel exhaust (DE) and nitrogen di...

Cyanide Antidotes for Mass Casualties: Comparison of Intramuscular Injector by Autoinjector, Intraosseous Injection, and Inhalational Delivery

DTIC Science & Technology

2013-10-01

silicon-based ultrasonic nozzle to produce high- throughput of monodisperse cobinamide antidote solution for detoxification of CN poisoning in a rabbit...model. Keywords- cyanide poisoning and detoxification, cobinamide antidote, Fourier-horn ultrasonic nozzles , monodisperse aerosol inhaler I...distributions. In contrast, the MHz multiple-Fourier horn ultrasonic nozzle reported recently [8-10] has demonstrated its capability of producing high

Modeling Inhalational Tularemia: Deliberate Release and Public Health Response

PubMed Central

Hall, Ian M.; Leach, Steve

2011-01-01

Two epidemic modeling studies of inhalational tularemia were identified in the published literature, both demonstrating the high number of potential casualties that could result from a deliberate aerosolized release of the causative agent in an urban setting. However, neither study analyzed the natural history of inhalational tularemia nor modeled the relative merits of different mitigation strategies. We first analyzed publicly available human/primate experimental data and reports of naturally acquired inhalational tularemia cases to better understand the epidemiology of the disease. We then simulated an aerosolized release of the causative agent, using airborne dispersion modeling to demonstrate the potential number of casualties and the extent of their spatial distribution. Finally, we developed a public health intervention model that compares 2 mitigation strategies: targeting antibiotics at symptomatic individuals with or without mass distribution of antibiotics to potentially infected individuals. An antibiotic stockpile that is sufficient to capture all areas where symptomatic individuals were infected is likely to save more lives than treating symptomatic individuals alone, providing antibiotics can be distributed rapidly and their uptake is high. However, with smaller stockpiles, a strategy of treating symptomatic individuals alone is likely to save many more lives than additional mass distribution of antibiotics to potentially infected individuals. The spatial distribution of symptomatic individuals is unlikely to coincide exactly with the path of the dispersion cloud if such individuals are infected near their work locations but then seek treatment close to their homes. The optimal mitigation strategy will depend critically on the size of the release relative to the stockpile level and the effectiveness of treatment relative to the speed at which antibiotics can be distributed. PMID:22044315

Hygroscopic aerosol deposition in the human upper respiratory tract under various thermo-humidity conditions.

PubMed

Xi, Jinxiang; Kim, Jongwon; Si, Xiuhua A; Zhou, Yue

2013-01-01

The deposition of hygroscopic aerosols is highly complex in nature, which results from a cumulative effect of dynamic particle growth and the real-time size-specific deposition mechanisms. The objective of this study is to evaluate hygroscopic effects on the particle growth, transport, and deposition of nasally inhaled aerosols across a range of 0.2-2.5 μm in an adult image-based nose-throat model. Temperature and relative humidity fields were simulated using the LRN k-ω turbulence model and species transport model under a spectrum of thermo-humidity conditions. Particle growth and transport were simulated using a well validated Lagrangian tracking model coupled with a user-defined hygroscopic growth module. Results of this study indicate that the saturation level and initial particle size are the two major factors that determine the particle growth rate (d/d0), while the effect of inhalation flow rate is found to be not significant. An empirical correlation of condensation growth of nasally inhaled hygroscopic aerosols in adults has been developed based on a variety of thermo-humidity inhalation conditions. Significant elevated nasal depositions of hygroscopic aerosols could be induced by condensation growth for both sub-micrometer and small micrometer particulates. In particular, the deposition of initially 2.5 μm hygroscopic aerosols was observed to be 5-8 times that of inert particles under warm to hot saturated conditions. Results of this study have important implications in exposure assessment in hot humid environments, where much higher risks may be expected compared to normal conditions.

Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails.

PubMed

Wlaź, Piotr; Knaga, Sebastian; Kasperek, Kornel; Wlaź, Aleksandra; Poleszak, Ewa; Jeżewska-Witkowska, Grażyna; Winiarczyk, Stanisław; Wyska, Elżbieta; Heinekamp, Thorsten; Rundfeldt, Chris

2015-08-01

Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 × 10(6) spores (3 groups) or 5 × 10(7) spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis.

Neither xenon nor fentanyl induces neuroapoptosis in the newborn pig brain.

PubMed

Sabir, Hemmen; Bishop, Sarah; Cohen, Nicki; Maes, Elke; Liu, Xun; Dingley, John; Thoresen, Marianne

2013-08-01

Some inhalation anesthetics increase apoptotic cell death in the developing brain. Xenon, an inhalation anesthetic, increases neuroprotection when combined with therapeutic hypothermia after hypoxic-ischemic brain injury in newborn animals. The authors, therefore, examined whether there was any neuroapoptotic effect of breathing 50% xenon with continuous fentanyl sedation for 24 h at normothermia or hypothermia on newborn pigs. Twenty-six healthy pigs (<24-h old) were randomized into four groups: (1) 24  h of 50% inhaled xenon with fentanyl at hypothermia (Trec = 33.5 °C), (2) 24 h of 50% inhaled xenon with fentanyl at normothermia (Trec = 38.5 °C), (3) 24 h of fentanyl at normothermia, or (4) nonventilated juvenile controls at normothermia. Five additional nonrandomized pigs inhaled 2% isoflurane at normothermia for 24 h to verify any proapoptotic effect of inhalation anesthetics in our model. Pathological cells were morphologically assessed in cortex, putamen, hippocampus, thalamus, and white matter. To quantify the findings, immunostained cells (caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling) were counted in the same brain regions. For groups (1) to (4), the total number of apoptotic cells was less than 5 per brain region, representing normal developmental neuroapoptosis. After immunostaining and cell counting, regression analysis showed that neither 50% xenon with fentanyl nor fentanyl alone increased neuroapoptosis. Isoflurane caused on average a 5- to 10-fold increase of immunostained cells. At normothermia or hypothermia, neither 24 h of inhaled 50% xenon with fentanyl sedation nor fentanyl alone induces neuroapoptosis in the neonatal pig brain. Breathing 2% isoflurane increases neuroapoptosis in neonatal pigs.

Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis.

PubMed

Sobieraj, Diana M; Baker, William L; Nguyen, Elaine; Weeda, Erin R; Coleman, Craig I; White, C Michael; Lazarus, Stephen C; Blake, Kathryn V; Lang, Jason E

2018-04-10

Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma. To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting β-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma. MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017). Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest. Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers. Asthma exacerbations. Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]). In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.

Details of regional particle deposition and airflow structures in a realistic model of human tracheobronchial airways: two-phase flow simulation.

PubMed

Rahimi-Gorji, Mohammad; Gorji, Tahereh B; Gorji-Bandpy, Mofid

2016-07-01

In the present investigation, detailed two-phase flow modeling of airflow, transport and deposition of micro-particles (1-10µm) in a realistic tracheobronchial airway geometry based on CT scan images under various breathing conditions (i.e. 10-60l/min) was considered. Lagrangian particle tracking has been used to investigate the particle deposition patterns in a model comprising mouth up to generation G6 of tracheobronchial airways. The results demonstrated that during all breathing patterns, the maximum velocity change occurred in the narrow throat region (Larynx). Due to implementing a realistic geometry for simulations, many irregularities and bending deflections exist in the airways model. Thereby, at higher inhalation rates, these areas are prone to vortical effects which tend to entrap the inhaled particles. According to the results, deposition fraction has a direct relationship with particle aerodynamic diameter (for dp=1-10µm). Enhancing inhalation flow rate and particle size will largely increase the inertial force and consequently, more particle deposition is evident suggesting that inertial impaction is the dominant deposition mechanism in tracheobronchial airways. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparisons of calculated respiratory tract deposition of particles based on the NCRP/ITRI model and the new ICRP66 model

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

Yeh, Hsu-Chi; Phalen, R.F.; Chang, I.

1995-12-01

The National Council on Radiation Protection and Measurements (NCRP) in the United States and the International Commission on Radiological Protection (ICRP) have been independently reviewing and revising respiratory tract dosimetry models for inhaled radioactive aerosols. The newly proposed NCRP respiratory tract dosimetry model represents a significant change in philosophy from the old ICRP Task Group model. The proposed NCRP model describes respiratory tract deposition, clearance, and dosimetry for radioactive substances inhaled by workers and the general public and is expected to be published soon. In support of the NCRP proposed model, ITRI staff members have been developing computer software. Althoughmore » this software is still incomplete, the deposition portion has been completed and can be used to calculate inhaled particle deposition within the respiratory tract for particle sizes as small as radon and radon progeny ({approximately} 1 nm) to particles larger than 100 {mu}m. Recently, ICRP published their new dosimetric model for the respiratory tract, ICRP66. Based on ICRP66, the National Radiological Protection Board of the UK developed PC-based software, LUDEP, for calculating particle deposition and internal doses. The purpose of this report is to compare the calculated respiratory tract deposition of particles using the NCRP/ITRI model and the ICRP66 model, under the same particle size distribution and breathing conditions. In summary, the general trends of the deposition curves for the two models were similar.« less

System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

NASA Technical Reports Server (NTRS)

1979-01-01

The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

Investigation of electrostatic behavior of a lactose carrier for dry powder inhalers.

PubMed

Chow, Keat Theng; Zhu, Kewu; Tan, Reginald B H; Heng, Paul W S

2008-12-01

This study aims to elucidate the electrostatic behavior of a model lactose carrier used in dry powder inhaler formulations by examining the effects of ambient relative humidity (RH), aerosolization air flow rate, repeated inhaler use, gelatin capsule and tapping on the specific charge (nC/g) of bulk and aerosolized lactose. Static and dynamic electrostatic charge measurements were performed using a Faraday cage connected to an electrometer. Experiments were conducted inside a walk-in environmental chamber at 25 degrees C and RHs of 20% to 80%. Aerosolization was achieved using air flow rates of 30, 45, 60 and 75 L/min. The initial charges of the bulk and capsulated lactose were a magnitude lower than the charges of tapped or aerosolized lactose. Dynamic charge increased linearly with aerosolization air flow rate and RH. Greater frictional forces at higher air flow rate induced higher electrostatic charges. Increased RH enhanced charge generation. Repeated inhaler use significantly influenced electrostatic charge due to repeated usage. This study demonstrated the significance of interacting influences by variables commonly encountered in the use DPI such as variation in patient's inspiratory flow rate, ambient RH and repeated inhaler use on the electrostatic behavior of a lactose DPI carrier.

Estimating Supplies Program: Evaluation Report

DTIC Science & Technology

2002-12-24

Inhalation, Non-vaccinated1, Incubating, Asymptomatic 352 Anthrax, Inhalation, Non-vaccinated, Prodromal 353 Anthrax, Inhalation, Non-vaccinated, Acute...B-11 PC Code PC Description 354 Anthrax, Inhalation, Vaccinated, Asymptomatic 355 Anthrax, Inhalation, Vaccinated, Prodromal 356...Anthrax, Inhalation, Vaccinated, Acute 357 Plague, Inhalation, Incubating, Asymptomatic 358 Plague, Inhalation, Acute 359 Plague Meningitis 360

Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

PubMed

Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

2015-02-01

During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

Analysis of Intervention Strategies for Inhalation Exposure to Polycyclic Aromatic Hydrocarbons and Associated Lung Cancer Risk Based on a Monte Carlo Population Exposure Assessment Model

PubMed Central

Zhou, Bin; Zhao, Bin

2014-01-01

It is difficult to evaluate and compare interventions for reducing exposure to air pollutants, including polycyclic aromatic hydrocarbons (PAHs), a widely found air pollutant in both indoor and outdoor air. This study presents the first application of the Monte Carlo population exposure assessment model to quantify the effects of different intervention strategies on inhalation exposure to PAHs and the associated lung cancer risk. The method was applied to the population in Beijing, China, in the year 2006. Several intervention strategies were designed and studied, including atmospheric cleaning, smoking prohibition indoors, use of clean fuel for cooking, enhancing ventilation while cooking and use of indoor cleaners. Their performances were quantified by population attributable fraction (PAF) and potential impact fraction (PIF) of lung cancer risk, and the changes in indoor PAH concentrations and annual inhalation doses were also calculated and compared. The results showed that atmospheric cleaning and use of indoor cleaners were the two most effective interventions. The sensitivity analysis showed that several input parameters had major influence on the modeled PAH inhalation exposure and the rankings of different interventions. The ranking was reasonably robust for the remaining majority of parameters. The method itself can be extended to other pollutants and in different places. It enables the quantitative comparison of different intervention strategies and would benefit intervention design and relevant policy making. PMID:24416436

Dose-dependent transitions in Nrf2-mediated adaptive response and related stress responses to hypochlorous acid in mouse macrophages

PubMed Central

Woods, Courtney G.; Fu, Jingqi; Xue, Peng; Hou, Yongyong; Pluta, Linda J.; Yang, Longlong; Zhang, Qiang; Thomas, Russell S.; Andersen, Melvin E.; Pi, Jingbo

2009-01-01

Hypochlorous acid (HOCl) is potentially an important source of cellular oxidative stress. Human HOCl exposure can occur from chlorine gas inhalation or from endogenous sources of HOCl, such as respiratory burst by phagocytes. Transcription factor Nrf2 is a key regulator of cellular redox status and serves as a primary source of defense against oxidative stress. We recently demonstrated that HOCl activates Nrf2-mediated antioxidant response in cultured mouse macrophages in a biphasic manner. In an effort to determine whether Nrf2 pathways overlap with other stress pathways, gene expression profiling was performed in RAW 264.7 macrophages exposed to HOCl using whole genome mouse microarrays. Benchmark dose (BMD) analysis on gene expression data revealed that Nrf2-mediated antioxidant response and protein ubiquitination were the most sensitive biological pathways that were activated in response to low concentrations of HOCl (< 0.35 mM). Genes involved in chromatin architecture maintenance and DNA-dependent transcription were also sensitive to very low doses. Moderate concentrations of HOCl (0.35 to 1.4 mM) caused maximal activation of the Nrf2-pathway and innate immune response genes, such as IL-1β, IL-6, IL-10 and chemokines. At even higher concentrations of HOCl (2.8 to 3.5 mM) there was a loss of Nrf2-target gene expression with increased expression of numerous heat shock and histone cluster genes, AP-1-family genes, cFos and Fra1 and DNA damage-inducible Gadd45 genes. These findings confirm an Nrf2-centric mechanism of action of HOCl in mouse macrophages and provide evidence of interactions between Nrf2, inflammatory, and other stress pathways. PMID:19376150

The effects of fenoterol inhalation after acid aspiration-induced lung injury.

PubMed

Pawlik, Michael T; Schubert, Thomas; Hopf, Susanne; Lubnow, Matthias; Gruber, Michael; Selig, Christoph; Taeger, Kai; Ittner, Karl P

2009-07-01

Acid aspiration is a serious complication that can occur during general anesthesia. Studies show that beta-agonists have beneficial effects on lung injury. Therefore, we tested the effect of the nebulized beta-agonist fenoterol on lung variables in a rodent model of acid-induced lung injury. In a prospective, randomized, and controlled study, we evaluated the effects of fenoterol inhalation on lung oxygenation, inflammation, and pulmonary histology in a rat model of acid-induced lung injury. Sprague-Dawley rats underwent sevoflurane anesthesia with tracheotomy and carotid catheter insertion. Lung injury was induced by instillation of 0.4 mL/kg 0.1 M hydrochloric acid. The lungs were ventilated for 6 h and randomized to receive either fenoterol inhalation 10 microg or saline inhalation, both at 15 and 180 min after acid aspiration. Mean arterial blood pressures and peak airway pressures were documented, arterial blood gases were determined at 30, 90, 180, 270, and 360 min, and postmortem histology was subsequently examined. Additionally, fenoterol concentrations in bronchoalveolar lavage fluid (BALF) and plasma were determined by liquid chromatography/tandem mass spectroscopy. After 360 min tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined in the BALF, and lungs were dried for determination of the wet/dry ratio. Inhalation treatment with 10 microg fenoterol significantly increased oxygenation after 270 and 360 min when compared with placebo. Fenoterol-treated rats showed a significant decrease in IL-6 and TNF-alpha levels and in the wet/dry weight ratio of the lungs. The histologic appearance showed significantly less interstitial edema and leukocyte infiltration in the fenoterol group. The concentration of fenoterol was 10.3 microg/L (median) in the BALF and <1 microg/L in the plasma. Fenoterol inhalation improved oxygenation after 270 and 360 min, attenuated the release of TNF-alpha and IL-6, and diminished the lung edema and infiltration of polymorphonuclear leukocytes.

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

PubMed

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Inhalation of diesel exhaust does not exacerbate cardiac hypertrophy or heart failure in two mouse models of cardiac hypertrophy

PubMed Central

2013-01-01

Background Strong associations have been observed between exposure to fine ambient particulate matter (PM2.5) and adverse cardiovascular outcomes. In particular, exposure to traffic related PM2.5 has been associated with increases in left ventricular hypertrophy, a strong risk factor for cardiovascular mortality. As much of traffic related PM2.5 is derived from diesel exhaust (DE), we investigated the effects of chronic DE exposure on cardiac hypertrophy and heart failure in the adult mouse by exposing mice to DE combined with either of two mouse models of cardiac hypertrophy: angiotensin II infusion or pressure overload induced by transverse aortic banding. Methods Wild type male C57BL/6 J mice were either infused with angiotensin II (800 ng/kg/min) via osmotic minipump implanted subcutaneously for 1 month, or underwent transverse aortic banding (27 gauge needle 1 week for observing acute reactions, 26 gauge needle 3 months or 6 months for observing chronic reactions). Vehicle (saline) infusion or sham surgery was used as a control. Shortly after surgery, mice were transferred to our exposure facility and randomly assigned to either diesel exhaust (300 or 400 μg/m3) or filtered air exposures. After reaching the end of designated time points, echocardiography was performed to measure heart structure and function. Gravimetric analysis was used to measure the ventricular weight to body weight ratio. We also measured heart rate by telemetry using implanted ambulatory ECG monitors. Results Both angiotensin II and transverse aortic banding promoted cardiac hypertrophy compared to vehicle or sham controls. Transverse aortic banding for six months also promoted heart failure in addition to cardiac hypertrophy. In all cases, DE failed to exacerbate the development of hypertrophy or heart failure when compared to filtered air controls. Prolonged DE exposure also led to a decrease in average heart rate. Conclusions Up to 6-months of DE exposure had no effect on cardiac hypertrophy and heart function induced by angiotensin II stimulation or pressure overload in adult C57BL/6 J mice. This study highlights the potential importance of particle constituents of ambient PM2.5 to elicit cardiotoxic effects. Further investigations on particle constituents and cardiotoxicity are warranted. PMID:24093778

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

Dimensionality of Hallucinogen and Inhalant/Solvent Abuse and Dependence Criteria: Implications for the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition

PubMed Central

Kerridge, Bradley T.; Saha, Tulshi D.; Smith, Sharon; Chou, Patricia S.; Pickering, Roger P.; Huang, Boji; Ruan, June W.; Pulay, Attila J.

2012-01-01

Background Prior research has demonstrated the dimensionality of Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria. The purpose of this study was to examine the dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria. In addition, we assessed the impact of elimination of the legal problems abuse criterion on the information value of the aggregate abuse and dependence criteria, another proposed change for DSM- IV currently lacking empirical justification. Methods Factor analyses and item response theory (IRT) analyses were used to explore the unidimisionality and psychometric properties of hallucinogen and inhalant/solvent abuse and dependence criteria using a large representative sample of the United States (U.S.) general population. Results Hallucinogen and inhalant/solvent abuse and dependence criteria formed unidimensional latent traits. For both substances, IRT models without the legal problems abuse criterion demonstrated better fit than the corresponding model with the legal problem abuse criterion. Further, there were no differences in the information value of the IRT models with and without the legal problems abuse criterion, supporting the elimination of that criterion. No bias in the new diagnoses was observed by sex, age and race-ethnicity. Conclusion Consistent with findings for alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria, hallucinogen and inhalant/solvent criteria reflect underlying dimensions of severity. The legal problems criterion associated with each of these substance use disorders can be eliminated with no loss in informational value and an advantage of parsimony. Taken together, these findings support the changes to substance use disorder diagnoses recommended by the DSM-V Substance and Related Disorders Workgroup, that is, combining DSM-IV abuse and dependence criteria and eliminating the legal problems abuse criterion. PMID:21621334

Dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria: implications for the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition.

PubMed

Kerridge, Bradley T; Saha, Tulshi D; Smith, Sharon; Chou, Patricia S; Pickering, Roger P; Huang, Boji; Ruan, June W; Pulay, Attila J

2011-09-01

Prior research has demonstrated the dimensionality of Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria. The purpose of this study was to examine the dimensionality of hallucinogen and inhalant/solvent abuse and dependence criteria. In addition, we assessed the impact of elimination of the legal problems abuse criterion on the information value of the aggregate abuse and dependence criteria, another proposed change for DSM-IV currently lacking empirical justification. Factor analyses and item response theory (IRT) analyses were used to explore the unidimisionality and psychometric properties of hallucinogen and inhalant/solvent abuse and dependence criteria using a large representative sample of the United States (U.S.) general population. Hallucinogen and inhalant/solvent abuse and dependence criteria formed unidimensional latent traits. For both substances, IRT models without the legal problems abuse criterion demonstrated better fit than the corresponding model with the legal problem abuse criterion. Further, there were no differences in the information value of the IRT models with and without the legal problems abuse criterion, supporting the elimination of that criterion. No bias in the new diagnoses was observed by sex, age and race-ethnicity. Consistent with findings for alcohol, nicotine, cannabis, cocaine and amphetamine abuse and dependence criteria, hallucinogen and inhalant/solvent criteria reflect underlying dimensions of severity. The legal problems criterion associated with each of these substance use disorders can be eliminated with no loss in informational value and an advantage of parsimony. Taken together, these findings support the changes to substance use disorder diagnoses recommended by the DSM-V Substance and Related Disorders Workgroup, that is, combining DSM-IV abuse and dependence criteria and eliminating the legal problems abuse criterion. Published by Elsevier Ltd.

Effects of 7.5% Carbon Dioxide Inhalation on Anxiety and Mood in Cigarette Smokers

PubMed Central

Attwood, Angela S.; Ataya, Alia F.; Bailey, Jayne E.; Lightman, Stafford L.; Munafò, Marcus R.

2016-01-01

Cigarette smoking is associated with elevated risk of anxiety and mood disorder. Using the 7.5% carbon dioxide (CO2) inhalation model of anxiety induction, we examined the effects of smoking status and abstinence from smoking on anxiety responses. Physiological and subjective responses to CO2 and medical air were compared in smokers and non-smokers (Experiment One) and in overnight abstinent and non-abstinent smokers (Experiment Two). CO2 induced greater increases in blood pressure in non-smokers compared with smokers (ps < 0.043), and greater increases in anxiety (p = 0.005) and negative affect (p = 0.054) in non-abstinent compared with abstinent smokers. CO2 increased physiological and subjective indices of anxiety. There were differences across smoking groups indicating that the CO2 inhalation model is a useful tool for examining the relationship between smoking and anxiety. The findings suggested that both acute smoking and acute abstinence may protect against anxious responding. Further investigation is needed in long-term heavy smokers. PMID:24763184

Effects of 7.5% carbon dioxide inhalation on anxiety and mood in cigarette smokers.

PubMed

Attwood, Angela S; Ataya, Alia F; Bailey, Jayne E; Lightman, Stafford L; Munafò, Marcus R

2014-08-01

Cigarette smoking is associated with elevated risk of anxiety and mood disorder. Using the 7.5% carbon dioxide (CO2) inhalation model of anxiety induction, we examined the effects of smoking status and abstinence from smoking on anxiety responses. Physiological and subjective responses to CO2 and medical air were compared in smokers and non-smokers (Experiment One) and in overnight abstinent and non-abstinent smokers (Experiment Two). CO2 induced greater increases in blood pressure in non-smokers compared with smokers (ps < 0.043), and greater increases in anxiety (p = 0.005) and negative affect (p = 0.054) in non-abstinent compared with abstinent smokers. CO2 increased physiological and subjective indices of anxiety. There were differences across smoking groups indicating that the CO2 inhalation model is a useful tool for examining the relationship between smoking and anxiety. The findings suggested that both acute smoking and acute abstinence may protect against anxious responding. Further investigation is needed in long-term heavy smokers. © The Author(s) 2014.

PREFACE: Inhaled Particles X: 23-25 September 2008, Sheffield UK

NASA Astrophysics Data System (ADS)

Kenny, Lee; Hurley, Fintan

2009-07-01

Multi-disciplinary research is vital to the science of particle-mediated lung disease and a distinctive feature of the Inhaled Particles Conference series. Continuing this tradition, Inhaled Particles X brought together world-renowned and up-and-coming researchers from a wide range of specialist disciplines, but with a common interest and purpose: to understand better the nature of inhalable particles and their effects once inhaled, for the protection of workers' and public health. IPX was an integrative Conference, in three ways. First, as usual with Inhaled Particles, IPX welcomed the full range of disciplines and scientists concerned with protection of health from inhaled particles. This included engineers concerned with dust control; scientists characterising and modelling emissions; exposure measurement, in the field and in the laboratory; experts in particle deposition and clearance; toxicologists discovering mechanisms of damage; epidemiologists developing and applying methods to link exposure with risk; and those concerned with policy - with setting standards, with protection of individuals. Secondly, IPX was concerned with particles in the workplace, in outdoor air, and in the general indoor environment; and tried to find common threads and encourage cross-over of ideas between these three broad fields. And thirdly, IPX integrated experience and perspectives internationally, including issues such as silicosis and pneumoconiosis that are now unfashionable as research topics in the developed Western economies but still constitute a major public health risk internationally. Contributors to IPX were invited to submit extended abstracts for publication in these Proceedings; in addition, all authors were asked to prepare a short abstract. These short abstracts (including those attached to extended abstracts and papers) are collected and published together in this Conference Overview, to maintain the integrity of the Proceedings as a record of the Conference as a whole.

The inhalation characteristics of patients when they use different dry powder inhalers.

PubMed

Azouz, Wahida; Chetcuti, Philip; Hosker, Harold S R; Saralaya, Dinesh; Stephenson, John; Chrystyn, Henry

2015-02-01

The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their "real-life" DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (ΔP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. PIF, ΔP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, ΔP, and ACCEL (p<0.001). The results showed a large variability in inhalation characteristics and demonstrate the advantages of ΔP and ACCEL rather than PIFs. Overall inhaled volumes were low, and only one patient achieved an IV >4 L and ΔP >4 kPa. The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation.

Assessment of increased sampling pump flow rates in a disposable, inhalable aerosol sampler

PubMed Central

Stewart, Justin; Sleeth, Darrah K.; Handy, Rod G.; Pahler, Leon F.; Anthony, T. Renee; Volckens, John

2017-01-01

A newly designed, low-cost, disposable inhalable aerosol sampler was developed to assess workers personal exposure to inhalable particles. This sampler was originally designed to operate at 10 L/min to increase sample mass and, therefore, improve analytical detection limits for filter-based methods. Computational fluid dynamics modeling revealed that sampler performance (relative to aerosol inhalability criteria) would not differ substantially at sampler flows of 2 and 10 L/min. With this in mind, the newly designed inhalable aerosol sampler was tested in a wind tunnel, simultaneously, at flows of 2 and 10 L/min flow. A mannequin was equipped with 6 sampler/pump assemblies (three pumps operated at 2 L/min and three pumps at 10 L/min) inside a wind tunnel, operated at 0.2 m/s, which has been shown to be a typical indoor workplace wind speed. In separate tests, four different particle sizes were injected to determine if the sampler’s performance with the new 10 L/min flow rate significantly differed to that at 2 L/min. A comparison between inhalable mass concentrations using a Wilcoxon signed rank test found no significant difference in the concentration of particles sampled at 10 and 2 L/min for all particle sizes tested. Our results suggest that this new aerosol sampler is a versatile tool that can improve exposure assessment capabilities for the practicing industrial hygienist by improving the limit of detection and allowing for shorting sampling times. PMID:27676440

Assessment of increased sampling pump flow rates in a disposable, inhalable aerosol sampler.

PubMed

Stewart, Justin; Sleeth, Darrah K; Handy, Rod G; Pahler, Leon F; Anthony, T Renee; Volckens, John

2017-03-01

A newly designed, low-cost, disposable inhalable aerosol sampler was developed to assess workers personal exposure to inhalable particles. This sampler was originally designed to operate at 10 L/min to increase sample mass and, therefore, improve analytical detection limits for filter-based methods. Computational fluid dynamics modeling revealed that sampler performance (relative to aerosol inhalability criteria) would not differ substantially at sampler flows of 2 and 10 L/min. With this in mind, the newly designed inhalable aerosol sampler was tested in a wind tunnel, simultaneously, at flows of 2 and 10 L/min flow. A mannequin was equipped with 6 sampler/pump assemblies (three pumps operated at 2 L/min and three pumps at 10 L/min) inside a wind tunnel, operated at 0.2 m/s, which has been shown to be a typical indoor workplace wind speed. In separate tests, four different particle sizes were injected to determine if the sampler's performance with the new 10 L/min flow rate significantly differed to that at 2 L/min. A comparison between inhalable mass concentrations using a Wilcoxon signed rank test found no significant difference in the concentration of particles sampled at 10 and 2 L/min for all particle sizes tested. Our results suggest that this new aerosol sampler is a versatile tool that can improve exposure assessment capabilities for the practicing industrial hygienist by improving the limit of detection and allowing for shorting sampling times.

A simple prediction tool for inhaled corticosteroid response in asthmatic children.

PubMed

Wu, Yi-Fan; Su, Ming-Wei; Chiang, Bor-Luen; Yang, Yao-Hsu; Tsai, Ching-Hui; Lee, Yungling L

2017-12-07

Inhaled corticosteroids are recommended as the first-line controller medication for childhood asthma owing to their multiple clinical benefits. However, heterogeneity in the response towards these drugs remains a significant clinical problem. Children aged 5 to 18 years with mild to moderate persistent asthma were recruited into the Taiwanese Consortium of Childhood Asthma Study. Their responses to inhaled corticosteroids were assessed based on their improvements in the asthma control test and peak expiratory flow. The predictors of responsiveness were demographic and clinical features that were available in primary care settings. We have developed a prediction model using logistic regression and have simplified it to formulate a practical tool. We assessed its predictive performance using the area under the receiver operating characteristic curve. Of the 73 asthmatic children with baseline and follow-up outcome measurements for inhaled corticosteroids treatment, 24 (33%) were defined as non-responders. The tool we have developed consisted of three predictors yielding a total score between 0 and 5, which are comprised of the following parameters: the age at physician-diagnosis of asthma, sex, and exhaled nitric oxide. Sensitivity and specificity of the tool for prediction of inhaled corticosteroids non-responsiveness, for a score of 3, were 0.75 and 0.69, respectively. The areas under the receiver operating characteristic curve for the prediction tool was 0.763. Our prediction tool represents a simple and low-cost method for predicting the response of inhaled corticosteroids treatment in asthmatic children.

Cycling to work in London and inhaled dose of black carbon.

PubMed

Nwokoro, Chinedu; Ewin, Clare; Harrison, Clare; Ibrahim, Mubin; Dundas, Isobel; Dickson, Iain; Mushtaq, Naseem; Grigg, Jonathan

2012-11-01

Modelling studies suggest that urban cycling is associated with an increased inhaled dose of fossil fuel-derived black carbon (BC). Using the amount of black material in airway macrophages as a marker of long-term inhaled BC, we sought to compare inhaled BC dose in London (UK) cyclists and non-cyclists. Airway macrophage carbon was assessed in 28 (58%) out of 48 healthy adults (14 cyclists and 14 non-cyclists) who attended for induced sputum. Short-term (24 h) exposure to BC was assessed on a representative working day in 27 out of 28 subjects. Serum interleukin (IL)-1β, IL-2, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor and tumour necrosis factor (TNF)-α were assessed in 26 out of the 28 subjects. Cyclists were found to have increased airway macrophage carbon when compared with non-cyclists (mean ± se 1.81 ± 0.21 versus 1.11 ± 0.07 μm(2); p<0.01). Short-term monitoring showed no difference in 24 h BC exposure between the two groups. However, cyclists were exposed to higher concentrations of BC during commuting (p<0.01). Airway macrophage carbon was associated with monitored commute BC (n=28; r=0.47, p<0.05). TNF-α was found to be increased in cyclists (p<0.05), but no other cytokines were increased. Commuting to work by bicycle in London is associated with increased long-term inhaled dose of BC. Whether cycling per se increases inhaled BC dose remains unclear.

PBTK Modeling Demonstrates Contribution of Dermal and Inhalation Exposure Components to End-Exhaled Breath Concentrations of Naphthalene

PubMed Central

Kim, David; Andersen, Melvin E.; Chao, Yi-Chun E.; Egeghy, Peter P.; Rappaport, Stephen M.; Nylander-French, Leena A.

2007-01-01

Background Dermal and inhalation exposure to jet propulsion fuel 8 (JP-8) have been measured in a few occupational exposure studies. However, a quantitative understanding of the relationship between external exposures and end-exhaled air concentrations has not been described for occupational and environmental exposure scenarios. Objective Our goal was to construct a physiologically based toxicokinetic (PBTK) model that quantitatively describes the relative contribution of dermal and inhalation exposures to the end-exhaled air concentrations of naphthalene among U.S. Air Force personnel. Methods The PBTK model comprised five compartments representing the stratum corneum, viable epidermis, blood, fat, and other tissues. The parameters were optimized using exclusively human exposure and biological monitoring data. Results The optimized values of parameters for naphthalene were a) permeability coefficient for the stratum corneum 6.8 × 10−5 cm/hr, b) permeability coefficient for the viable epidermis 3.0 × 10−3 cm/hr, c) fat:blood partition coefficient 25.6, and d) other tissue:blood partition coefficient 5.2. The skin permeability coefficient was comparable to the values estimated from in vitro studies. Based on simulations of workers’ exposures to JP-8 during aircraft fuel-cell maintenance operations, the median relative contribution of dermal exposure to the end-exhaled breath concentration of naphthalene was 4% (10th percentile 1% and 90th percentile 11%). Conclusions PBTK modeling allowed contributions of the end-exhaled air concentration of naphthalene to be partitioned between dermal and inhalation routes of exposure. Further study of inter- and intraindividual variations in exposure assessment is required to better characterize the toxicokinetic behavior of JP-8 components after occupational and/or environmental exposures. PMID:17589597

PBTK modeling demonstrates contribution of dermal and inhalation exposure components to end-exhaled breath concentrations of naphthalene.

PubMed

Kim, David; Andersen, Melvin E; Chao, Yi-Chun E; Egeghy, Peter P; Rappaport, Stephen M; Nylander-French, Leena A

2007-06-01

Dermal and inhalation exposure to jet propulsion fuel 8 (JP-8) have been measured in a few occupational exposure studies. However, a quantitative understanding of the relationship between external exposures and end-exhaled air concentrations has not been described for occupational and environmental exposure scenarios. Our goal was to construct a physiologically based toxicokinetic (PBTK) model that quantitatively describes the relative contribution of dermal and inhalation exposures to the end-exhaled air concentrations of naphthalene among U.S. Air Force personnel. The PBTK model comprised five compartments representing the stratum corneum, viable epidermis, blood, fat, and other tissues. The parameters were optimized using exclusively human exposure and biological monitoring data. The optimized values of parameters for naphthalene were a) permeability coefficient for the stratum corneum 6.8 x 10(-5) cm/hr, b) permeability coefficient for the viable epidermis 3.0 x 10(-3) cm/hr, c) fat:blood partition coefficient 25.6, and d) other tissue:blood partition coefficient 5.2. The skin permeability coefficient was comparable to the values estimated from in vitro studies. Based on simulations of workers' exposures to JP-8 during aircraft fuel-cell maintenance operations, the median relative contribution of dermal exposure to the end-exhaled breath concentration of naphthalene was 4% (10th percentile 1% and 90th percentile 11%). PBTK modeling allowed contributions of the end-exhaled air concentration of naphthalene to be partitioned between dermal and inhalation routes of exposure. Further study of inter- and intraindividual variations in exposure assessment is required to better characterize the toxicokinetic behavior of JP-8 components after occupational and/or environmental exposures.

Metabolic rate M  0.75 in human beings

NASA Astrophysics Data System (ADS)

Agrawal, D. C.

2014-11-01

Human beings consume energy every day. Even at rest, energy is still needed for the working of the internal organs. This is achieved by the metabolism of consumed food in the presence of inhaled oxygen. During the resting state this is called the maintenance rate, and follows the mouse-to-elephant formula, Pmet = 70M0.75 kcal per day. Here, M is the body mass of the subject in kilograms. The heat generated in metabolism is lost through the body surface of the subject, so the metabolic rate should also be proportional to the body surface area. In other words, the body surface area in the case of a human being must also depend on M0.75. The present paper examines this issue by finding a relationship between human body surface area and its mass through a very simple model that can be easily understood and verified by physics students, who can also compare it with all the expressions for body surface area available in the literature. This will build confidence in the students that the heat generated from metabolism in fact dissipates through the surface of the body.

Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation.

PubMed

Pariollaud, Marie; Gibbs, Julie E; Hopwood, Thomas W; Brown, Sheila; Begley, Nicola; Vonslow, Ryan; Poolman, Toryn; Guo, Baoqiang; Saer, Ben; Jones, D Heulyn; Tellam, James P; Bresciani, Stefano; Tomkinson, Nicholas Co; Wojno-Picon, Justyna; Cooper, Anthony Wj; Daniels, Dion A; Trump, Ryan P; Grant, Daniel; Zuercher, William; Willson, Timothy M; MacDonald, Andrew S; Bolognese, Brian; Podolin, Patricia L; Sanchez, Yolanda; Loudon, Andrew Si; Ray, David W

2018-06-01

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

PubMed Central

Bassett, David J. P.; Bradley, Matthews O.; Jaffar, Zeina

2013-01-01

Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation. PMID:23936192

Inhalation devices: from basic science to practical use, innovative vs generic products.

PubMed

Pirozynski, Michal; Sosnowski, Tomasz R

2016-11-01

Inhalation therapy is a convenient method of treating respiratory diseases. The key factors required for inhalation are the preparation of drug carriers (aerosol particles) allowing reproducible dosing during administration. These technical challenges are accomplished with a variety of inhalation devices (inhalers) and medicinal formulations, which are optimized to be easily converted into inhalable aerosols. Areas covered: This review is focused on the most important, but often overlooked, effects, which are required for the reliable and reproducible inhalable drug administration. The effects of patient-related issues that influence inhalation therapy, such as proper selection of inhalers for specific cases is discussed. We also discuss factors that are the most essential if generic inhalation product should be considered equivalent to the drugs with the clinically confirmed efficacy. Expert opinion: Proper device selection is crucial in clinical results of inhalation therapy. The patients' ability to coordinate inhalation with actuation, generation of optimal flow through the device, use of optimal inspiratory volume, all produces crucial effects on disease control. Also the severity of the disease process effects proper use of inhalers. Interchanging of inhalers can produce potentially conflicting problem regarding efficacy and safety of inhalation therapy.

Drug discovery in prostate cancer mouse models.

PubMed

Valkenburg, Kenneth C; Pienta, Kenneth J

2015-01-01

The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

Modeling of inertial deposition in scaled models of rat and human nasal airways: Towards in vitro regional dosimetry in small animals

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

Xi, Jinxiang; Kim, JongWon; Si, Xiuhua A.

Rodents are routinely used in inhalation toxicology tests as human surrogates. However, in vitro dosimetry tests in rodent casts are still scarce due to small rodent airways and in vitro tests to quantify sub-regional dosimetry are still impractical. We hypothesized that for inertial particles whose deposition is dominated by airflow convection (Reynolds number) and particle inertia (Stokes number), the deposition should be similar among airway replicas of different scales if their Reynolds and Stokes numbers are kept the same. In this study, we aimed to (1) numerically test the hypothesis in three airway geometries: a USP induction port, a humanmore » nose model, and a Sprague-Dawley rat nose model, and (2) find the range of applicability of this hypothesis. Five variants of the USP and human nose models and three variants of the rat nose model were tested. Inhalation rates and particle sizes were scaled to match the Reynolds number and Stokes numbers. A low-Reynolds-number k–ω model was used to resolve the airflow and a Lagrangian tracking algorithm was used to simulate the particle transport and deposition. Statistical analysis of predicted doses was conducted using ANOVA. For normal inhalation rates and particle dia- meters ranging from 0.5 to 24 mm, the deposition differences between the life-size and scaled models are insignificant for all airway geometries considered (i.e., human nose, USP, and rat nose). Furthermore, the deposition patterns and exit particle profiles also look similar among scaled models. However, deposition rates and patterns start to deviate if inhalation rates are too low, or particle sizes are too large. For the rat nose, the threshold velocity was found to be 0.71 m/s and the threshold Froude number to be 50. Results of this study provide a theoretical foundation for sub-regional in vitro dosimetry tests in small animals and for interpretation of data from inter-species or intra-species with varying body sizes.« less

Orthology for comparative genomics in the mouse genome database.

PubMed

Dolan, Mary E; Baldarelli, Richard M; Bello, Susan M; Ni, Li; McAndrews, Monica S; Bult, Carol J; Kadin, James A; Richardson, Joel E; Ringwald, Martin; Eppig, Janan T; Blake, Judith A

2015-08-01

The mouse genome database (MGD) is the model organism database component of the mouse genome informatics system at The Jackson Laboratory. MGD is the international data resource for the laboratory mouse and facilitates the use of mice in the study of human health and disease. Since its beginnings, MGD has included comparative genomics data with a particular focus on human-mouse orthology, an essential component of the use of mouse as a model organism. Over the past 25 years, novel algorithms and addition of orthologs from other model organisms have enriched comparative genomics in MGD data, extending the use of orthology data to support the laboratory mouse as a model of human biology. Here, we describe current comparative data in MGD and review the history and refinement of orthology representation in this resource.

Postconditioning with inhaled hydrogen promotes survival of retinal ganglion cells in a rat model of retinal ischemia/reperfusion injury.

PubMed

Wang, Ruobing; Wu, Jiangchun; Chen, Zeli; Xia, Fangzhou; Sun, Qinglei; Liu, Lin

2016-02-01

Retinal ischemia/reperfusion (I/R) injury plays a crucial role in the pathophysiology of various ocular diseases. Intraperitoneal injection or ocular instillation with hydrogen (H2)-rich saline was recently shown to be neuroprotective in the retina due to its anti-oxidative and anti-inflammatory effects. Our study aims to explore whether postconditioning with inhaled H2 can protect retinal ganglion cells (RGCs) in a rat model of retinal I/R injury. Retinal I/R injury was performed on the right eyes of rats and was followed by inhalation of 67% H2 mixed with 33% oxygen immediately after ischemia for 1h daily for one week. RGC density was counted using haematoxylin and eosin (HE) staining and retrograde labeling with cholera toxin beta (CTB). Visual function was assessed using flash visual evoked potentials (FVEP) and pupillary light reflex (PLR). Potential biomarkers of retinal oxidative stress and inflammatory responses were measured, including the expression of 4-Hydroxynonenalv (4-HNE), interleukin-1 beta (IL1-β) and tumor necrosis factor alpha (TNF-α). HE and CTB tracing showed that the survival rate of RGCs in the H2-treated group was significantly higher than the rate in the I/R group. Rats with H2 inhalation showed better visual function in assessments of FVEP and PLR. Moreover, H2 treatment significantly decreased the number of 4-HNE-stained cells in the ganglion cell layer and inhibited the retinal overexpression of IL1-β and TNF-α that was induced by retinal I/R injury. Our results demonstrate that postconditioning with inhaled high-dose H2 appears to confer neuroprotection against retinal I/R injury via anti-oxidative, anti-inflammatory and anti-apoptosis pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Thrall, Karla D.; Schwartz, Ronald E.; Weitz, Karl K.

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled 13C-acetone at approximately 1 ppm concentration for 30 minutes under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhalemore » mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 sec. A second ion-trap mass spectrometer simultaneously sampled from the volunteer?s exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the 13C-acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in 13C-acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analysis of 13C-acetone concentrations indicate that between 40-75% of the compound is absorbed upon inhalation and nearly all of that absorbed released back into the breath stream during exhalation.« less

Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

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

Jarabek, A.M.; Foureman, G.L.; Gift, J.S.

1997-12-31

Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regressionmore » model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).« less

Assessing the inhalation cancer risk of particulate matter bound polycyclic aromatic hydrocarbons (PAHs) for the elderly in a retirement community of a mega city in North China.

PubMed

Han, Bin; Liu, Yating; You, Yan; Xu, Jia; Zhou, Jian; Zhang, Jiefeng; Niu, Can; Zhang, Nan; He, Fei; Ding, Xiao; Bai, Zhipeng

2016-10-01

Assessment of the health risks resulting from exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is limited by the lack of environmental exposure data among different subpopulations. To assess the exposure cancer risk of particulate carcinogenic polycyclic aromatic hydrocarbon pollution for the elderly, this study conducted a personal exposure measurement campaign for particulate PAHs in a community of Tianjin, a city in northern China. Personal exposure samples were collected from the elderly in non-heating (August-September, 2009) and heating periods (November-December, 2009), and 12 PAHs individuals were analyzed for risk estimation. Questionnaire and time-activity log were also recorded for each person. The probabilistic risk assessment model was integrated with Toxic Equivalent Factors (TEFs). Considering that the estimation of the applied dose for a given air pollutant is dependent on the inhalation rate, the inhalation rate from both EPA exposure factor book was applied to calculate the carcinogenic risk in this study. Monte Carlo simulation was used as a probabilistic risk assessment model, and risk simulation results indicated that the inhalation-ILCR values for both male and female subjects followed a lognormal distribution with a mean of 4.81 × 10 -6 and 4.57 × 10 -6 , respectively. Furthermore, the 95 % probability lung cancer risks were greater than the USEPA acceptable level of 10 -6 for both men and women through the inhalation route, revealing that exposure to PAHs posed an unacceptable potential cancer risk for the elderly in this study. As a result, some measures should be taken to reduce PAHs pollution and the exposure level to decrease the cancer risk for the general population, especially for the elderly.

Toxicity of inhaled plutonium dioxide in beagle dogs

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

Muggenburg, M.A.; Guilmette, R.A.; Mewhinney, J.A.

This study was conducted to determine the biological effects of inhaled {sup 238}PuO{sub 2} over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of {sup 238}PuO{sub 2} to achieve graded levels of initial lung burden (ILB). The aerosols also contained {sup 169}Yb to provide a {gamma}-ray-emitting label for the {sup 238}Pu inhaled by each dog. Excreta were collected periodically over each dog`s life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimatemore » the ILB. These data for each dog were used in a dosimetry model to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest {alpha}-particle doses, ranging from 0.16-68 Gy for the liver. At death, all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to {sup 238}PuO{sub 2}. 89 refs., 10 figs., 11 tab.« less

Effects of pulmonary inhalation on hyperpolarized krypton-83 magnetic resonance T1 relaxation

NASA Astrophysics Data System (ADS)

Stupic, K. F.; Elkins, N. D.; Pavlovskaya, G. E.; Repine, J. E.; Meersmann, T.

2011-07-01

The 83Kr magnetic resonance (MR) relaxation time T1 of krypton gas in contact with model surfaces was previously found to be highly sensitive to surface composition, surface-to-volume ratio, and surface temperature. The work presented here explored aspects of pulmonary 83Kr T1 relaxation measurements in excised lungs from healthy rats using hyperpolarized (hp) 83Kr with approximately 4.4% spin polarization. MR spectroscopy without spatial resolution was applied to the ex vivo lungs that actively inhale hp 83Kr through a custom designed ventilation system. Various inhalation schemes were devised to study the influence of anatomical dead space upon the measured 83Kr T1 relaxation times. The longitudinal 83Kr relaxation times in the distal airways and the respiratory zones were independent of the lung inhalation volume, with T1 = 1.3 s and T1 = 1.0 s, depending only on the applied inhalation scheme. The obtained data were highly reproducible between different specimens. Further, the 83Kr T1 relaxation times in excised lungs were unaffected by the presence of up to 40% oxygen in the hp gas mixture. The results support the possible importance of 83Kr as a biomarker for evaluating lung function.

Quantitative risk assessment for a glass fiber insulation product.

PubMed

Fayerweather, W E; Bender, J R; Hadley, J G; Eastes, W

1997-04-01

California Proposition 65 (Prop65) provides a mechanism by which the manufacturer may perform a quantitative risk assessment to be used in determining the need for cancer warning labels. This paper presents a risk assessment under this regulation for professional and do-it-yourself insulation installers. It determines the level of insulation glass fiber exposure (specifically Owens Corning's R-25 PinkPlus with Miraflex) that, assuming a working lifetime exposure, poses no significant cancer risk under Prop65's regulations. "No significant risk" is defined under Prop65 as a lifetime risk of no more than one additional cancer case per 100,000 exposed persons, and nonsignificant exposure is defined as a working lifetime exposure associated with "no significant risk." This determination can be carried out despite the fact that the relevant underlying studies (i.e., chronic inhalation bioassays) of comparable glass wool fibers do not show tumorigenic activity. Nonsignificant exposures are estimated from (1) the most recent RCC chronic inhalation bioassay of nondurable fiberglass in rats; (2) intraperitoneal fiberglass injection studies in rats; (3) a distributional, decision analysis approach applied to four chronic inhalation rat bioassays of conventional fiberglass; (4) an extrapolation from the RCC chronic rat inhalation bioassay of durable refractory ceramic fibers; and (5) an extrapolation from the IOM chronic rat inhalation bioassay of durable E glass microfibers. When the EPA linear nonthreshold model is used, central estimates of nonsignificant exposure range from 0.36 fibers/cc (for the RCC chronic inhalation bioassay of fiberglass) through 21 fibers/cc (for the i.p. fiberglass injection studies). Lower 95% confidence bounds on these estimates vary from 0.17 fibers/cc through 13 fibers/cc. Estimates derived from the distributional approach or from applying the EPA linear nonthreshold model to chronic bioassays of durable fibers such as refractory ceramic fiber or E glass microfibers are intermediate to the other approaches. Estimates based on the Weibull 1.5-hit nonthreshold and 2-hit threshold models exceed by at least a factor of 10 the corresponding EPA linear nonthreshold estimates. The lowest nonsignificant exposures derived in this assessment are at least a factor of two higher than field exposures measured for professionals installing the R-25 fiberglass insulation product and are orders of magnitude higher than the estimated lifetime exposures for do-it-yourselfers.

Model framework for integrating multiple exposure pathways to chemicals in household cleaning products.

PubMed

Shin, H-M; McKone, T E; Bennett, D H

2017-07-01

We present a screening-level exposure-assessment method which integrates exposure from all plausible exposure pathways as a result of indoor residential use of cleaning products. The exposure pathways we considered are (i) exposure to a user during product use via inhalation and dermal, (ii) exposure to chemical residues left on clothing, (iii) exposure to all occupants from the portion released indoors during use via inhalation and dermal, and (iv) exposure to the general population due to down-the-drain disposal via inhalation and ingestion. We use consumer product volatilization models to account for the chemical fractions volatilized to air (f volatilized ) and disposed down the drain (f down-the-drain ) during product use. For each exposure pathway, we use a fate and exposure model to estimate intake rates (iR) in mg/kg/d. Overall, the contribution of the four exposure pathways to the total exposure varies by the type of cleaning activities and with chemical properties. By providing a more comprehensive exposure model and by capturing additional exposures from often-overlooked exposure pathways, our method allows us to compare the relative contribution of various exposure routes and could improve high-throughput exposure assessment for chemicals in cleaning products. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Modeling In Vivo Interactions of Engineered Nanoparticles in the Pulmonary Alveolar Lining Fluid

PubMed Central

Mukherjee, Dwaipayan; Porter, Alexandra; Ryan, Mary; Schwander, Stephan; Chung, Kian Fan; Tetley, Teresa; Zhang, Junfeng; Georgopoulos, Panos

2015-01-01

Increasing use of engineered nanomaterials (ENMs) in consumer products may result in widespread human inhalation exposures. Due to their high surface area per unit mass, inhaled ENMs interact with multiple components of the pulmonary system, and these interactions affect their ultimate fate in the body. Modeling of ENM transport and clearance in vivo has traditionally treated tissues as well-mixed compartments, without consideration of nanoscale interaction and transformation mechanisms. ENM agglomeration, dissolution and transport, along with adsorption of biomolecules, such as surfactant lipids and proteins, cause irreversible changes to ENM morphology and surface properties. The model presented in this article quantifies ENM transformation and transport in the alveolar air to liquid interface and estimates eventual alveolar cell dosimetry. This formulation brings together established concepts from colloidal and surface science, physics, and biochemistry to provide a stochastic framework capable of capturing essential in vivo processes in the pulmonary alveolar lining layer. The model has been implemented for in vitro solutions with parameters estimated from relevant published in vitro measurements and has been extended here to in vivo systems simulating human inhalation exposures. Applications are presented for four different ENMs, and relevant kinetic rates are estimated, demonstrating an approach for improving human in vivo pulmonary dosimetry. PMID:26240755

Development of a Zealand White Rabbit Deposition Model to Study Inhalation Anthrax

PubMed Central

Asgharian, Bahman; Price, Owen; Kabilan, Senthil; Jacob, Richard E.; Einstein, Daniel R.; Kuprat, A.P.; Corley, Richard A.

2016-01-01

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits as a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits. PMID:26895308

Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

PubMed Central

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2015-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

Effectiveness of Nurse-Driven Inhaler Education on Inhaler Proficiency and Compliance Among Obstructive Lung Disease Patients: A Quasi-Experimental Study.

PubMed

Al-Kalaldeh, Mahmoud; El-Rahman, Mona Abd; El-Ata, Amal

2016-06-01

Background Health education on proper inhaler usage is the most feasible and accessible strategy to increase inhaler effectiveness. Purpose To assess the impact of nurse-driven inhaler education on the compliance and proficiency of using inhalers among inhaler users. Methods This single-center, quasi-experimental study included the implementation of an individualized 60-min educational session on inhalers use. Health education and pretest and posttest outcomes were assessed by the Inhaler Proficiency Schedule and Patient Reported Behaviour tools. Results One hundred and twenty-one participants joined the study. At pretest, participants showed inadequate knowledge of general inhaler use. No previous training had been received by participants and difficulty with use and complications from using the inhalers were reported. At posttest, participants reported improvement in inhaler proficiency scores from 5.72 to 8.60 ( t = 17.99, df = 220, p < 0.001). Likewise, they showed a significant reduction towards the noncompliant behaviors from 15.21 to 11.19 ( t = 16.388, df = 238, p < 0.001). Conclusions Nurse-driven inhaler education yielded positive outcomes in both inhaler proficiency and compliance. The patients' assessment of using inhalers is crucial to determine the patients' educational deficits.

Checklists for the Assessment of Correct Inhalation Therapy.

PubMed

Knipel, V; Schwarz, S; Magnet, F S; Storre, J H; Criée, C P; Windisch, W

2017-02-01

Introduction  For the long-term treatment of obstructive lung diseases inhalation therapy with drugs being delivered directly to the lungs as an aerosol has become the method of choice. However, patient-related mistakes in inhalation techniques are frequent and recognized to be associated with reduced disease control. Since the assessment of patient-mistakes in inhalation has yet not been standardized, the present study was aimed at developing checklists for the assessment of correct inhalation. Methods  Checklists were developed in German by an expert panel of pneumologists and professionally translated into English following back-translation procedures. The checklists comparably assessed three major steps of inhalation: 1) inhalation preparation, 2) inhalation routine, and 3) closure of inhalation. Results  Checklists for eight frequently used inhalers were developed: Aerolizer, Breezhaler, Diskus (Accuhaler), metered-dose inhaler, Handihaler, Novolizer, Respimat, Turbohaler. Each checklist consists of ten items: three for inhalation preparation, six for inhalation routine, and one for closure of inhalation. Discussion  Standardized checklists for frequently used inhalers are available in German and English. These checklists can be used for clinical routines or for clinical trials. All checklists can be downloaded free of charge for non-profit application from the homepage of the German Airway League (Deutsche Atemwegsliga e. V.): www.atemwegsliga.de. © Georg Thieme Verlag KG Stuttgart · New York.

The small airway epithelium as a target for the adverse pulmonary effects of silver nanoparticle inhalation.

PubMed

Guo, Chang; Buckley, Alison; Marczylo, Tim; Seiffert, Joanna; Römer, Isabella; Warren, James; Hodgson, Alan; Chung, Kian Fan; Gant, Timothy W; Smith, Rachel; Leonard, Martin O

2018-05-11

Experimental modeling to identify specific inhalation hazards for nanomaterials has in the main focused on in vivo approaches. However, these models suffer from uncertainties surrounding species-specific differences and cellular targets for biologic response. In terms of pulmonary exposure, approaches which combine 'inhalation-like' nanoparticulate aerosol deposition with relevant human cell and tissue air-liquid interface cultures are considered an important complement to in vivo work. In this study, we utilized such a model system to build on previous results from in vivo exposures, which highlighted the small airway epithelium as a target for silver nanoparticle (AgNP) deposition. RNA-SEQ was used to characterize alterations in mRNA and miRNA within the lung. Organotypic-reconstituted 3D human primary small airway epithelial cell cultures (SmallAir) were exposed to the same spark-generated AgNP and at the same dose used in vivo, in an aerosol-exposure air-liquid interface (AE-ALI) system. Adverse effects were characterized using lactate, LDH release and alterations in mRNA and miRNA. Modest toxicological effects were paralleled by significant regulation in gene expression, reflective mainly of specific inflammatory events. Importantly, there was a level of concordance between gene expression changes observed in vitro and in vivo. We also observed a significant correlation between AgNP and mass equivalent silver ion (Ag + ) induced transcriptional changes in SmallAir cultures. In addition to key mechanistic information relevant for our understanding of the potential health risks associated with AgNP inhalation exposure, this work further highlights the small airway epithelium as an important target for adverse effects.

Prevalidation of the ex-vivo model PCLS for prediction of respiratory toxicity.

PubMed

Hess, A; Wang-Lauenstein, L; Braun, A; Kolle, S N; Landsiedel, R; Liebsch, M; Ma-Hock, L; Pirow, R; Schneider, X; Steinfath, M; Vogel, S; Martin, C; Sewald, K

2016-04-01

In acute inhalation toxicity studies, animals inhale substances at given concentrations. Without additional information, however, appropriate starting concentrations for in-vivo inhalation studies are difficult to estimate. The goal of this project was the prevalidation of precision-cut lung slices (PCLS) as an ex-vivo alternative to reduce the number of animals used in inhalation toxicity studies. According to internationally agreed principles for Prevalidation Studies, the project was conducted in three independent laboratories. The German BfR provided consultancy in validation principles and independent support with biostatistics. In all laboratories, rat PCLS were prepared and exposed to 5 concentrations of 20 industrial chemicals under submerged culture conditions for 1h. After 23 h post-incubation, toxicity was assessed by measurement of released lactate dehydrogenase and mitochondrial activity. In addition, protein content and pro-inflammatory cytokine IL-1α were measured. For all endpoints IC50 values were calculated if feasible. For each endpoint test acceptance criteria were established. This report provides the final results for all 20 chemicals. More than 900 concentration-response curves were analyzed. Log10[IC50 (μM)], obtained for all assay endpoints, showed best intra- and inter-laboratory consistency for the data obtained by WST-1 and BCA assays. While WST-1 and LDH indicated toxic effects for the majority of substances, only some of the substances induced an increase in extracellular IL-1α. Two prediction models (two-group classification model, prediction of LC50 by IC50) were developed and showed promising results. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A murine inhalation model to characterize pulmonary exposure to dry Aspergillus fumigatus conidia.

PubMed

Buskirk, Amanda D; Green, Brett J; Lemons, Angela R; Nayak, Ajay P; Goldsmith, W Travis; Kashon, Michael L; Anderson, Stacey E; Hettick, Justin M; Templeton, Steven P; Germolec, Dori R; Beezhold, Donald H

2014-01-01

Most murine models of fungal exposure are based on the delivery of uncharacterized extracts or liquid conidia suspensions using aspiration or intranasal approaches. Studies that model exposure to dry fungal aerosols using whole body inhalation have only recently been described. In this study, we aimed to characterize pulmonary immune responses following repeated inhalation of conidia utilizing an acoustical generator to deliver dry fungal aerosols to mice housed in a nose only exposure chamber. Immunocompetent female BALB/cJ mice were exposed to conidia derived from Aspergillus fumigatus wild-type (WT) or a melanin-deficient (Δalb1) strain. Conidia were aerosolized and delivered to mice at an estimated deposition dose of 1×105 twice a week for 4 weeks (8 total). Histopathological and immunological endpoints were assessed 4, 24, 48, and 72 hours after the final exposure. Histopathological analysis showed that conidia derived from both strains induced lung inflammation, especially at 24 and 48 hour time points. Immunological endpoints evaluated in bronchoalveolar lavage fluid (BALF) and the mediastinal lymph nodes showed that exposure to WT conidia led to elevated numbers of macrophages, granulocytes, and lymphocytes. Importantly, CD8+ IL17+ (Tc17) cells were significantly higher in BALF and positively correlated with germination of A. fumigatus WT spores. Germination was associated with specific IgG to intracellular proteins while Δalb1 spores elicited antibodies to cell wall hydrophobin. These data suggest that inhalation exposures may provide a more representative analysis of immune responses following exposures to environmentally and occupationally prevalent fungal contaminants.

Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

PubMed

Helyes, Z; Kemény, Á; Csekő, K; Szőke, É; Elekes, K; Mester, M; Sándor, K; Perkecz, A; Kereskai, L; Márk, L; Bona, Á; Benkő, A; Pintér, E; Szolcsányi, J; Ledent, C; Sperlágh, B; Molnár, T F

2017-08-01

Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor. Copyright © 2017 the American Physiological Society.

A Recombinant 63-kDa Form of Bacillus anthracis Protective Antigen Produced in the Yeast Saccharomyces cerevisiae Provides Protection in Rabbit and Primate Inhalational Challenge Models of Anthrax Infection

DTIC Science & Technology

2005-10-21

provides protection in rabbit and primate inhalational challenge models of anthrax infection Robert W. Hepler a, 1 , Rosemarie Kelly b,∗, 1 , Tessie B. McNeely a...October 2005 A t t y i H k r e a © K 1 B 9 9 0 d Approved for public release. Distribution is unlimited.bstract Infection by Bacillus anthracis is...Corresponding author. Tel.: + 1 732 594 6385; fax: + 1 732 594 1399. E-mail address: rosemarie kelly@merck.com (R. Kelly). 1 Authors made an equal contribution to

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

DTIC Science & Technology

2012-06-13

plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over...develop and deliver low-doses of B. anthracis spores via inhalation in a reproducible manner. The pilot feasibility study (see Table 1 for results) enabled...results presented in Figure 3 show that exposures produced by the aerosol system were stable and reproducible from day-to-day. In all testing, the

Heat dissipation by blood circulation and airway tissue heat absorption in a canine model of inhalational thermal injury.

PubMed

Wan, Jiangbo; Zhang, Guoan; Qiu, Yuxuan; Wen, Chunquan; Fu, Tairan

2016-05-01

This study aimed to further explore heat dissipation by blood circulation and airway tissue heat absorption in an inhalational thermal injury model. Twelve adult male Beagle dogs were divided into four groups to inhale heated air for 10min: the control group, group I (100.5°C), group II (161.5°C), and group III (218°C). The relative humidity and temperature of the inhaled heated air were measured in the heating tube and trachea, as were blood temperatures and flow velocities in both common jugular veins. Formulas were used to calculate the total heat quantity reduction of the heated air, heat dissipation by the blood, and airway tissue heat absorption. The blood temperatures of both the common jugular veins increased by 0.29°C±0.07°C to 2.96°C±0.24°C and the mean blood flow volume after injury induction was about 1.30-1.74 times greater than before injury induction. The proportions of heat dissipated by the blood and airway tissue heat absorption were 68.92%±14.88% and 31.13%±14.87%, respectively. The heat dissipating ability of the blood circulation was demonstrated and improved upon along with tissue heat absorption owing to increased regional blood flow. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin.

PubMed

Andrade, Fernanda; das Neves, José; Gener, Petra; Schwartz, Simó; Ferreira, Domingos; Oliva, Mireia; Sarmento, Bruno

2015-10-01

Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus®, Pluronic® F68, Pluronic® F108 and Pluronic® F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<6 μm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic® F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluation of air-interfaced Calu-3 cell layers for investigation of inhaled drug interactions with organic cation transporters in vitro.

PubMed

Mukherjee, Manali; Pritchard, D I; Bosquillon, C

2012-04-15

A physiologically pertinent in vitro model is urgently needed for probing interactions between inhaled drugs and the organic cation transporters (OCT) in the bronchial epithelium. This study evaluated OCT expression, functionality, inhibition by common inhaled drugs and impact on formoterol transepithelial transport in layers of human bronchial epithelial Calu-3 cells grown at an air-liquid interface. 21 day old Calu-3 layers expressed OCT1, OCT3, OCTN1 and OCTN2 whereas OCT2 could not be detected. Quantification of the cellular uptake of the OCT substrate ASP(+) in presence of inhibitors suggested several OCT were functional at the apical side of the cell layers. ASP(+) uptake was reduced by the bronchodilators formoterol, salbutamol (albuterol), ipratropium and the glucocorticoid budesonide. However, the OCT inhibitory properties of the two β(2)-mimetics were suppressed at therapeutically relevant concentrations. The absorptive permeability of formoterol across the cell layers was enhanced at a high drug concentration shown to decrease ASP(+) uptake by ∼50% as well as in presence of the OCT inhibitor tetraethylammonium (TEA). Secretory transport was unaffected by the drug concentration but was reduced by TEA. Our data indicate air-interfaced Calu-3 layers offer a low-cost in vitro model suitable for assessing inhaled drug-OCT interactions in the bronchial epithelium. Copyright © 2011 Elsevier B.V. All rights reserved.

Efficacy of ETI-204 monoclonal antibody as an adjunct therapy in a New Zealand white rabbit partial survival model for inhalational anthrax.

PubMed

Biron, Bethany; Beck, Katie; Dyer, David; Mattix, Marc; Twenhafel, Nancy; Nalca, Aysegul

2015-04-01

Inhalational anthrax is characterized by extensive bacteremia and toxemia as well as nonspecific to mild flu-like symptoms, until the onset of hypotension, shock, and mortality. Without treatment, the mortality rate approaches 100%. Antibiotic treatment is not always effective, and alternative treatments are needed, such as monotherapy for antibiotic-resistant inhalational anthrax or as an adjunct therapy in combination with antibiotics. The Bacillus anthracis antitoxin monoclonal antibody (MAb) ETI-204 is a high-affinity chimeric deimmunized antibody which targets the anthrax toxin protective antigen (PA). In this study, a partial protection New Zealand White (NZW) rabbit model was used to evaluate the protective efficacy of the adjunct therapy with the MAb. Following detection of PA in the blood, NZW rabbits were administered either an antibiotic (doxycycline) alone or the antibiotic in conjunction with ETI-204. Survival was evaluated to compare the efficacy of the combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Protease-Activated Receptor-2 Activation Contributes to House Dust Mite-Induced IgE Responses in Mice

PubMed Central

Post, Sijranke; Heijink, Irene H.; Petersen, Arjen H.; de Bruin, Harold G.; van Oosterhout, Antoon J. M.; Nawijn, Martijn C.

2014-01-01

Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM-driven allergic airway disease. PMID:24651123

Cyclohexane produces behavioral deficits associated with astrogliosis and microglial reactivity in the adult hippocampus mouse brain.

PubMed

Campos-Ordonez, Tania; Zarate-Lopez, David; Galvez-Contreras, Alma Y; Moy-Lopez, Norma; Guzman-Muniz, Jorge; Gonzalez-Perez, Oscar

2015-05-01

Cyclohexane is a volatile substance that has been utilized as a safe substitute of several organic solvents in diverse industrial processes, such as adhesives, paints, paint thinners, fingernail polish, lacquers, and rubber industry. A number of these commercial products are ordinarily used as inhaled drugs. However, it is not well known whether cyclohexane has noxious effects in the central nervous system. The aim of this study was to analyze the effects of cyclohexane inhalation on motor behavior, spatial memory, and reactive gliosis in the hippocampus of adult mice. We used a model that mimics recreational drug use in male Balb/C mice (P60), divided into two groups: controls and the cyclohexane group (exposed to 9,000 ppm of cyclohexane for 30 days). Both groups were then evaluated with a functional observational battery (FOB) and the Morris water maze (MWM). Furthermore, the relative expression of AP endonuclease 1 (APE1), and the number of astrocytes (GFAP+ cells) and microglia (Iba1+ cells) were quantified in the hippocampal CA1 and CA3 areas. Our findings indicated that cyclohexane produced severe functional deficits during a recreational exposure as assessed by the FOB. The MWM did not show statistically significant changes in the acquisition and retention of spatial memory. Remarkably, a significant increase in the number of astrocytes and microglia cells, as well as in the cytoplasmic processes of these cells were observed in the hippocampal CA1 and CA3 areas of cyclohexane-exposed mice. This cellular response was associated with an increase in the expression of APE1 in the same brain regions. In summary, cyclohexane exposure produces functional deficits that are associated with an important increase in the APE1 expression as well as the number of astrocytes and microglia cells and their cytoplasmic complexity in the CA1 and CA3 regions of the adult hippocampus.

Nebulized hyaluronan ameliorates lung inflammation in cystic fibrosis mice.

PubMed

Gavina, Manuela; Luciani, Alessandro; Villella, Valeria R; Esposito, Speranza; Ferrari, Eleonora; Bressani, Ilaria; Casale, Alida; Bruscia, Emanuela M; Maiuri, Luigi; Raia, Valeria

2013-08-01

Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. F508del homozygous mice (Cftr(F508del) ) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 µg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Nebulized HA reduced TNFα expression (P < 0.005); TNFα, MIP-2, and MPO protein levels (P < 0.05); MPO activity (P < 0.05); and CD68+ cells counts (P < 0.005) in lung tissues of Cftr(F508del) and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P < 0.05). Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy. Copyright © 2012 Wiley Periodicals, Inc.

Group-2 innate lymphoid cells mediate ozone induced airway inflammation and hyperresponsiveness in mice

PubMed Central

Yang, Qi; Ge, Moyar Q.; Kokalari, Blerina; Redai, Imre G.; Wang, Xinxin; Kemeny, David M.; Bhandoola, Avinash; Haczku, Angela

2015-01-01

Background Patients with asthma are highly susceptible to air pollution and in particular, to the effects of ozone (O3) inhalation, but the underlying mechanisms remain unclear. Objective Using mouse models of O3-induced airway inflammation and hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2). Methods C57BL/6 and Balb/c mice were exposed to Aspergillus fumigatus and/or O3 (2ppm, 2h). ILC2 were isolated by FACS sorting and studied for IL-5 and IL-13 mRNA expression. ILC2 were depleted with anti-Thy1.2 mAb and replaced by intratracheal transfer of ex vivo expanded Thy1.1 ILC2. Cytokines (ELISA, qPCR), inflammatory cell profile and AHR (FlexiVent) were assessed in the mice. Results In addition to neutrophil influx, O3 inhalation elicited the appearance of eosinophils and IL-5 in the airways of Balb/c but not C57BL/6 mice. Although O3 induced expression of IL-33, a known activator of ILC2 in the lung was similar between these strains, isolated pulmonary ILC2 from O3 exposed Balb/c mice had significantly greater IL-5 and IL-13 mRNA expression than those of C57BL/6 mice. This suggested that an altered ILC2 function in Balb/c mice may mediate the increased O3 responsiveness. Indeed, anti-Thy1.2 treatment abolished, whereas ILC2 add-back dramatically enhanced O3-induced AHR. Conclusions O3-induced activation of pulmonary ILC2 was necessary and sufficient to mediate asthma-like changes in Balb/c mice. This previously unrecognized role of ILC2 may help explain the heightened susceptibility of human asthmatic airways to O3 exposure. PMID:26282284

γ-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90

PubMed Central

Turner, Helen C.; Shuryak, Igor; Weber, Waylon; Doyle-Eisele, Melanie; Melo, Dunstana; Guilmette, Raymond; Amundson, Sally A.; Brenner, David J.

2015-01-01

In the event of a dirty bomb scenario or an industrial nuclear accident, a significant dose of volatile radionuclides such as 137Cs and 90Sr may be dispersed into the atmosphere as a component of fallout and inhaled or ingested by hundreds and thousands of people. To study the effects of prolonged exposure to ingested radionuclides, we have performed long-term (30 day) internal-emitter mouse irradiations using soluble-injected 137CsCl and 90SrCl2 radioisotopes. The effect of ionizing radiation on the induction and repair of DNA double strand breaks (DSBs) in peripheral mouse lymphocytes in vivo was determined using the γ-H2AX biodosimetry marker. Using a serial sacrifice experimental design, whole-body radiation absorbed doses for 137Cs (0 to 10 Gy) and 90Sr (0 to 49 Gy) were delivered over 30 days following exposure to each radionuclide. The committed absorbed doses of the two internal emitters as a function of time post exposure were calculated based on their retention parameters and their derived dose coefficients for each specific sacrifice time. In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software. A key finding was that a significant γ-H2AX signal was observed in vivo several weeks after a single radionuclide exposure. A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence. Exposure to either radionuclide showed two peaks of γ-H2AX: one within the first week, which may represent the death of mature, differentiated lymphocytes, and the second at approximately three weeks, which may represent the production of new lymphocytes from damaged progenitor cells. The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis. PMID:26618801

γ-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90.

PubMed

Turner, Helen C; Shuryak, Igor; Weber, Waylon; Doyle-Eisele, Melanie; Melo, Dunstana; Guilmette, Raymond; Amundson, Sally A; Brenner, David J

2015-01-01

In the event of a dirty bomb scenario or an industrial nuclear accident, a significant dose of volatile radionuclides such as 137Cs and 90Sr may be dispersed into the atmosphere as a component of fallout and inhaled or ingested by hundreds and thousands of people. To study the effects of prolonged exposure to ingested radionuclides, we have performed long-term (30 day) internal-emitter mouse irradiations using soluble-injected 137CsCl and 90SrCl2 radioisotopes. The effect of ionizing radiation on the induction and repair of DNA double strand breaks (DSBs) in peripheral mouse lymphocytes in vivo was determined using the γ-H2AX biodosimetry marker. Using a serial sacrifice experimental design, whole-body radiation absorbed doses for 137Cs (0 to 10 Gy) and 90Sr (0 to 49 Gy) were delivered over 30 days following exposure to each radionuclide. The committed absorbed doses of the two internal emitters as a function of time post exposure were calculated based on their retention parameters and their derived dose coefficients for each specific sacrifice time. In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software. A key finding was that a significant γ-H2AX signal was observed in vivo several weeks after a single radionuclide exposure. A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence. Exposure to either radionuclide showed two peaks of γ-H2AX: one within the first week, which may represent the death of mature, differentiated lymphocytes, and the second at approximately three weeks, which may represent the production of new lymphocytes from damaged progenitor cells. The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis.

Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis.

PubMed

Swindell, William R; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P; Voorhees, John J; Elder, James T; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P; DiGiovanni, John; Pittelkow, Mark R; Ward, Nicole L; Gudjonsson, Johann E

2011-04-04

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.

Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting.

PubMed

Yawn, Barbara P; Colice, Gene L; Hodder, Rick

2012-01-01

Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity. Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians. The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids. There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting. Patients' comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use. This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques. Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD.

Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting

PubMed Central

Yawn, Barbara P; Colice, Gene L; Hodder, Rick

2012-01-01

Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity. Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians. The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids. There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting. Patients’ comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use. This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques. Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD. PMID:22888221

Effects of Post-Treatment Hydrogen Gas Inhalation on Uveitis Induced by Endotoxin in Rats.

PubMed

Yan, Weiming; Chen, Tao; Long, Pan; Zhang, Zhe; Liu, Qian; Wang, Xiaocheng; An, Jing; Zhang, Zuoming

2018-06-07

BACKGROUND Molecular hydrogen (H2) has been widely reported to have benefiicial effects in diverse animal models and human disease through reduction of oxidative stress and inflammation. The aim of this study was to investigate whether hydrogen gas could ameliorate endotoxin-induced uveitis (EIU) in rats. MATERIAL AND METHODS Male Sprague-Dawley rats were divided into a normal group, a model group, a nitrogen-oxygen (N-O) group, and a hydrogen-oxygen (H-O) group. EIU was induced in rats of the latter 3 groups by injection of lipopolysaccharide (LPS). After that, rats in the N-O group inhaled a gas mixture of 67% N2 and 33% O2, while those in the H-O group inhaled a gas mixture of 67% H2 and 33% O2. All rats were graded according to the signs of uveitis after electroretinography (ERG) examination. Protein concentration in the aqueous humor (AqH) was measured. Furthermore, hematoxylin-eosin staining and immunostaining of anti-ionized calcium-binding adapter molecule 1 (Iba1) in the iris and ciliary body (ICB) were carried out. RESULTS No statistically significant differences existed in the graded score of uveitis and the b-wave peak time in the Dark-adapted 3.0 ERG among the model, N-O, and H-O groups (P>0.05), while rats of the H-O group showed a lower concentration of AqH protein than that of the model or N-O group (P<0.05). The number of the infiltrating cells in the ICB of rats from the H-O group was not significantly different from that of the model or N-O group (P>0.05), while the activation of microglia cells in the H-O group was somewhat reduced (P<0.05). CONCLUSIONS Post-treatment hydrogen gas inhalation did not ameliorate the clinical signs, or reduce the infiltrating cells of EIU. However, it inhibited the elevation of protein in the AqH and reduced the microglia activation.

Relationships between Personal Measurements of 'Total' Dust, Respirable, Thoracic, and Inhalable Aerosol Fractions in the Cement Production Industry.

PubMed

Notø, Hilde P; Nordby, Karl-Christian; Eduard, Wijnand

2016-05-01

The aims of this study were to examine the relationships and establish conversion factors between 'total' dust, respirable, thoracic, and inhalable aerosol fractions measured by parallel personal sampling on workers from the production departments of cement plants. 'Total' dust in this study refers to aerosol sampled by the closed face 37-mm Millipore filter cassette. Side-by-side personal measurements of 'total' dust and respirable, thoracic, and inhalable aerosol fractions were performed on workers in 17 European and Turkish cement plants. Simple linear and mixed model regressions were used to model the associations between the samplers. The total number of personal samples collected on 141 workers was 512. Of these 8.4% were excluded leaving 469 for statistical analysis. The different aerosol fractions contained from 90 to 130 measurements and-side-by side measurements of all four aerosol fractions were collected on 72 workers.The median ratios between observed results of the respirable, 'total' dust, and inhalable fractions relative to the thoracic aerosol fractions were 0.51, 2.4, and 5.9 respectively. The ratios between the samplers were not constant over the measured concentration range and were best described by regression models. Job type, position of samplers on left or right shoulder and plant had no substantial effect on the ratios. The ratios between aerosol fractions changed with different air concentrations. Conversion models for estimation of the fractions were established. These models explained a high proportion of the variance (74-91%) indicating that they are useful for the estimation of concentrations based on measurements of a different aerosol fraction. The calculated uncertainties at most observed concentrations were below 30% which is acceptable for comparison with limit values (EN 482, 2012). The cement industry will therefore be able to predict the health related aerosol fractions from their former or future measurements of one of the fractions. © The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

MECHANISTIC DOSIMETRY MODELS OF NANOMATERIAL DEPOSITION IN THE RESPIRATORY TRACT

EPA Science Inventory

Accurate health risk assessments of inhalation exposure to nanomaterials will require dosimetry models that account for interspecies differences in dose delivered to the respiratory tract. Mechanistic models offer the advantage to interspecies extrapolation that physicochemica...

National-scale Assessment of Air Toxics Risks

EPA Science Inventory

The national-scale assessment of air toxics risks is a modeling assessment which combines emission inventory development, atmospheric fate and transport modeling, exposure modeling, and risk assessment to characterize the risk associated with inhaling air toxics from outdoor sour...

Predicting pulmonary fibrosis in humans after exposure to multi-walled carbon nanotubes (MWCNTs).

PubMed

Sharma, Monita; Nikota, Jake; Halappanavar, Sabina; Castranova, Vincent; Rothen-Rutishauser, Barbara; Clippinger, Amy J

2016-07-01

The increased production and use of multi-walled carbon nanotubes (MWCNTs) in a diverse array of consumer, medical, and industrial applications have raised concerns about potential human exposure to these materials in the workplace and ambient environments. Inhalation is a primary route of exposure to MWCNTs, and the existing data indicate that they are potentially hazardous to human health. While a 90-day rodent inhalation test (e.g., OECD Test No. 413: subchronic inhalation toxicity: 90-day study or EPA Health Effects Test Guidelines OPPTS 870.3465 90-day inhalation toxicity) is recommended by the U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics for MWCNTs (and other CNTs) if they are to be commercially produced (Godwin et al. in ACS Nano 9:3409-3417, 2015), this test is time and cost-intensive and subject to scientific and ethical concerns. As a result, there has been much interest in transitioning away from studies on animals and moving toward human-based in vitro and in silico models. However, given the multiple mechanisms of toxicity associated with subchronic exposure to inhaled MWCNTs, a battery of non-animal tests will likely be needed to evaluate the key endpoints assessed by the 90-day rodent study. Pulmonary fibrosis is an important adverse outcome related to inhalation exposure to MWCNTs and one that the non-animal approach should be able to assess. This review summarizes the state-of-the-science regarding in vivo and in vitro toxicological methods for predicting MWCNT-induced pulmonary fibrosis.

Increased use of inhaled corticosteroids among young Danish adult asthmatics: an observational study.

PubMed

Davidsen, Jesper Rømhild; Søndergaard, Jens; Hallas, Jesper; Siersted, Hans Christian; Lykkegaard, Jesper; Andersen, Morten

2010-12-01

This population-based longitudinal study aimed to investigate trends in use of inhaled corticosteroids (ICS) and determinants of ICS use in young Danish adults with asthma. 106 757 users, aged 18-44 years, of anti-asthmatic drugs were identified in the Danish Register of Medical Product Statistics during 1997-2006. One year prevalences of ICS use were calculated in categories of gender, age, and annual consumption of inhaled beta-2-agonists (IBA) in defined daily doses (DDD) per year. Determinants of ICS use were estimated by logistic regression models. The one year prevalence of ICS use was constant, approximately 64%, during 1997-2000. An annual increase was observed from 67% in 2001 to 77% in 2006. This trend also existed when stratifying on gender, age and IBA use. Using 1997 as baseline, the adjusted odds ratios (ORs) of ICS use in 2000 was 0.98 (95% CI 0.96-1.01) compared to 1.12 (95% CI 1.09-1.15) in 2001, and 1.81 (95% CI 1.75-1.87) in 2006. Other determinants of high ICS use were female gender, young age, and high annual IBA consumption. Among those using at least 400 DDD of IBA per year (corresponding to 4.4 powder inhalations daily), nearly 20% had no ICS prescriptions in 2006. Treatment with ICS among young Danish adult asthmatics has increased since 2001. This apparent improvement was associated with the introduction of fixed dose combination inhalers with ICS and inhaled long-acting beta-2-agonists. However, there is still room for improvement. Copyright © 2010 Elsevier Ltd. All rights reserved.

Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis.

PubMed

Furlan, Larissa Lazzarini; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia; Salomão Junior, João Batista; Souza, Dorotéia Rossi Silva; Marson, Fernando Augusto Lima

Interleukin 8 protein promotes inflammatory responses, even in airways. The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators. Thus, this study analyzed the interleukin 8 variants (rs4073, rs2227306, and rs2227307) and their association with the response to inhaled bronchodilators in cystic fibrosis patients. Analysis of interleukin 8 gene variants was performed by restriction fragment length polymorphism of polymerase chain reaction. The association between spirometry markers and the response to inhaled bronchodilators was evaluated by Mann-Whitney and Kruskal-Wallis tests. The analysis included all cystic fibrosis patients, and subsequently patients with two mutations in the cystic fibrosis transmembrane conductance regulator gene belonging to classes I to III. This study included 186 cystic fibrosis patients. There was no association of the rs2227307 variant with the response to inhaled bronchodilators. The rs2227306 variant was associated with FEF 50% in the dominant group and in the group with two identified mutations in the cystic fibrosis transmembrane conductance regulator gene. The rs4073 variant was associated with spirometry markers in four genetic models: co-dominant (FEF 25-75% and FEF 75% ), dominant (FEV 1 , FEF 50% , FEF 75% , and FEF 25-75% ), recessive (FEF 75% and FEF 25-75% ), and over-dominant (FEV 1 /FVC). This study highlighted the importance of the rs4073 variant of the interleukin 8 gene, regarding response to inhaled bronchodilators, and of the assessment of mutations in the cystic fibrosis transmembrane conductance regulator gene. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Deposition and clearance of 2 μ particles in the tracheobronchial tree of normal subjects—smokers and nonsmokers

PubMed Central

Lourenço, Ruy V.; Klimek, Mary F.; Borowski, Claudia J.

1971-01-01

Deposition and clearance of inhaled particles of iron oxide labeled with 198Au were studied in 19 normal subjects (10 nonsmokers and 9 smokers). For this purpose, monodisperse aerosols of particles with a 2 μ diameter were produced in a spinning disc atomizer. Thoracic counts and images with a scintillation camera were begun immediately after inhalation of the aerosol and continued for 6 hr. In all subjects, smokers and nonsmokers, the deposition of the particles was uniform throughout both lung fields, with approximately half of the particles deposited in the ciliated airways (tracheobronchial deposition) and half in the nonciliated airways (alveolar deposition). Tracheobronchial clearance in nonsmokers occurred immediately after inhalation, first at a fast rate for particles deposited in the largest and most central airways, and then at a slower rate for particles from the smaller and more peripheral airways. Photoscintigrams showed that the particles cleared steadily with no retention in any area. The general pattern of clearance may be likened to a model of multiple conveyor belts with speed increasing from the peripheral to the central airways in such a way as to prevent “particle jams” at airway confluence points. In smokers, tracheobronchial clearance was delayed for periods of 1-4 hr after inhalation. Furthermore, in contrast with the findings in nonsmokers, significant clearance was still occurring in many of the smokers in the 5th and 6th hr after inhalation. Also, photoscintigrams showed an abnormal accumulation of particles in the large airways several hours after inhalation of the aerosol. Images PMID:5090057

Teaching inhaler use in chronic obstructive pulmonary disease patients.

PubMed

Lareau, Suzanne C; Hodder, Richard

2012-02-01

To review barriers to the successful use of inhalers in patients with chronic obstructive pulmonary disease (COPD), and the role of the nurse practitioner (NP) in facilitating optimum inhaler use. Review of the national and international scientific literature. Pharmacologic treatment of COPD patients comprises mainly inhaled medications. Incorrect use of inhalers is very common in these individuals. Some of the consequences of poor inhaler technique include reduced therapeutic dosing, medication adherence, and disease stability, which can lead to increased morbidity, decreased quality of life, and a high burden on the healthcare system. Knowledgeable evaluation and frequent reassessment of inhaler use coupled with education of patients, caregivers, and healthcare professionals can significantly improve the benefits COPD patients derive from inhaled therapy. Patient education is vital for correct use of inhalers and to ensure the effectiveness of inhaled medications. The NP has a critical role in assessing potential barriers to successful learning by the patient and improving inhaler technique and medication management. The NP can also facilitate success with inhaled medications by providing up-to-date inhaler education for other healthcare team members, who may then act as patient educators. ©2011 The Author(s) Journal compilation ©2011 American Academy of Nurse Practitioners.

The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.

PubMed

Xie, Zhongcong; Culley, Deborah J; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D; Frosch, Matthew P; Crosby, Gregory; Tanzi, Rudolph E

2008-12-01

An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed. We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.

Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects

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

Haschek, W.M.; Boyd, M.R.; Hakkinen, P.J.

1984-01-01

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male BALB/c mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 mumol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0%more » compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.« less

Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms.

PubMed

Croze, Marine L; Zimmer, Luc

2018-01-01

Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

Inhaled Asthma Medications

MedlinePlus

... metered – dose inhaler (MDI), which uses a chemical propellant to push the medication out of the inhaler. ... powder inhalers (DPIs) deliver medication without using chemical propellants, but they require a strong and fast inhalation. ...

Application of MODIS GPP to Forecast Risk of Hantavirus Pulmonary Syndrome Based on Fluctuations in Reservoir Population Density

NASA Astrophysics Data System (ADS)

Loehman, R.; Heinsch, F. A.; Mills, J. N.; Wagoner, K.; Running, S.

2003-12-01

Recent predictive models for hantavirus pulmonary syndrome (HPS) have used remotely sensed spectral reflectance data to characterize risk areas with limited success. We present an alternative method using gross primary production (GPP) from the MODIS sensor to estimate the effects of biomass accumulation on population density of Peromyscus maniculatus (deer mouse), the principal reservoir species for Sin Nombre virus (SNV). The majority of diagnosed HPS cases in North America are attributed to SNV, which is transmitted to humans through inhalation of excretions and secretions from infected rodents. A logistic model framework is used to evaluate MODIS GPP, temperature, and precipitation as predictors of P. maniculatus density at established trapping sites across the western United States. Rodent populations are estimated using monthly minimum number alive (MNA) data for 2000 through 2002. Both local meteorological data from nearby weather stations and 1.25 degree x 1 degree gridded data from the NASA DAO were used in the regression model to determine the spatial sensitivity of the response. MODIS eight-day GPP data (1-km resolution) were acquired and binned to monthly average and monthly sum GPP for 3km x 3km grids surrounding each rodent trapping site. The use of MODIS GPP to forecast HPS risk may result in a marked improvement over past reflectance-based risk area characterizations. The MODIS GPP product provides a vegetation dynamics estimate that is unique to disease models, and targets the fundamental ecological processes responsible for increased rodent density and amplified disease risk.

C 60 fullerene localization and membrane interactions in RAW 264.7 immortalized mouse macrophages

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

Russ, K. A.; Elvati, P.; Parsonage, T. L.

There continues to be a significant increase in the number and complexity of hydrophobic nanomaterials that are engineered for a variety of commercial purposes making human exposure a significant health concern. This study uses a combination of biophysical, biochemical and computational methods to probe potential mechanisms for uptake of C 60 nanoparticles into various compartments of living immune cells. Cultures of RAW 264.7 immortalized murine macrophage were used as a canonical model of immune-competent cells that are likely to provide the first line of defense following inhalation. Modes of entry studied were endocytosis/pinocytosis and passive permeation of cellular membranes. Themore » evidence suggests marginal uptake of C 60 clusters is achieved through endocytosis/pinocytosis, and that passive diffusion into membranes provides a significant source of biologically-available nanomaterial. Compu-tational modeling of both a single molecule and a small cluster of fullerenes predicts that low concentrations of fullerenes enter the membrane individually and produce limited perturbation; however, at higher concentrations the clusters in the membrane causes deformation of the membrane. These findings are bolstered by nuclear magnetic resonance (NMR) of model membranes that reveal defor-mation of the cell membrane upon exposure to high concentrations of fullerenes. The atomistic and NMR models fail to explain escape of the particle out of biological membranes, but are limited to idealized systems that do not completely recapitulate the complexity of cell membranes. Lastly, the surprising contribution of passive modes of cellular entry provides new avenues for toxicological research that go beyond the pharmacological inhibition of bulk transport systems such as pinocytosis.« less

C 60 fullerene localization and membrane interactions in RAW 264.7 immortalized mouse macrophages

DOE PAGES

Russ, K. A.; Elvati, P.; Parsonage, T. L.; ...

2016-01-01

There continues to be a significant increase in the number and complexity of hydrophobic nanomaterials that are engineered for a variety of commercial purposes making human exposure a significant health concern. This study uses a combination of biophysical, biochemical and computational methods to probe potential mechanisms for uptake of C 60 nanoparticles into various compartments of living immune cells. Cultures of RAW 264.7 immortalized murine macrophage were used as a canonical model of immune-competent cells that are likely to provide the first line of defense following inhalation. Modes of entry studied were endocytosis/pinocytosis and passive permeation of cellular membranes. Themore » evidence suggests marginal uptake of C 60 clusters is achieved through endocytosis/pinocytosis, and that passive diffusion into membranes provides a significant source of biologically-available nanomaterial. Compu-tational modeling of both a single molecule and a small cluster of fullerenes predicts that low concentrations of fullerenes enter the membrane individually and produce limited perturbation; however, at higher concentrations the clusters in the membrane causes deformation of the membrane. These findings are bolstered by nuclear magnetic resonance (NMR) of model membranes that reveal defor-mation of the cell membrane upon exposure to high concentrations of fullerenes. The atomistic and NMR models fail to explain escape of the particle out of biological membranes, but are limited to idealized systems that do not completely recapitulate the complexity of cell membranes. Lastly, the surprising contribution of passive modes of cellular entry provides new avenues for toxicological research that go beyond the pharmacological inhibition of bulk transport systems such as pinocytosis.« less

Empowering family physicians to impart proper inhaler teaching to patients with chronic obstructive pulmonary disease and asthma

PubMed Central

Leung, Janice M; Bhutani, Mohit; Leigh, Richard; Pelletier, Dan; Good, Cathy; Sin, Don D

2015-01-01

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and asthma depend on inhalers for management, but critical errors committed during inhaler use can limit drug effectiveness. Outpatient education in inhaler technique remains inconsistent due to limited resources and inadequate provider knowledge. OBJECTIVE: To determine whether a simple, two-session inhaler education program can improve physician attitudes toward inhaler teaching in primary care practice. METHODS: An inhaler education program with small-group hands-on device training was instituted for family physicians (FP) in British Columbia and Alberta. Sessions were spaced one to three months apart. All critical errors were corrected in the first session. Questionnaires surveying current inhaler teaching practices and attitudes toward inhaler teaching were distributed to physicians before and after the program. RESULTS: Forty-one (60%) of a total 68 participating FPs completed both before and after program questionnaires. Before the program, only 20 (49%) reported providing some form of inhaler teaching in their practices, and only four (10%) felt fully competent to teach patients inhaler technique. After the program, 40 (98%) rated their inhaler teaching as good to excellent. Thirty-four (83%) reported providing inhaler teaching in their practices, either by themselves or by an allied health care professional they had personally trained. All stated they could teach inhaler technique within 5 min. Observation of FPs during the second session by certified respiratory educators found that none made critical errors and all had excellent technique. CONCLUSION: A physician inhaler education program can improve attitudes toward inhaler teaching and facilitate implementation in clinical practices. PMID:26436910

Tea tree oil nanoemulsions for inhalation therapies of bacterial and fungal pneumonia.

PubMed

Li, Miao; Zhu, Lifei; Liu, Boming; Du, Lina; Jia, Xiaodong; Han, Li; Jin, Yiguang

2016-05-01

Tea tree oil (TTO) is a natural essential oil with strong antimicrobial efficacy and little drug resistance. However, the biomedical applications of TTO are limited due to its hydrophobicity and formulation problems. Here, we prepared an inhalable TTO nanoemulsion (nanoTTO) for local therapies of bacterial and fungal pneumonia. The optimal formulation of nanoTTOs consisted of TTO/Cremophor EL/water with a mean size of 12.5nm. The nanoTTOs showed strong in vitro antimicrobial activities on Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus and Candida albicans. After inhalation to the lung, the nanoTTOs had higher anti-fungal effect than fluconazole on the fungal pneumonia rat models with reduced lung injury, highly microbial clearance, blocking of leukocyte recruitment, and decrease of pro-inflammatory mediators. In the case of rat bacterial pneumonia, the nanoTTOs showed slightly lower therapeutic efficacy than penicillin though at a much lower dose. Taken together, our results show that the inhalable nanoTTOs are promising nanomedicines for local therapies of fungal and bacterial pneumonia with no obvious adverse events. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimizing mouse models of neurodegenerative disorders: are therapeutics in sight?

PubMed

Lutz, Cathleen M; Osborne, Melissa A

2013-01-01

The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease.

Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis

PubMed Central

von Scheidt, Moritz; Zhao, Yuqi; Kurt, Zeyneb; Pan, Calvin; Zeng, Lingyao; Yang, Xia; Schunkert, Heribert; Lusis, Aldons J.

2017-01-01

Most of the biological understanding of mechanisms underlying coronary artery disease (CAD) derives from studies of mouse models. The identification of multiple CAD loci and strong candidate genes in large human genome-wide association studies (GWAS) presented an opportunity to examine the relevance of mouse models for the human disease. We comprehensively reviewed the mouse literature, including 827 literature-derived genes, and compared it to human data. First, we observed striking concordance of risk factors for atherosclerosis in mice and humans. Second, there was highly significant overlap of mouse genes with human genes identified by GWAS. In particular, of the 46 genes with strong association signals in CAD-GWAS that were studied in mouse models all but one exhibited consistent effects on atherosclerosis-related phenotypes. Third, we compared 178 CAD-associated pathways derived from human GWAS with 263 from mouse studies and observed that over 50% were consistent between both species. PMID:27916529

Genetically engineered mouse models for studying inflammatory bowel disease.

PubMed

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2016-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mouse Tumor Biology (MTB): a database of mouse models for human cancer.

PubMed

Bult, Carol J; Krupke, Debra M; Begley, Dale A; Richardson, Joel E; Neuhauser, Steven B; Sundberg, John P; Eppig, Janan T

2015-01-01

The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer-reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

The latest animal models of ovarian cancer for novel drug discovery.

PubMed

Magnotti, Elizabeth; Marasco, Wayne A

2018-03-01

Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.

How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

PubMed Central

Politi, Katerina; Pao, William

2011-01-01

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review. PMID:21263096

Integrating model behavior, optimization, and sensitivity/uncertainty analysis: overview and application of the MOUSE software toolbox

USDA-ARS?s Scientific Manuscript database

This paper provides an overview of the Model Optimization, Uncertainty, and SEnsitivity Analysis (MOUSE) software application, an open-source, Java-based toolbox of visual and numerical analysis components for the evaluation of environmental models. MOUSE is based on the OPTAS model calibration syst...

Inhalant Use and Inhalant Use Disorders in the United States

PubMed Central

Howard, Matthew O.; Bowen, Scott E.; Garland, Eric L.; Perron, Brian E.; Vaughn, Michael G.

2011-01-01

More than 22 million Americans age 12 and older have used inhalants, and every year more than 750,000 use inhalants for the first time. Despite the substantial prevalence and serious toxicities of inhalant use, it has been termed “the forgotten epidemic.” Inhalant abuse remains the least-studied form of substance abuse, although research on its epidemiology, neurobiology, treatment, and prevention has accelerated in recent years. This review examines current findings in these areas, identifies gaps in the research and clinical literatures pertaining to inhalant use, and discusses future directions for inhalant-related research and practice efforts. PMID:22003419

Investigation into pedestrian exposure to near-vehicle exhaust emissions

PubMed Central

2009-01-01

Background Inhalation of diesel particulate matter (DPM) is known to have a negative impact on human health. Consequently, there are regulations and standards that limit the maximum concentrations to which persons may be exposed and the maximum concentrations allowed in the ambient air. However, these standards consider steady exposure over large spatial and time scales. Due to the nature of many vehicle exhaust systems, pedestrians in close proximity to a vehicle's tailpipe may experience events where diesel particulate matter concentrations are high enough to cause acute health effects for brief periods of time. Methods In order to quantify these exposure events, instruments which measure specific exhaust constituent concentrations were placed near a roadway and connected to the mouth of a mannequin used as a pedestrian surrogate. By measuring concentrations at the mannequin's mouth during drive-by events with a late model diesel truck, a representative estimate of the exhaust constituent concentrations to which a pedestrian may be exposed was obtained. Typical breathing rates were then multiplied by the measured concentrations to determine the mass of pollutant inhaled. Results The average concentration of diesel particulate matter measured over the duration of a single drive-by test often exceeded the low concentrations used in human clinical studies which are known to cause acute health effects. It was also observed that higher concentrations of diesel particulate matter were measured at the height of a stroller than were measured at the mouth of a mannequin. Conclusion Diesel particulate matter concentrations during drive-by incidents easily reach or exceed the low concentrations that can cause acute health effects for brief periods of time. For the case of a particularly well-tuned late-model year vehicle, the mass of particulate matter inhaled during a drive-by incident is small compared to the mass inhaled daily at ambient conditions. On a per breath basis, however, the mass of particulate matter inhaled is large compared to the mass inhaled at ambient conditions. Finally, it was determined that children, infants, or people breathing at heights similar to that of a passing vehicle's tailpipe may be exposed to higher concentrations of particulate matter than those breathing at higher locations, such as adults standing up. PMID:19331669

[Did the patients with chronic obstructive pulmonary disease in Primary Care center Anton de Borja correctly utilize inhalers?].

PubMed

Represas-Carrera, Francisco Jesús

2015-01-01

To determine the percentage of patients with Pulmonary Obstructive Chronic Disease who doing of incorrect form the inhaler technique. Descriptive transversal study made in the Primary Care Center "Antón de Borja" of Rubi (in Barcelona) during the period between May and December 2013, where it was studied a representative sample of 200 patients. To assess the inhaler technique was performed a personal interview with the patient in which it was requested him to carry out a demonstration of how he was using his inhaler regularly evaluating his inhaler technique by means of the regulations established by Spanish Society of Pneumology and Thoracic Surgery. 43% of the patients carry out inhaler technique incorrectly. The percentage of inadequate use of inhalers of dry powder was 26%, of the pressurized cartridge 38% and the inhaler chamber 10%. 82% of patients ≥ 65 years who have prescribed a pressurized inhaler cartridge do not perform accompanied by an inhaler chamber. A high percentage of patients do not correctly carry out inhaler technique, pointing the rare use made of the inhaler chamber despite its proven efficacy and the high number of patients with pressurized inhaler cartridge. These results reflect the need for the implementation of an educational program in our Primary Care Center to teach patients to use inhaler devices. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Predictive Models and Tools for Screening Chemicals under TSCA: Consumer Exposure Models 1.5

EPA Pesticide Factsheets

CEM contains a combination of models and default parameters which are used to estimate inhalation, dermal, and oral exposures to consumer products and articles for a wide variety of product and article use categories.

Computational 3-D Model of the Human Respiratory System

EPA Science Inventory

We are developing a comprehensive, morphologically-realistic computational model of the human respiratory system that can be used to study the inhalation, deposition, and clearance of contaminants, while being adaptable for age, race, gender, and health/disease status. The model ...

Evaluation of Nicotine Pharmacokinetics and Subjective Effects following Use of a Novel Nicotine Delivery System.

PubMed

Teichert, Axel; Brossard, Patrick; Felber Medlin, Loyse; Sandalic, Larissa; Franzon, Mikael; Wynne, Chris; Laugesen, Murray; Lüdicke, Frank

2018-03-06

Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated. This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff, delivered by the P3L system were evaluated consecutively on different days after the use of the Nicorette inhalator. Venous nicotine PK, subjective effects, and tolerability were assessed. Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette inhalator. Craving reduction was slightly faster than with the Nicorette inhalator as assessed with the visual analog scale craving score. The mean Questionnaire of Smoking Urges -brief total scores did not differ for both products. P3L was well tolerated. At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette inhalator. The plasma nicotine concentration-time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette inhalator. The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems. Altogether, the PK profile, subjective effects, and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.

AGE-DEPENDENT INHALATION DOSE DUE TO EXPOSURE OF SHORT LIVED PROGENY OF RADON AND THORON FOR DIFFERENT AGE GROUPS IN JAMMU & KASHMIR, HIMALAYAS.

PubMed

Sharma, Sumit; Kumar, Ajay; Mehra, Rohit

2018-05-16

Dosimetric approach is used in this study for the assessment of doses due to inhalation of short lived radon/thoron progeny to the inhabitants of Udhampur district of Jammu & Kashmir. This paper also presents the activity concentrations and unattached fraction of radon and thoron progeny. The observed annual concentration of attached and unattached 222Rn and 220Rn progeny has been found to vary from 8 to 32 and 0.09 to 14 Bq/m3, 0.75 to 3.16 and 0.01 to 1.13 Bq/m3, respectively. The inhalation doses from radon progeny to different body organs of different age groups have been calculated by using the age dependent biokinetic model. The attachment rate of 222Rn and indoor aerosol concentration of 222Rn and 220Rn have been estimated and their relation between them has also been studied. The dose conversion factor for mouth and nasal breathing to different exposure conditions has been obtained from Porstendorfer model.

Estimating human-equivalent no observed adverse-effect levels for VOCs (volatile organic compounds) based on minimal knowledge of physiological parameters. Technical paper

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

Overton, J.H.; Jarabek, A.M.

1989-01-01

The U.S. EPA advocates the assessment of health-effects data and calculation of inhaled reference doses as benchmark values for gauging systemic toxicity to inhaled gases. The assessment often requires an inter- or intra-species dose extrapolation from no observed adverse effect level (NOAEL) exposure concentrations in animals to human equivalent NOAEL exposure concentrations. To achieve this, a dosimetric extrapolation procedure was developed based on the form or type of equations that describe the uptake and disposition of inhaled volatile organic compounds (VOCs) in physiologically-based pharmacokinetic (PB-PK) models. The procedure assumes allometric scaling of most physiological parameters and that the value ofmore » the time-integrated human arterial-blood concentration must be limited to no more than to that of experimental animals. The scaling assumption replaces the need for most parameter values and allows the derivation of a simple formula for dose extrapolation of VOCs that gives equivalent or more-conservative exposure concentrations values than those that would be obtained using a PB-PK model in which scaling was assumed.« less

ASSESSING INTERNAL CONTAMINATION AFTER THE DETONATION OF A RADIOLOGICAL DISPERSION DEVICE USING A 2×2-INCH SODIUM IODIDE DETECTOR

PubMed Central

Dewji, S.; Hertel, N.; Ansari, A.

2017-01-01

The detonation of a radiological dispersion device may result in a situation where individuals inhale radioactive materials and require rapid assessment of internal contamination. The feasibility of using a 2×2-inch sodium-iodide detector to determine the committed effective dose to an individual following acute inhalation of gamma-emitting radionuclides was investigated. Experimental configurations of point sources with a polymethyl methacrylate slab phantom were used to validate Monte Carlo simulations. The validated detector model was used to simulate the responses for four detector positions on six different anthropomorphic phantoms. The nuclides examined included 241Am, 60Co, 137Cs, 131I and 192Ir. Biokinetic modelling was employed to determine the distributed activity in the body as a function of post-inhalation time. The simulation and biokinetic data were used to determine time-dependent count-rate values at optimal detector locations on the body for each radionuclide corresponding to a target committed effective dose (E50) value of 250 mSv. PMID:23436621

Disrupting the male germ line to find infertility and contraception targets.

PubMed

Archambeault, Denise R; Matzuk, Martin M

2014-05-01

Genetically-manipulated mouse models have become indispensible for broadening our understanding of genes and pathways related to male germ cell development. Until suitable in vitro systems for studying spermatogenesis are perfected, in vivo models will remain the gold standard for inquiry into testicular function. Here, we discuss exciting advances that are allowing researchers faster, easier, and more customizable access to their mouse models of interest. Specifically, the trans-NIH Knockout Mouse Project (KOMP) is working to generate knockout mouse models of every gene in the mouse genome. The related Knockout Mouse Phenotyping Program (KOMP2) is performing systematic phenotypic analysis of this genome-wide collection of knockout mice, including fertility screening. Together, these programs will not only uncover new genes involved in male germ cell development but also provide the research community with the mouse models necessary for further investigations. In addition to KOMP/KOMP2, another promising development in the field of mouse models is the advent of CRISPR (clustered regularly interspaced short palindromic repeat)-Cas technology. Utilizing 20 nucleotide guide sequences, CRISPR/Cas has the potential to introduce sequence-specific insertions, deletions, and point mutations to produce null, conditional, activated, or reporter-tagged alleles. CRISPR/Cas can also successfully target multiple genes in a single experimental step, forgoing the multiple generations of breeding traditionally required to produce mouse models with deletions, insertions, or mutations in multiple genes. In addition, CRISPR/Cas can be used to create mouse models carrying variants identical to those identified in infertile human patients, providing the opportunity to explore the effects of such mutations in an in vivo system. Both the KOMP/KOMP2 projects and the CRISPR/Cas system provide powerful, accessible genetic approaches to the study of male germ cell development in the mouse. A more complete understanding of male germ cell biology is critical for the identification of novel targets for potential non-hormonal contraceptive intervention. Copyright © 2014. Published by Elsevier Masson SAS.

Synergistic effect of sevoflurane and isoflurane on inhibition of the adult-type muscle nicotinic acetylcholine receptor by rocuronium.

PubMed

Liu, Li; Li, Wei; Wei, Ke; Cao, Jun; Luo, Jie; Wang, Bin; Min, Su

2013-06-01

Inhaled anesthetics increase the incidence of postoperative residual neuromuscular blockade, and the mechanism is still unclear. We have investigated the synergistic effect of low-concentration inhaled anesthetics and rocuronium on inhibition of the inward current of the adult-type muscle nicotinic acetylcholine receptor (ε-nAChR). Adult-type mouse muscle ε-nAChR was expressed in HEK293 cells by liposome transfection. The inward current of the ε-nAChR was activated by use of 10 μmol/L acetylcholine alone or in combination with different concentrations of sevoflurane, isoflurane, or rocuronium. The concentration-response curves of five cells were constructed, and the data yielded the 5, 25, and 50 % inhibitory concentrations (IC5, IC25, and IC50, respectively) for single-drug application. Subsequently, the functional channels were perfused by adding 0.5 IC5 of either sevoflurane or isoflurane (aqueous concentrations 140 and 100 μmol/L, respectively) to the solution, followed by addition of IC5, IC25, or IC50 rocuronium. The amount of inhibition was calculated to quantify their synergistic effect. The inhibitory effect of rocuronium was enhanced by sevoflurane or isoflurane in a concentration-dependent manner. Sevoflurane or isoflurane (0.5 IC5) with rocuronium at IC5, IC25, and IC50 synergistically inhibited the current amplitude of adult-type muscle ε-nAChR. When the IC5 of rocuronium was used, isoflurane had a stronger synergistic effect than sevoflurane (p < 0.05). When rocuronium was applied at higher concentrations (IC25 and IC50), sevoflurane had an effect similar to that of isoflurane. For both inhaled anesthetics, the synergistic effect was more intense for rocuronium at IC5 than for rocuronium at IC25 or IC50. Residual-concentration sevoflurane or isoflurane has a strong synergistic effect with rocuronium at clinically relevant residual concentrations. A lower rocuronium concentration resulted in a stronger synergistic effect.

Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

PubMed Central

Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.

2011-01-01

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. PMID:21483750

Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta)

PubMed Central

Chang, Steve W. C.; Barter, Joseph W.; Ebitz, R. Becket; Watson, Karli K.; Platt, Michael L.

2012-01-01

People attend not only to their own experiences, but also to the experiences of those around them. Such social awareness profoundly influences human behavior by enabling observational learning, as well as by motivating cooperation, charity, empathy, and spite. Oxytocin (OT), a neurosecretory hormone synthesized by hypothalamic neurons in the mammalian brain, can enhance affiliation or boost exclusion in different species in distinct contexts, belying any simple mechanistic neural model. Here we show that inhaled OT penetrates the CNS and subsequently enhances the sensitivity of rhesus macaques to rewards occurring to others as well as themselves. Roughly 2 h after inhaling OT, monkeys increased the frequency of prosocial choices associated with reward to another monkey when the alternative was to reward no one. OT also increased attention to the recipient monkey as well as the time it took to render such a decision. In contrast, within the first 2 h following inhalation, OT increased selfish choices associated with delivery of reward to self over a reward to the other monkey, without affecting attention or decision latency. Despite the differences in species typical social behavior, exogenous, inhaled OT causally promotes social donation behavior in rhesus monkeys, as it does in more egalitarian and monogamous ones, like prairie voles and humans, when there is no perceived cost to self. These findings potentially implicate shared neural mechanisms. PMID:22215593

STATUS REPORT: EVIDENCE BASED ADVANCES IN ...

EPA Pesticide Factsheets

This report summarizes the status of specific inhalation dosimetry procedures for gases as outlined in U.S. EPA’s 1994 Methods for Derivation of Inhalation Reference Concentrations and Applications of Inhalation Dosimetry (U.S. EPA 1994) and reviews recent scientific advances in gas dosimetry related to these procedures. These procedures are used predominately for interspecies extrapolation, typically from laboratory animal inhalation exposures to humans. The specific procedures addressed in this report are those used for the tracheobronchial (TB) and pulmonary (PU) regions of the respiratory tract and the procedure used for the systemic or extrarespiratory (ER) region. In addition, this report presents, reviews and discusses information and data on inhalation dosimetry in children and the adequacy of the procedures in the RfC Methods with regard to children. For the purposes of this report the scientific literature was searched from 1985 (about 10 years prior to the issuance of RfC Methods) to April 30, 2011. The studies identified in this update addressing overall concepts and approaches for portal-of-entry gas dosimetry in the TB and PU regions of the airways support the principles and procedures in RfC Methods. In some cases these studies suggest and provide examples of further refinement within the existing dosimetry modeling framework of the RfC Methods through development and application of mass transfer coefficients as regional measures of gas up

Quantitative cancer risk assessment for ethylene oxide inhalation in occupational settings.

PubMed

Valdez-Flores, Ciriaco; Sielken, Robert L; Teta, M Jane

2011-10-01

The estimated occupational ethylene oxide (EO) exposure concentrations corresponding to specified extra risks are calculated for lymphoid mortality as the most appropriate endpoint, despite the lack of a statistically significant exposure-response relationship. These estimated concentrations are for occupational exposures--40 years of occupational inhalation exposure to EO from age 20 to age 60 years. The estimated occupational inhalation exposure concentrations (ppm) corresponding to specified extra risks of lymphoid mortality to age 70 years in a population of male and female EO workers are based on Cox proportional hazards models of the most recent updated epidemiology cohort mortality studies of EO workers and a standard life-table calculation. An occupational exposure at an inhalation concentration of 2.77 ppm EO is estimated to result in an extra risk of lymphoid mortality of 4 in 10,000 (0.0004) in the combined worker population of men and women from the two studies. The corresponding estimated concentration decreases slightly to 2.27 ppm when based on only the men in the updated cohorts combined. The difference in these estimates reflects the difference between combining all of the available data or focusing on only the men and excluding the women who did not show an increase in lymphoid mortality with EO inhalation exposure. The results of sensitivity analyses using other mortality endpoints (all lymphohematopoietic tissue cancers, leukemia) support the choice of lymphoid tumor mortality for estimation of extra risk.

Development of an Improved Inhalable Powder Formulation of Pirfenidone by Spray-Drying: In Vitro Characterization and Pharmacokinetic Profiling.

PubMed

Seto, Yoshiki; Suzuki, Gen; Leung, Sharon Shui Yee; Chan, Hak-Kim; Onoue, Satomi

2016-06-01

Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method. Spray-dried PFD (SD/PFD) was prepared by spray-drying with L-leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations. Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 μm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose. SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD.

Size distribution of salbutamol/ipratropium aerosols produced by different nebulizers in the absence and presence of heat and humidification.

PubMed

Yang, Ssu-Han; Yang, Tsung-Ming; Lin, Hui-Ling; Tsai, Ying-Huang; Fang, Tien-Pei; Wan, Gwo-Hwa

2018-02-01

Few studies have evaluated the size distribution of inhaled and exhaled aerosolized drugs, or the effect of heated humidification on particle size and lung deposition. The present study evaluated these aspects of bronchodilator (salbutamol/ipratropium) delivery using a lung model in the absence and presence of heat and humidification. We positioned filters to collect and measure the initial drug, inhaled drug, and exhaled drug. Particle size distribution was evaluated using an 8-stage Marple personal cascade impactor with 0.2-μm polycarbonate filters. A greater inhaled drug mass was delivered using a vibrating mesh nebulizer (VMN) than by using a small volume nebulizer (SVN), when heated humidifiers were not employed. When heated and humidified medical gas was used, there was no significant difference between the inhaled drug mass delivered by the VMN and that delivered by the SVN. A significantly greater mass of inhaled 1.55-μm drug particles was produced by the VMN than with the SVN, under heated and humidified conditions. However, the mass median aerodynamic diameters (MMADs) of the aerosolized drug produced by the SVN and VMN did not differ significantly under the same conditions. The VMN produced more fine particles of salbutamol/ipratropium, and the drug particle size clearly increased in the presence of heat and humidification. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation.

PubMed

Leifer, Franziska G; Konicek, Donna M; Chen, Kuan-Ju; Plaunt, Adam J; Salvail, Dany; Laurent, Charles E; Corboz, Michel R; Li, Zhili; Chapman, Richard W; Perkins, Walter R; S Malinin, Vladimir

2018-05-23

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C max compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high C max -associated adverse events which could provide patients with an improved treprostinil therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Dosimetric assessment from 212Pb inhalation at a thorium purification plant.

PubMed

Campos, M P; Pecequilo, B R S

2004-01-01

At the Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, Brazil, there is a facility (thorium purification plant) where materials with high thorium concentrations are manipulated. In order to estimate afterwards the lung cancer risk for the workers, the thoron daughter (212Pb) levels were assessed and the committed effective and lung committed equivalent doses for workers in place. A total of 28 air filter samples were measured by total alpha counting through the modified Kusnetz method, to determine the 212Pb concentraion. The committed effective dose and lung committed equivalent dose due to 212Pb inhalation were derived from compartmental analysis following the ICRP 66 lung compartmental model, and ICRP 67 lead metabolic model.

CEM-Consumer Exposure Model Download and Install Instructions

EPA Pesticide Factsheets

CEM contains a combination of models and default parameters which are used to estimate inhalation, dermal, and oral exposures to consumer products and articles for a wide variety of product and article use categories.

Assessing fullness of asthma patients' aerosol inhalers.

PubMed

Rickenbach, M A; Julious, S A

1994-07-01

The importance of regular medication in order to control asthma symptoms is recognized. However, there is no accurate mechanism for assessing the fullness of aerosol inhalers. The contribution to asthma morbidity of unexpectedly running out of inhaled medication is unknown. A study was undertaken to determine how patients assess inhaler fullness and the accuracy of their assessments, and to evaluate the floatation method of assessing inhaler fullness. An interview survey of 98 patients (51% of those invited to take part), using 289 inhalers, was completed at one general practice in Hampshire. One third of participants said they had difficulty assessing aerosol inhaler fullness and those aged 60 years and over were found to be more inaccurate in assessing fullness than younger participants. Shaking the inhaler to feel the contents move was the commonest method of assessment. When placed in water, an inhaler canister floating on its side with a corner of the canister valve exposed to air indicates that the canister is less than 15% full (sensitivity 90%, specificity 99%). Floating a canister in water provides an objective measurement of aerosol inhaler fullness. Providing the method is recommended by the aerosol inhaler manufacturer, general practitioners should demonstrate the floatation method to patients experiencing difficulty in assessing inhaler fullness.

Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats

PubMed Central

Pravetoni, M; Keyler, DE; Raleigh, MD; Harris, AC; LeSage, MG; Mattson, CK; Pettersson, S; Pentel, PR

2011-01-01

Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 minute nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a two hour whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular midday smoking. Vaccination prior to 10 min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 hr smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 hr WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21–25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation. PMID:21333633

[Effect of topical application of a recombinant adenovirus carrying promyelocytic leukemia gene in a psoriasis-like mouse model].

PubMed

Wang, Qiongyu; Zhang, Aijun; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

2013-03-01

To investigate the effects of topical treatment with adenovirus-mediated promyelocytic leukemia gene (PML) gene in a psoriasis-like mouse model. The effect of adenovirus-mediated PML gene on the granular layer of mouse tail scale epidermis and epithelial mitosis were observed on longitudinal histological sections prepared from the tail skin and vaginal epithelium of the mice. Adenovirus-mediated PML gene significantly inhibited mitosis of mouse vaginal epithelial cells and promoted the formation of granular layer in mouse tail scale epidermis. The therapeutic effect of PML gene in the psoriasis-like mouse model may be associated with increased granular cells and suppressed epidemic cell proliferation.

[Application of predictive model to estimate concentrations of chemical substances in the work environment].

PubMed

Kupczewska-Dobecka, Małgorzata; Czerczak, Sławomir; Jakubowski, Marek; Maciaszek, Piotr; Janasik, Beata

2010-01-01

Based on the Estimation and Assessment of Substance Exposure (EASE) predictive model implemented into the European Union System for the Evaluation of Substances (EUSES 2.1.), the exposure to three chosen organic solvents: toluene, ethyl acetate and acetone was estimated and compared with the results of measurements in workplaces. Prior to validation, the EASE model was pretested using three exposure scenarios. The scenarios differed in the decision tree of pattern of use. Five substances were chosen for the test: 1,4-dioxane tert-methyl-butyl ether, diethylamine, 1,1,1-trichloroethane and bisphenol A. After testing the EASE model, the next step was the validation by estimating the exposure level and comparing it with the results of measurements in the workplace. We used the results of measurements of toluene, ethyl acetate and acetone concentrations in the work environment of a paint and lacquer factory, a shoe factory and a refinery. Three types of exposure scenarios, adaptable to the description of working conditions were chosen to estimate inhalation exposure. Comparison of calculated exposure to toluene, ethyl acetate and acetone with measurements in workplaces showed that model predictions are comparable with the measurement results. Only for low concentration ranges, the measured concentrations were higher than those predicted. EASE is a clear, consistent system, which can be successfully used as an additional component of inhalation exposure estimation. If the measurement data are available, they should be preferred to values estimated from models. In addition to inhalation exposure estimation, the EASE model makes it possible not only to assess exposure-related risk but also to predict workers' dermal exposure.

Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways

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

Kabilan, S.; Suffield, S. R.; Recknagle, K. P.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation–exhalation breathingmore » conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.« less

Development of Combining of Human Bronchial Mucosa Models with XposeALI® for Exposure of Air Pollution Nanoparticles.

PubMed

Ji, Jie; Hedelin, Anna; Malmlöf, Maria; Kessler, Vadim; Seisenbaeva, Gulaim; Gerde, Per; Palmberg, Lena

2017-01-01

Exposure to agents via inhalation is of great concerns both in workplace environment and in the daily contact with particles in the ambient air. Reliable human airway exposure systems will most likely replace animal experiment in future toxicity assessment studies of inhaled agents. In this study, we successfully established a combination of an exposure system (XposeALI) with 3D models mimicking both healthy and chronic bronchitis-like mucosa by co-culturing human primary bronchial epithelial cells (PBEC) and fibroblast at air-liquid interface (ALI). Light-, confocal microscopy, scanning- and transmission electron microscopy, transepithelial electrical resistance (TEER) measurement and RT-PCR were performed to identify how the PBEC differentiated under ALI culture condition. Both models were exposed to palladium (Pd) nanoparticles which sized 6-10 nm, analogous to those released from modern car catalysts, at three different concentrations utilizing the XposeALI module of the PreciseInhale® exposure system. Exposing the 3D models to Pd nanoparticles induced increased secretion of IL-8, yet the chronic bronchitis-like model released significantly more IL-8 than the normal model. The levels of IL-8 in basal medium (BM) and apical lavage medium (AM) were in the same ranges, but the secretion of MMP-9 was significantly higher in the AM compared to the BM. This combination of relevant human bronchial mucosa models and sophisticated exposure system can mimic in vivo conditions and serve as a useful alternative animal testing tool when studying adverse effects in humans exposed to aerosols, air pollutants or particles in an occupational setting.

Generation of transgenic mouse model using PTTG as an oncogene.

PubMed

Kakar, Sham S; Kakar, Cohin

2015-01-01

The close physiological similarity between the mouse and human has provided tools to understanding the biological function of particular genes in vivo by introduction or deletion of a gene of interest. Using a mouse as a model has provided a wealth of resources, knowledge, and technology, helping scientists to understand the biological functions, translocation, trafficking, and interaction of a candidate gene with other intracellular molecules, transcriptional regulation, posttranslational modification, and discovery of novel signaling pathways for a particular gene. Most importantly, the generation of the mouse model for a specific human disease has provided a powerful tool to understand the etiology of a disease and discovery of novel therapeutics. This chapter describes in detail the step-by-step generation of the transgenic mouse model, which can be helpful in guiding new investigators in developing successful models. For practical purposes, we will describe the generation of a mouse model using pituitary tumor transforming gene (PTTG) as the candidate gene of interest.

Development of a Zealand white rabbit deposition model to study inhalation anthrax

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

Asgharian, Bahman; Price, Owen; Kabilan, Senthil

Despite using rabbits in several inhalation exposure experiments to study diseases such as anthrax, there is a lack of understanding regarding deposition characteristics and fate of inhaled particles (bio-aerosols and viruses) in the respiratory tracts of rabbits. Such information allows dosimetric extrapolation to humans to inform human outcomes. The lung geometry of the New Zealand white rabbit (referred to simply as rabbits throughout the article) was constructed using recently acquired scanned images of the conducting airways of rabbits and available information on its acinar region. In addition, functional relationships were developed for the lung and breathing parameters of rabbits asmore » a function of body weight. The lung geometry and breathing parameters were used to extend the existing deposition model for humans and several other species to rabbits. Evaluation of the deposition model for rabbits was made by comparing predictions with available measurements in the literature. Deposition predictions in the lungs of rabbits indicated smaller deposition fractions compared to those found in humans across various particle diameter ranges. The application of the deposition model for rabbits was demonstrated by extrapolating deposition predictions in rabbits to find equivalent human exposure concentrations assuming the same dose-response relationship between the two species. Human equivalent exposure concentration levels were found to be much smaller than those for rabbits.« less

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.

Modeling Environment for Total Risk-2E

EPA Science Inventory

MENTOR-2E uses an integrated, mechanistically consistent source-to-dose-to-response modeling framework to quantify inhalation exposure and doses resulting from emergency events. It is an implementation of the MENTOR system that is focused towards modeling of the impacts of rele...

An in-premise model for Legionella exposure during showering events

EPA Science Inventory

An exposure model was constructed to predict the critical Legionella densities in an engineered water system that might result in infection from inhalation of aerosols containing the pathogen while showering. The model predicted the Legionella densities in the shower air, water ...

Salmeterol inhaler using a non-chlorinated propellant, HFA134a: systemic pharmacodynamic activity in healthy volunteers.

PubMed Central

Kirby, S. M.; Smith, J.; Ventresca, G. P.

1995-01-01

BACKGROUND--Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants. These face an international ban due to their effect on the ozone layer. Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a. METHODS--The safety, tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler, the current salmeterol inhaler, and placebo (HFA134a) were compared in 12 healthy volunteers in a double blind, randomised crossover study using a cumulative dosing design. RESULTS--Safety and tolerability were similar and the response was related to the dose over the range used (50-400 micrograms) with both salmeterol inhalers. The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate, blood pressure, tremor, QTc interval, and plasma glucose levels. The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels. CONCLUSIONS--In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler, and has similar systemic pharmacodynamic activity. PMID:7638815

Pharmacoeconomics of volatile inhalational anaesthetic agents: an 11-year retrospective analysis.

PubMed

Weinberg, L; Story, D; Nam, J; McNicol, L

2010-09-01

With continuously increasing expenditure on health care resources, various cost containment strategies have been suggested in regard to controlling the cost of inhalational anaesthetic agents. We performed a cost identification analysis assessing inhalational anaesthetic agent expenditure at a tertiary level hospital, along with an evaluation of strategies to contain the cost of these agents. The number of bottles of isoflurane, sevoflurane and desflurane used during the financial years 1997 to 2007 was retrospectively determined and the acquisition costs and cumulative drug expenditure calculated. Pharmacoeconomic modelling using low fresh gas flow anaesthesia was performed to evaluate practical methods of cost reduction. The use of isoflurane decreased from 384 bottles during 1997 to 204 in 2007. In contrast, use of sevoflurane increased from 226 bottles during 1998 to 875 during 2007. Desflurane use increased from 34 bottles per year during 2002 (its year of introduction) to 163 bottles per year in 2007. While the inflation-adjusted cumulative expenditure for these inhalational agents (Australian dollars) increased from $132,000 in 1997 to over $326,000 in 2007, an increase of 168%, patient workload over the same period increased by only 11%. Pharmacoeconomic modelling demonstrated that sevoflurane at 2 l/minute costs 19 times more than isoflurane at 0.5 l/minute. For the financial years 1997 to 2007, we found a progressive shift from the cheaper isoflurane to the more expensive agents, sevoflurane and desflurane, a shift associated with marked increases in costs. Low flow anaesthesia with isoflurane is one strategy to reduce costs.

Burn-center quality improvement: are burn outcomes dependent on admitting facilities and is there a volume-outcome "sweet-spot"?

PubMed

Hranjec, Tjasa; Turrentine, Florence E; Stukenborg, George; Young, Jeffrey S; Sawyer, Robert G; Calland, James F

2012-05-01

Risk factors of mortality in burn patients such as inhalation injury, patient age, and percent of total body surface area (%TBSA) burned have been identified in previous publications. However, little is known about the variability of mortality outcomes between burn centers and whether the admitting facilities or facility volumes can be recognized as predictors of mortality. De-identified data from 87,665 acute burn observations obtained from the National Burn Repository between 2003 and 2007 were used to estimate a multivariable logistic regression model that could predict patient mortality with reference to the admitting burn facility/facility volume, adjusted for differences in age, inhalation injury, %TBSA burned, and an additional factor, percent full thickness burn (%FTB). As previously reported, all three covariates (%TBSA burned, inhalation injury, and age) were found to be highly statistically significant risk factors of mortality in burn patients (P value < 0.0001). The additional variable, %FTB, was also found to be a statistically significant determinant, although it did not greatly improve the multivariable model. The treatment/admitting facility was found to be an independent mortality predictor, with certain hospitals having increased odds of death and others showing a protective effect (decreased odds ratio). Hospitals with high burn volumes had the highest risk of mortality. Mortality outcomes of patients with similar risk factors (%TBSA burned, inhalation injury, age, and %FTB) are significantly affected by the treating facility and their admission volumes.

Safety assessment for hair-spray resins: risk assessment based on rodent inhalation studies.

PubMed

Carthew, Philip; Griffiths, Heather; Keech, Stephen; Hartop, Peter

2002-04-01

The methods involved in the safety assessment of resins used in hair-spray products have received little peer review, or debate in the published literature, despite their widespread use, in both hairdressing salons and the home. The safety assessment for these resins currently involves determining the type of lung pathology that can be caused in animal inhalation exposure studies, and establishing the no-observable-effect level (NOEL) for these pathologies. The likely human consumer exposure is determined by techniques that model the simulated exposure under "in use" conditions. From these values it is then possible to derive the likely safety factors for human exposure. An important part of this process would be to recognize the intrinsic differences between rodents and humans in terms of the respiratory doses that each species experiences during inhalation exposures, for the purpose of the safety assessment. Interspecies scaling factors become necessary when comparing the exposure doses experienced by rats, compared to humans, because of basic differences between species in lung clearance rates and the alveolar area in the lungs. The rodent inhalation data and modeled human exposure to Resin 6965, a resin polymer that is based on vinyl acetate, has been used to calculate the safety factor for human consumer exposure to this resin, under a range of "in use" exposure conditions. The use of this safety assessment process clearly demonstrates that Resin 6965 is acceptable for human consumer exposure under the conditions considered in this risk assessment.

Evaluation of the butter flavoring chemical diacetyl and a fluorochemical paper additive for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.

PubMed

Whittaker, Paul; Clarke, Jane J; San, Richard H C; Begley, Timothy H; Dunkel, Virginia C

2008-08-01

Diacetyl (2,3-butanedione) is a yellowish liquid that is usually mixed with other ingredients to produce butter flavor or other flavors in a variety of food products. Inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Recent findings have shown irreversible obstructive lung disease among workers not only in the microwave popcorn industry, but also in flavoring manufacture, and in chemical synthesis of diacetyl, a predominant chemical for butter flavoring. It has been reported that perfluorochemicals utilized in food packaging are migrating into foods and may be sources of oral exposure. Relatively small quantities of perfluorochemicals are used in the manufacturing of paper or paperboard that is in direct contact with food to repel oil or grease and water. Because of recent concerns about perfluorochemicals such as those found on microwave popcorn bags (e.g. Lodyne P208E) and diacetyl in foods, we evaluated both compounds for mutagenicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Lodyne P208E was less toxic than diacetyl and did not induce a mutagenic response. Diacetyl induced a highly mutagenic response in the L5178Y mouse lymphoma mutation assay in the presence of human liver S9 for activation. The increase in the frequency of small colonies in the assay with diacetyl indicates that diacetyl causes damage to multiple loci on chromosome 11 in addition to functional loss of the thymidine kinase locus.

Inhalation Therapy in Horses.

PubMed

Cha, Mandy L; Costa, Lais R R

2017-04-01

This article discusses the benefits and limitations of inhalation therapy in horses. Inhalation drug therapy delivers the drug directly to the airways, thereby achieving maximal drug concentrations at the target site. Inhalation therapy has the additional advantage of decreasing systemic side effects. Inhalation therapy in horses is delivered by the use of nebulizers or pressured metered dose inhalers. It also requires the use of a muzzle or nasal mask in horses. Drugs most commonly delivered through inhalation drug therapy in horses include bronchodilators, antiinflammatories, and antimicrobials. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhalers and nebulizers: basic principles and preliminary measurements

NASA Astrophysics Data System (ADS)

Misik, Ondrej; Lizal, Frantisek; Asl, Vahid Farhikhteh; Belka, Miloslav; Jedelsky, Jan; Elcner, Jakub; Jicha, Miroslav

2018-06-01

Inhalers are hand-held devices which are used for administration of therapeutic aerosols via inhalation. Nebulizers are larger devices serving for home and hospital care using inhaled medication. This contribution describes the basic principles of dispersion of aerosol particles used in various types of inhalers and nebulizers, and lists the basic physical mechanisms contributing to the deposition of inhaled particles in the human airways. The second part of this article presents experimental setup, methodology and preliminary results of particle size distributions produced by several selected inhalers and nebulizers.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Reevaluating the Potential of Mouse Models for the Human Immune System.

PubMed

Jameson, Stephen C; Masopust, David

2018-04-02

Much of what we understand about immunology, including the response to vaccines, come from studies in mice because they provide many practical advantages compared with research in higher mammals and humans. Nevertheless, modalities for preventing or treating disease do not always translate from mouse to humans, which has led to increasing scrutiny of the continued merits of mouse research. Here, we summarize the pros and cons of current laboratory mouse models for immunology research and discuss whether overreliance on nonphysiological, ultra-hygienic animal husbandry approaches has limited the ultimate translation potential of mouse-derived data to humans. Alternative approaches are discussed that may extend the use of the mouse model for preclinical studies. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat.

PubMed

Martin, Sheppard A; Campbell, Jerry L; Tremblay, Raphael T; Fisher, Jeffrey W

2012-01-01

The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

Human respiratory tract model for radiological protection: a revision of the ICRP Dosimetric Model for the Respiratory System.

PubMed

Bair, W J

1989-01-01

In 1984, the International Commission on Radiological Protection (ICRP) appointed a task group of Committee 2 to review and revise, as necessary, the ICRP Dosimetric Model for the Respiratory System. The model was originally published in 1966, modified slightly in Publication No. 19, and again in Publication No. 30 (in 1979). The task group concluded that research during the past 20 y suggested certain deficiencies in the ICRP Dosimetric Model for the Respiratory System. Research has also provided sufficient information for a revision of the model. The task group's approach has been to review, in depth, morphology and physiology of the respiratory tract; deposition of inhaled particles in the respiratory tract; clearance of deposited materials; and the nature and specific sites of damage to the respiratory tract caused by inhaled radioactive substances. This review has led to a redefinition of the regions of the respiratory tract for dosimetric purposes. The redefinition has a morphologic and physiological basis and is consistent with observed deposition and clearance of particles and with resultant pathology. Regions, as revised, are the extrathoracic (E-T) region, comprising the nasal and oral regions, the pharynx, larynx, and upper part of the trachea; the fast-clearing thoracic region (T[f]), comprising the remainder of the trachea and bronchi; and the slow-clearing thoracic region (T[s]), comprising the bronchioles, alveoli, and thoracic lymph nodes. A task group report will include models for calculating radiation doses to these regions of the respiratory tract following inhalation of representative alpha-, beta-, and gamma-emitting particulate and gaseous radionuclides. The models may be implemented as a package of computer codes available to a wide range of users. This should facilitate application of the revised human respiratory tract model to worldwide radiation protection needs.

The brain acid-base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic.

PubMed

Leibold, N K; van den Hove, D L A; Esquivel, G; De Cort, K; Goossens, L; Strackx, E; Buchanan, G F; Steinbusch, H W M; Lesch, K P; Schruers, K R J

2015-06-01

Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Practice makes perfect: self-reported adherence a positive marker of inhaler technique maintenance.

PubMed

Azzi, Elizabeth; Srour, Pamela; Armour, Carol; Rand, Cynthia; Bosnic-Anticevich, Sinthia

2017-04-24

Poor inhaler technique and non-adherence to treatment are major problems in the management of asthma. Patients can be taught how to achieve good inhaler technique, however maintenance remains problematic, with 50% of patients unable to demonstrate correct technique. The aim of this study was to determine the clinical, patient-related and/or device-related factors that predict inhaler technique maintenance. Data from a quality-controlled longitudinal community care dataset was utilized. 238 patients using preventer medications where included. Data consisted of patient demographics, clinical data, medication-related factors and patient-reported outcomes. Mixed effects logistic regression was used to identify predictors of inhaler technique maintenance at 1 month. The variables found to be independently associated with inhaler technique maintenance using logistic regression (Χ 2 (3,n = 238) = 33.24, p < 0.000) were inhaler technique at Visit 1 (OR 7.1), device type (metered dose inhaler and dry powder inhalers) (OR 2.2) and self-reported adherent behavior in the prior 7 days (OR 1.3). This research is the first to unequivocally establish a predictive relationship between inhaler technique maintenance and actual patient adherence, reinforcing the notion that inhaler technique maintenance is more than just a physical skill. Inhaler technique maintenance has an underlying behavioral component, which future studies need to investigate. BEHAVIORAL ELEMENT TO CORRECT LONG-TERM INHALER TECHNIQUES: Patients who consciously make an effort to perfect asthma inhaler technique will maintain their skills long-term. Elizabeth Azzi at the University of Sydney, Australia, and co-workers further add evidence that there is a strong behavioral component to patients retaining correct inhaler technique over time. Poor inhaler technique can limit asthma control, affecting quality of life and increasing the chances of severe exacerbations. Azzi's team followed 238 patients to determine the key predictors of inhaler technique maintenance from factors including age, asthma knowledge and perceived future risks. Correct inhaler technique at initial assessment was the strongest predictor of long-term success, but this was strengthened further when patients reported good adherence to their own medication regimen. This suggests that maintaining correct inhaler technique is more than just a physical skill. Careful guidance towards this 'practice makes perfect' approach may improve patients' long-term technique maintenance.

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

PubMed Central

Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

2012-01-01

Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662