Lung effects of inhaled corticosteroids in a rhesus monkey model of childhood asthma.

Background: The risks for infants and young children receiving inhaled corticosteroid (ICS) therapy are largely unknown. Recent clinical studies indicate that ICS therapy in pre-school children with symptoms of asthma result in decreased symptoms without influencing the clinical disease course, but potentially affect postnatal growth and development. The current study employs a primate experimental model to identify the risks posed by ICS therapy.

Effectiveness of common shelter-in-place techniques in reducing ammonia exposure following accidental release.

Shelter-in-place strategies such as remaining indoors; breathing through a damp cloth; sealing cracks in windows and doors using towels, duct tape, or plastic sheeting; and running a shower are often recommended by emergency response officials to protect against accidental or intentional release of hazardous airborne chemicals and biologicals. Similar recommendations have been made to and used by community members exposed to anhydrous ammonia after catastrophic release of ammonia gas due to a derailment or other accidents. Such incidents have resulted in fatalities and serious injury to exposed individuals; however, other individuals within the same area have escaped injury and, in many cases, sustained no injuries as a result of sheltering-in-place.

Elevation of susceptibility to ozone-induced acute tracheobronchial injury in transgenic mice deficient in Clara cell secretory protein.

Increases in Clara cell abundance or cellular expression of Clara cell secretory protein (CCSP) may cause increased tolerance of the lung to acute oxidant injury by repeated exposure to ozone (O3). This study defines how disruption of the gene for CCSP synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone (0.

Effect of rapid shallow breathing on the distribution of 18O-labeled ozone reaction product in the respiratory tract of the rat.

We examined the effect of breathing pattern on ozone reaction product content within the respiratory tract. Thirty-four anesthetized, male Wistar rats were exposed to oxygen-18 ((18)O)-labeled ozone at 1.0 ppm for 2 h using a dual-chamber, negative-pressure ventilation system.

Proximal airway mucous cells of ovalbumin-sensitized and -challenged Brown Norway rats accumulate the neuropeptide calcitonin gene-related peptide.

Mucous cell hypersecretion and increased neuropeptide production play a role in the exacerbation of symptoms associated with asthma. The source of these neuropeptides have been confined to the contributions of small afferent nerves or possibly neuroendocrine cells. We tested the hypothesis that repeated exposure to allergen would alter the sources and abundance of neuropeptides in airways.

Postnatal remodeling of the neural components of the epithelial-mesenchymal trophic unit in the proximal airways of infant rhesus monkeys exposed to ozone and allergen.

Nerves and neuroendocrine cells located within the airway epithelium are ideally situated to sample a changing airway environment, to transmit that information to the central nervous system, and to promote trophic interactions between epithelial and mesenchymal cellular and acellular components. We tested the hypothesis that the environmental stresses of ozone (O(3)) and house dust mite allergen (HDMA) in atopic infant rhesus monkeys alter the distribution of airway nerves. Midlevel bronchi and bronchioles from 6-month-old infant monkeys that inhaled filtered air (FA), house dust mite allergen HDMA, O(3), or HDMA + O(3) for 11 episodes (5 days each, 0.

Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys.

Twenty-four infant rhesus monkeys (30 days old) were exposed to 11 episodes of filtered air (FA), house dust mite allergen aerosol (HDMA), ozone (O3), or HDMA + O3 (5 days each followed by 9 days of FA). Ozone was delivered for 8 h/day at 0.5 ppm.

In vitro exposure of proteins to ozone.

An in vitro system has been developed to expose proteins to ozone. The system is designed to deliver consistent and accurate levels of ozone over a range of concentrations (between 0.1 and >/=10 ppm) with extended exposure times (24 h or longer) in a humidified environment (100%).

Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae).

To establish whether allergic asthma could be induced experimentally in a nonhuman primate using a common human allergen, three female rhesus monkeys (Macaca mulatta) were sensitized with house dust mite (Dermatophagoides farinae) allergen (HDMA) by subcutaneous injection, followed by four intranasal sensitizations, and exposure to allergen aerosol 3 hours per day, 3 days per week for up to 13 weeks. Before aerosol challenge, all three monkeys skin-tested positive for HDMA. During aerosol challenge with HDMA, sensitized monkeys exhibited cough and rapid shallow breathing and increased airway resistance, which was reversed by albuterol aerosol treatment.

Differential expression of stress proteins in nonhuman primate lung and conducting airway after ozone exposure.

The presence of seven stress proteins including various heat shock proteins [27-kDa (HSP27), 60-kDa (HSP60), 70-kDa (HSP70) and its constitutive form HSC70, and 90-kDa (HSP90) HSPs] and two glucose-regulated proteins [75-kDa (GRP75) and 78-kDa (GRP78) GRPs] in ozone-exposed lungs of nonhuman primates and in cultured tracheobronchial epithelial cells was examined immunohistochemically by various monoclonal antibodies. Heat treatment (42 degrees C) resulted in increased HSP70, HSP60, and HSP27 and slightly increased HSC70 and GRP75 but no increase in GRP78 in primary cultures of monkey tracheobronchial epithelial cells. Ozone exposure did not elevate the expression of these HSPs and GRPs.

Relationship of inhaled ozone concentration to acute tracheobronchial epithelial injury, site-specific ozone dose, and glutathione depletion in rhesus monkeys.

Acute pulmonary epithelial injury produced by short-term exposure to ozone varies by site within the tracheobronchial tree. To test whether this variability is related to the local dose of ozone at the tissue site or to local concentrations of glutathione, we exposed adult male rhesus monkeys for 2 h to filtered air or to 0.4 or 1.

Cytochrome P450 2E1 in rat tracheobronchial airways: response to ozone exposure.

The distal trachea and centriacinus of the lung are primary sites of acute injury during short-term ozone exposure; long-term exposure yields cells in these areas that are resistant to high doses of oxidant gases. Epithelial cells located in primary sites for ozone injury are also targets for chemicals that undergo cytochrome P450 (CYP)-dependent activation. These studies were designed to compare the effects of ozone exposure on pulmonary CYP2E1 in susceptible and nonsusceptible sites within the airway tree of lung.

Neutrophils enhance removal of ozone-injured alveolar epithelial cells in vitro.

After acute exposure to oxidant gases in vivo, migration and accumulation of inflammatory cells in pulmonary epithelium coincides with epithelial cell necrosis. The present study was designed to test quantitatively the hypothesis that quiescent neutrophils enhance the removal of oxidant-injured pulmonary epithelial cells after exposure to ozone in vitro. Primary isolated rat alveolar type II cells were cultured as monolayers, using serum-free medium.

In vitro exposure of tracheobronchial epithelial cells and of tracheal explants to ozone.

An in vitro system for exposing respiratory epithelial cells or explant tissues to ozone has been developed and characterized. This system is designed to generate and monitor consistent, reproducible levels of ozone, over a range of concentrations, in a humidified atmosphere, and to allow an exposure time of 24 h or longer. Based on chemical analysis, highly reproducible concentrations of ozone are delivered throughout the chamber, with a coefficient of variation of < 5% between five replicate vials exposed to 0.

Ozone injury to alveolar epithelium in vitro does not reflect loss of antioxidant defenses.

The objective of this study was to characterize an in vitro model of oxidant gas toxicity, using primary cultures of alveolar type II cells maintained in serum-free medium, by evaluating (1) epithelial barrier function, (2) the stability of cellular antioxidant defenses, and (3) the response of alveolar epithelial barrier properties to ozone exposure. Antioxidant enzyme activities and glutathione levels were measured in rat type II cells that were freshly isolated, cultured for 1 day in serum-supplemented medium, and subsequently grown in serum-free nutrient medium. After measurement of peak bioelectric properties on Day 4 in primary culture, alveolar epithelial monolayers were exposed to ozone at various concentrations and lengths of exposure.

Aerosolized fluorescent microspheres detected in the lung using confocal scanning laser microscopy.

Aerosolized fluorescent microspheres were used to study particle deposition in site-specific regions of the lung with confocal laser scanning microscopy. A nebulizer was used to aerosolize microspheres followed by passage through a heated discharging column to reduce static charge and to remove water surrounding each microsphere. Precoating of microspheres with albumin helped to minimize displacement during vascular fixation of the lungs.

Interaction of nitrogen dioxide with human plasma. Antioxidant depletion and oxidative damage.

Nitrogen dioxide (NO2.) is often present in inhaled air and may be generated in vivo from nitric oxide. Exposure of human blood plasma to NO2.

Functional and morphologic changes caused by acute ozone exposure in the isolated and perfused rat lung.

Ozone has been shown to increase airway resistance and/or airway reactivity in vivo in animals and humans. Because of the complexities inherent in studying this phenomenon in whole animals, we developed a model of ozone-induced effects on airway physiology using the isolated perfused rat lung. Rat lungs were suspended in an airtight chamber and perfused via the pulmonary circulation with a modified Krebs-Henseleit buffer containing 4.

Increased carbon monoxide excretion in Bolivian squirrel monkeys with fasting hyperbilirubinemia.

Pulmonary carbon monoxide (CO) excretion rates (VeCO) were 50% greater, on average, in Bolivian squirrel monkeys (BoSMs) which exhibit a unique fasting hyperbilirubinemia (FH), than in fasted control Brazilian squirrel monkeys (BrSMs). Since the catabolism of heme produces equimolar amounts of CO and bilirubin, the increased VeCOs are consistent with concurrent increases in endogenous bilirubin production rates. Tin-protoporphyrin, a competitive inhibitor of heme oxygenase, significantly decreased both the VeCO and serum bilirubin level in fasted BoSMs.

Effect of ferrous sulfate aerosols and nitrogen dioxide on murine pulmonary defense.

A murine infectivity model was used to test the effect of exposure to atmospheres containing 290 +/- 50 microgram/m3 of respirable sized ferrous sulfate (FeSO4) particles (0.4 micron mass median aerodynamic diameter) and 1.0 ppm nitrogen dioxide (NO2) prior to infection with aerosols of Staphylococcus aureus or group C streptococci.

Generatation and characterization of sodium sulfite aerosols for applications in inhalation toxicologic research.

A method has been developed for generation of submicrometer aerosols of sodium sulfite suitable for use in inhalation toxicologic research. Concentrations ranging up to about 30 mg/m3 Na2SO3 were achieved in a 0.44 m3 exposure chamber with an air flow rate of 0.

Effect of near ambient exposures to sulfur dioxide and ferrous sulfate particles on murine pulmonary defense mechanisms.

An infectivity model was used to test the safety margins for presently established air quality standards for sulfur dioxide and sulfate particles. Mice and rats were exposed to atmospheres of sulfur dioxide and mono-disperse ferrous sulfate particles from 3 to 6 times the standard for 17 hr prior to, or 4 hr after infection with aerosols of Staphylococcus aureus or Group C Streptococci. Exposure to these concentrations of pollutants did not impair the rodents' ability to ingest and inactivate the minimally virulent Straphylococcus or enhance the virulence of the Group C Streptococci.