Biomedical subjects

E S Schelegle

Publications and source records attributed to E S Schelegle.

At least 19 recordsLinked to original sources

PubMed2005

Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys.

BACKGROUND: Accumulation of immune cell populations and their cytokine products within tracheobronchial airways contributes to the pathogenesis of allergic asthma. It has been postulated that peripheral regions of the lung play a more significant role than proximal airways with regard to inflammatory events and airflow obstruction. OBJECTIVE: To determine whether immune cell populations and associated cytokines are uniformly distributed throughout the conducting airway tree in a non-human primate model of allergic asthma. METHODS: We used a stereologic approach with a stratified sampling scheme to measure the volume density of immune cells within the epithelium and interstitium of trachea and 4-5 intrapulmonary airway generations from house dust mite (HDM) (Dermatophagoides farinae)-challenged adult monkeys. In conjunction with immune cell distribution profiles, mRNA levels for 21 cytokines/chemokines and three chemokine receptors were evaluated at four different airway generations from microdissected lungs. RESULTS: In HDM-challenged monkeys, the volume of CD1a+ dendritic cells, CD4+ T helper lymphocytes, CD25+ cells, IgE+ cells, eosinophils, and proliferating cells were significantly increased within airways. All five immune cell types accumulated within airways in unique patterns of distribution, suggesting compartmentalized responses with regard to trafficking. Although cytokine mRNA levels were elevated throughout the conducting airway tree of HDM-challenged animals, the distal airways (terminal and respiratory bronchioles) exhibited the most pronounced up-regulation. CONCLUSION: These findings demonstrate that key effector immune cell populations and cytokines associated with asthma differentially accumulate within distinct regions and compartments of tracheobronchial airways from allergen-challenged primates.

Animals↗

PubMed2004

The remodelled tracheal basement membrane zone of infant rhesus monkeys after 6 months of recovery.

BACKGROUND: In previous studies, we showed that repeated exposure to (1) house dust mite allergen (HDMA) (Dermatophagoides farinae) caused thickening of the basement membrane zone (BMZ) and (2) HDMA+ozone (O3) caused depletion of BMZ perlecan and atypical development of BMZ collagen (irregular thin areas<2.0 microm in width). OBJECTIVE: The purpose of this study was to determine if these remodelling changes were reversible after 6 months of recovery. METHODS: Rhesus monkeys were exposed to a regimen of HDMA and or O3 or filtered air (FA) for 6 months. After the exposure protocol was completed FA and O3 groups were allowed to recover in FA for 6 months. The HDMA and HDMA+O3 exposure groups recovered in a modified environment. They were re-exposed to HDMA aerosol for 2 h at monthly intervals during recovery in order to maintain sensitization for pulmonary function testing. To detect structural changes in the BMZ, collagen I and perlecan immunoreactivity were measured and compared to data from the previous papers. RESULTS: The remodelled HDMA group had a significantly thicker BMZ and after 6 months of recovery the width had not regressed. In the remodelled BMZ of the HDMA+O3 group, perlecan had returned to the BMZ after 6 months of the recovery protocol, and the thin, irregular, collagen BMZ had been resolved. CONCLUSION: In summary, this study has shown that: (1) The width of the remodelled HDMA BMZ did not regress during a recovery protocol that included a sensitizing dose of HDMA. (2) The atypical collagen BMZ in the HDMA+O3 BMZ was resolved in the absence of O3. (3) Depletion of perlecan from the BMZ by O3 was reversed by recovery in the absence of O3.

Animals↗

PubMed2004

Smooth muscle hypertrophy in distal airways of sensitized infant rhesus monkeys exposed to house dust mite allergen.

BACKGROUND: Airway smooth muscle hypertrophy is closely associated with the pathophysiology of hyper-reactive airways in allergic asthma. OBJECTIVE: To determine whether repeated exposure to allergens during postnatal lung development promotes remodelling of airway smooth muscle. METHODS: Infant, male rhesus monkeys (30-day-old) were sensitized to house dust mite allergen (HDMA) and then exposed to HDMA aerosol periodically over 5 months. Smooth muscle mass and bundle size and abundance in conducting airways were measured and compared with age-matched control (filtered air-exposed) monkeys. RESULTS: Total smooth muscle mass and average bundle size were significantly greater in the conducting airways of monkeys exposed to HDMA. Smooth muscle bundle abundance was not affected by exposure to HDMA. CONCLUSION: Repeated cycles of allergen exposure alter postnatal morphogenesis of smooth muscle, affecting both total mass and bundle size, in conducting airways of infant monkeys.

Allergens↗

PubMed2003

Allergen-specific IgG and IgA in serum and bronchoalveolar lavage fluid in a model of experimental feline asthma.

Allergic asthma, a Th2 cell driven response to inhaled allergens, has classically been thought of as predominantly mediated by IgE antibodies. To investigate the role of other immunoglobulin classes (e.g., IgG and IgA) in the immunopathogenesis of allergic asthma, levels of these allergen-specific immunoglobulins were measured in serum and mucosal fluids. Bermuda grass allergen (BGA)-specific IgG and IgA ELISAs in serum and bronchoalveolar lavage fluid (BALF) were developed and optimized in an experimental model of BGA-induced feline asthma. Levels of BGA-specific IgG and IgA significantly increased over time in serum and BALF after allergen sensitization. Additionally, these elevated levels of BGA-specific IgG and IgA were seen in conjunction with the development of an asthmatic phenotype indicated by positive intradermal skin tests, enhanced airways hyperreactivity, and increased eosinophil percentages in the BALF.

Allergens↗

PubMed2003

Production of polyclonal antisera against feline immunoglobulin E and its use in an ELISA in cats with experimentally induced asthma.

Serum samples from six cats with experimentally induced asthma were used to purify feline IgE using gel filtration and affinity chromatography. The resultant IgE, evaluated for purity by immunoelectrophoresis (IEP) and reactivity by Prausnitz-Kustner (PK) testing, was used to develop polyclonal rabbit anti-feline IgE antisera. Using reverse cutaneous anaphylaxis (RCA), the antisera were determined to be specific for feline IgE. The polyclonal rabbit anti-feline IgE antiserum was then validated in an allergen-specific ELISA. Serum samples from an additional five asthmatic cats sensitized with Bermuda grass allergen (BGA) were evaluated prior to sensitization, after parenteral sensitization, and after aerosol sensitization and challenge. A significant increase in serum BGA-specific IgE was noted over time.

Allergens↗

PubMed2003

Immune and airway effects of house dust mite aeroallergen exposures during postnatal development of the infant rhesus monkey.

BACKGROUND: The effect of chronic environmental aeroallergen exposure on the immune system and airways has not been experimentally defined in very young children. OBJECTIVE: The purpose of this study was to determine the immunophenotype of peripheral blood and airway leucocytes in the newborn rhesus macaque monkey, following recurrent aerosol exposure to house dust mite (HDM) (Dermatophagoides farinae). METHODS: A regimen of HDM aerosolization was initiated for 2 h per day, three times per week, starting when rhesus macaque monkeys were 1 week of age. All monkeys were inoculated with diptheria, tetanus, and acellular pertussis vaccine at 5 weeks of age to simulate human infant vaccination schedules. RESULTS: Following 8 weeks of HDM aeroallergen exposure, infant monkeys exhibited a significant reduction in the total peripheral blood lymphocyte numbers and a decreased frequency of peripheral blood CD4+ T lymphocytes with a CD45RA-'memory' immunophenotype. Lavage CD4+ T lymphocytes from HDM-exposed monkeys showed elevated expression of CD25, as well as an increase in CD45RA-/CD62L-/CD11ahigh immunophenotype. Eosinophils were more abundant within airways of HDM-exposed monkeys, accumulating maximally within the trachea. CONCLUSION: These data demonstrate the development of immunological responses following chronic inhalation of a common environmental allergen during postnatal maturation in the non-human primate.

Animals↗

PubMed2001

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. Compared to nonsensitized monkeys, there was a fourfold reduction in the dose of histamine aerosol necessary to produce a 150% increase in airway resistance in sensitized monkeys. After aerosol challenge, serum levels of histamine were elevated in sensitized monkeys. Sensitized monkeys exhibited increased levels of HDMA-specific IgE in serum, numbers of eosinophils and exfoliated cells within lavage, and elevated CD25 expression on circulating CD4(+) lymphocytes. Intrapulmonary bronchi of sensitized monkeys had focal mucus cell hyperplasia, interstitial infiltrates of eosinophils, and thickening of the basement membrane zone. We conclude that a model of allergic asthma can be induced in rhesus monkeys using a protocol consisting of subcutaneous injection, intranasal instillation, and aerosol challenge with HDMA.

Animals↗

PubMed2001

An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors.

Since the original work of by Hering and Breuer in 1868 numerous studies have demonstrated that slowly adapting pulmonary stretch receptors (SARs) are the lung vagal afferents responsible for eliciting the reflexes evoked by moderate lung inflation. SARs play a role in controlling breathing pattern, airway smooth muscle tone, systemic vascular resistance and heart rate. Both anatomical and physiological studies support the contention that SARs, by their close association with airway smooth muscle, continuously sense the tension within the myoelastic components of the airways caused by lung inflation, smooth muscle contraction and/or tethering of small intrapulmonary airways to the lung parenchyma. In addition, intrapulmonary SAR discharge activity is sensitive to changes in P(CO2) within the physiological range. Despite this extensive characterization of SARs, their role in determining breathing pattern and airway tone in individuals with respiratory diseases is only recently being appreciated.

Adaptation, Physiological↗

PubMed2001

Lung vagal afferent activity in rats with bleomycin-induced lung fibrosis.

Bleomycin treatment in rats results in pulmonary fibrosis that is characterized by a rapid shallow breathing pattern, a decrease in quasi-static lung compliance and a blunting of the Hering-Breuer Inflation Reflex. We examined the impulse activity of pulmonary vagal afferents in anesthetized, mechanically ventilated rats with bleomycin-induced lung fibrosis during the ventilator cycle and static lung inflations/deflations and following the injection of capsaicin into the right atrium. Bleomycin enhanced volume sensitivity of slowly adapting stretch receptors (SARs), while it blunted the sensitivity of these receptors to increasing transpulmonary pressure. Bleomycin treatment increased the inspiratory activity, while it decreased the expiratory activity of rapidly adapting stretch receptors (RARs). Pulmonary C-fiber impulse activity did not appear to be affected by bleomycin treatment. We conclude that the fibrosis-related shift in discharge profile and enhanced volume sensitivity of SARs combined with the increased inspiratory activity of RARs contributes to the observed rapid shallow breathing of bleomycin-induced lung fibrosis.

Adaptation, Physiological↗

PubMed2001

Extended allergen exposure in asthmatic monkeys induces neuroplasticity in nucleus tractus solitarius.

BACKGROUND: Extended exposure to allergen exacerbates asthma symptoms, in part via complex interactions between inflammatory cells and mediators. One consequence of these interactions is the triggering of local and central nervous system (CNS) neuronal activity that might further exacerbate the asthma-like symptoms by causing bronchoconstriction, mucous secretion, increased microvascular leak, and cough. One CNS region that might be particularly important is the caudomedial nucleus tractus solitarius (NTS). NTS neurons not only integrate primary afferent inputs from lung sensory nerve fibers but also have direct exposure to inhaled allergens and allergen-induced blood-borne inflammatory mediators via a deficient blood-brain barrier. Given the capacity of CNS neurons to undergo plasticity, allergen-induced changes in NTS neuronal properties could contribute to the exaggerated respiratory responses to extended allergen exposure. OBJECTIVE: In a recently developed rhesus monkey model of allergic asthma, we tested the hypothesis that extended exposure to allergen increases the intrinsic excitability of NTS neurons. METHODS: Three adult monkeys were sensitized and then repeatedly exposed to aerosols of house dust mite allergen; 4 monkeys served as controls. Whole-cell current-clamp recordings were made to measure 3 indices of excitability: resting membrane potential, input resistance, and number of action potentials evoked by current injections. RESULTS: Extended allergen exposure depolarized the resting membrane potential by 14% and increased the number of action potentials evoked by current injections (5-fold). CONCLUSION: The finding that NTS neurons in a primate model of allergic asthma undergo intrinsic increases in excitability suggests that CNS mechanisms might contribute to the exaggerated symptoms in asthmatic individuals exposed to allergen.

Allergens↗

PubMed2001

Role of airway receptors in altitude-induced dyspnea.

PURPOSE: The purpose of this study was to examine the role of airway receptors in respiratory-related sensations after ascent to altitude. METHODS: Ratings of respiratory-related sensations, perceived exertion and acute mountain sickness, heart rate, and peripheral oxygen saturation were recorded at rest and exercise in male and female subjects who had inhaled either aerosolized saline or saline with tetracaine after acute ascent to an altitude of 3500 m and after prolonged acclimatization of 18 d at altitudes between 4000 and 5000 m. RESULTS: Tetracaine had no effect on respiratory-related sensations at altitude either at rest or during exercise, and male and female subjects experienced similar respiratory-related sensations. Sensations of rapid breathing were experienced at rest after acute exposure to 3500 m as compared with sea level, but not after acclimatization to 5000 m. Sensations of rapid breathing, air hunger, and heavy breathing were experienced during exercise after acute and prolonged altitude exposure as compared with sea level, with a sensation of chest tightness experienced at 3500 m and a sensation of gasping experienced at 5000 m. CONCLUSION: These results suggest that airway afferents play no role in the respiratory-related sensations experienced by male and female subjects either during acute ascent to altitude or after prolonged acclimatization at altitude.

Adult↗

PubMed2001

Effect of C-fiber-mediated, ozone-induced rapid shallow breathing on airway epithelial injury in rats.

We examined the relationship between C-fiber-mediated, ozone-induced rapid shallow breathing and airway epithelial cell injury at different airway sites within the lower respiratory tract of conscious Wistar rats (n = 24). We combined an acute 8-h ozone inhalation with vagal perineural capsaicin treatment, a selective C-fiber conduction block, and 5-bromo-2'-deoxyuridine (BrdU) labeling as an index of epithelial injury. Vehicle-treated rats that inhaled ozone developed a rapid shallow breathing pattern during ozone inhalation, whereas the capsaicin-treated rats that inhaled ozone showed no changes in respiratory frequency. In vehicle-treated, ozone-exposed rats that developed rapid shallow breathing, a progressive increase in BrdU-labeling density (no. of BrdU-labeled cells/mm(2) airway) was observed starting at the bifurcation of the left main stem bronchi (central airway) and going down either a short or long airway path. In vehicle-treated, ozone-exposed rats, terminal bronchioles supplied by short and long airway paths had a similar degree of BrdU-labeling density that was significantly (P < 0.05) greater than the BrdU-labeling density of the proximal airways that supply them. In contrast, the attenuation of rapid shallow breathing produced by capsaicin treatment resulted in a significantly reduced BrdU-labeling density in the terminal bronchioles supplied by short airway paths compared with the terminal bronchioles supplied by long airway paths. Our data indicate that ozone-induced rapid shallow breathing protects large conducting airways while producing a more even distribution of injury to terminal bronchioles.

Animals↗

PubMed2001

Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects.

We examined the effect of tetracaine aerosol inhalation, a local anesthetic, on lung volume decrements, rapid shallow breathing, and subjective symptoms of breathing discomfort induced by the acute inhalation of 0.30 ppm ozone for 65 min in 22 ozone-sensitive healthy human subjects. After 50 min of ozone inhalation FEV(1) was reduced 24%, breathing frequency was increased 40%, tidal volume was decreased 31%, and total subjective symptom score was increased (71.2, compared with 3.8 for filtered air exposure). Inhalation of tetracaine aerosol resulted in marked reductions in ozone-induced subjective symptoms of throat tickle and/or irritation (92.1%), cough (78.5%), shortness of breath (72.5%), and pain on deep inspiration (69.4%). In contrast, inhalation of tetracaine aerosol (mass median aerodynamic diameter of 3.52 microm with a geometric standard deviation of 1.92) resulted in only minor and inconsistent rectification of FEV(1) decrements (5.0%) and breathing frequency (-3.8%) that was not significantly different from that produced by saline aerosol alone (FEV(1), 5.1% and breathing frequency, -2.7%). Our data are consistent with afferent endings located within the large conducting airways of the tracheobronchial tree being primarily responsible for ozone-induced subjective symptoms and provides strong evidence that ozone-induced inhibition of maximal inspiratory effort is not dependent on conscious sensations of inspiratory discomfort.

Administration, Inhalation↗

PubMed2000

Interaction of vagal lung afferents with inhalation of histamine aerosol in anesthetized dogs.

In seven alpha-chloralose anesthetized dogs we examined the contribution of lung afferents to the rapid, shallow breathing induced by inhalation of 10 breaths of histamine aerosol. In four spontaneously breathing dogs, the inhalation of histamine caused an increased respiratory frequency, decreased tidal volume, and decreased dynamic lung compliance. Selective blockade of pulmonary C-fibers abolished a reflex-induced increase in respiratory frequency but did not significantly affect the reductions in tidal volume or lung compliance. Terbutaline treatment in combination with C-fiber blockade abolished the reductions in tidal volume and lung compliance induced by histamine. In three separate alpha-chloralose anesthetized, open-chest, mechanically ventilated dogs, we recorded an increase in the inspiratory activity of rapidly adapting pulmonary stretch receptors (RARs) induced by the inhalation of histamine aerosol. Selective C-fiber blockade abolished histamine-induced increases in RAR activity while only partially attenuating reductions in lung compliance. We conclude that the increase in RAR activity induced by histamine depends on intact C-fibers and not on a direct effect of histamine on RARs or an indirect effect of histamine reducing lung compliance. In addition, our data illustrate the multiple interactions that occur between the various vagal afferents and their roles in the reflexes induced by histamine inhalation.

Administration, Inhalation↗

PubMed2000

Three-dimensional mapping of ozone-induced acute cytotoxicity in tracheobronchial airways of isolated perfused rat lung.

Acute lung injury induced by reactive oxygen gases such as ozone (O(3)) is focal and site-selective. To define patterns of acute epithelial injury along intrapulmonary airways, we developed a new analytic approach incorporating labeling of permeable cells, airway microdissection, and laser scanning confocal microscopy, and applied it to isolated perfused rat lungs where ventilation and breathing pattern could be controlled. After exposure to O(3) (0, 0.25, 0.5, or 1.0 ppm), lungs were lavaged to assess lactate dehydrogenase (LDH) and protein, or infused with the permeability marker ethidium homodimer-1 (EthD-1) via tracheal cannula, gently lavaged, and fixed by airway infusion. The airway tree of the right middle lobe was exposed by microdissection of the axial pathway down to the terminal bronchioles; the dissection was incubated with a second nuclear dye, YOPRO-1, to label all nuclei; and whole mounts were examined by confocal microscopy. Abundance of EthD-1-positive (injured) cells was estimated as the number per epithelial volume using stereology on Z-series of projected images. For ozone concentrations of 1.0 ppm, lavage fluid LDH and total protein did not increase over controls. Exposure produced a concentration- dependent but nonhomogeneous increase in the abundance of EthD-1-labeled cells in proximal and distal conducting airways both in the main pathway, including terminal bronchioles, and in side branches. Overall, the highest EthD-1 labeling occurred in the side branches of the most proximal part of the airway tree at 1 ppm with the adjacent axial pathway airway having approximately one-third the labeling density. Density of EthD-1-labeled cells was lowest in terminal bronchioles at all O(3) doses. For the model we used, identification of injured epithelial cells by differential permeability and laser confocal microscopy appeared to be highly sensitive and permitted mapping of acute cytotoxicity throughout the airway tree and quantitative comparisons of sites with different branching histories and potential dosimetry rates.

Animals↗

PubMed2000

Effects of vagal perineural capsaicin treatment on vagal efferent and airway neurogenic responses in anesthetized rats.

The acute effect of vagal perineural capsaicin treatment (VPCT) on parasympathetic bradycardia and tracheal neurogenic protein extravasation was examined. In nine anesthetized male Wistar rats the effect of VPCT on the bradycardia induced by electrical stimulation of the vagus was examined. In 24 anesthetized male Wistar rats the effect of VPCT on the tracheal protein extravasation induced by the inhalation of capsaicin aerosols was also studied. VPCT did not alter the bradycardia induced by vagal stimulation or the tracheal protein extravasation induced by the inhalation of capsaicin aerosol. The results of these studies further demonstrate the selectivity of perineural capsaicin treatment on vagal sensory nonmyelinated fibers in the rat and indicate that it is a useful tool for examining the role of sensory vagal C-fibers in pulmonary and cardiovascular reflexes and in isolating C-fiber-mediated reflex responses from those mediated by the release of neuropeptides.

Action Potentials↗

PubMed1999

Capsaicin-sensitive C-fiber-mediated protective responses in ozone inhalation in rats.

To assess the role of lung sensory C fibers during and after inhalation of 1 part/million ozone for 8 h, we compared breathing pattern responses and epithelial injury-inflammation-repair in rats depleted of C fibers by systemic administration of capsaicin as neonates and in vehicle-treated control animals. Capsaicin-treated rats did not develop ozone-induced rapid, shallow breathing. Capsaicin-treated rats showed more severe necrosis in the nasal cavity and greater inflammation throughout the respiratory tract than did control rats exposed to ozone. Incorporation of 5-bromo-2'-deoxyuridine (a marker of DNA synthesis associated with proliferation) into terminal bronchiolar epithelial cells was not significantly affected by capsaicin treatment in rats exposed to ozone. However, when normalized to the degree of epithelial necrosis present in each rat studied, there was less 5-bromo-2'-deoxyuridine labeling in the terminal bronchioles of capsaicin-treated rats. These observations suggest that the ozone-induced release of neuropeptides does not measurably contribute to airway inflammation but may play a role in modulating basal and reparative airway epithelial cell proliferation.

Administration, Inhalation↗

PubMed1999

Breathing pattern response and epithelial labeling in ozone-induced airway injury in neutrophil-depleted rats.

To test the hypothesis that neutrophils enhance the repair of ozone (O3)-injured airway epithelium, we investigated breathing pattern responses and airway epithelial injury and repair in rats depleted of neutrophils using rabbit antirat neutrophil serum (ANS) and control rats treated with normal rabbit serum (NRS). Thirty-seven Wistar rats were exposed to O3 (1 ppm) or filtered air (FA) for 8 h followed by 8 h in FA. O3-exposed NRS- and ANS-treated rats showed similar progressive decreases in tidal volume and increase in breathing frequency, with maximal changes occurring at 8 h of exposure, whereas FA-exposed rats showed no significant changes. O3-exposed ANS-treated rats showed more epithelial necrosis in the nasal cavity, bronchi, and distal airways than did O3-exposed NRS-treated rats. Incorporation of 5-bromo-2-deoxyuridine (BrdU), a measure of cellular proliferation, was assessed using an optical disector to count BrdU- labeled terminal bronchiolar epithelial cells. O3-exposed ANS-treated rats had significantly less BrdU- labeled epithelial cells than did O3-exposed NRS-treated rats. We conclude that neutrophils contribute to the repair process by enhancing the proliferation of O3-injured airway epithelial cells.

Animals↗