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Publications (64)189.08 Total impact


  • No preview · Article · Nov 2014 · Journal of Pharmacological and Toxicological Methods
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    ABSTRACT: The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
    Full-text · Article · Aug 2013 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: Spleen Tyrosine Kinase (SYK) is a key activator of signaling pathways downstream of multiple surface receptors implicated in asthma. SYK function has been extensively studied in mast cells downstream of the high affinity IgE-receptor (FcR1). Preclinical studies have demonstrated a role for SYK in models of allergic inflammation, but a role in airway constriction has not been demonstrated. Here we have utilized a potent and selective pharmacological inhibitor of SYK to determine the role of SYK in allergen mediated inflammation and airway constriction in preclinical models. Attenuation of allergic airway responses was evaluated in a rat passive anaphylaxis model, and rat and sheep inhaled allergen challenge models as well as an ex vivo model of allergen-mediated airway constriction in rats and Cynomolgus monkeys. Pharmacological inhibition of SYK dose-dependently blocked IgE-mediated tracheal extravasation in rat. In a rat ovalbumin-sensitized airway challenge model, oral dosing with a SYK inhibitor (SYKi) led to a dose-dependent reduction in lung inflammatory cells. Ex vivo analysis of allergen induced airway constriction in ovalbumin-sensitized Brown Norway rats showed complete attenuation with treatment of a SYK inhibitor as a well as a complete block of allergen-induced serotonin release. Similarly, allergen mediated airway constriction was attenuated in ex vivo studies from non-human primate lungs. Intravenous administration of a SYKi attenuated both early and late phase allergen-induced increases in airway resistance in an Ascaris-sensitive sheep allergen challenge model. These data support a key role for SYK signaling in mediating allergic airway responses.
    Full-text · Article · Jul 2013 · American Journal of Respiratory Cell and Molecular Biology
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    ABSTRACT: Late phase airflow obstruction and reduction in forced vital capacity are characteristic features of human asthma. Airway microvascular leakage and lung edema are also present in the inflammatory phase of asthma, but the impact of this vascular response on lung functions has not been precisely defined. This study was designed to evaluate the role of increased lung microvascular leakage and edema on the late phase changes in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats using pharmacological inhibitors of the allergic inflammatory response. Rats were sensitized and challenged with ovalbumin aerosol and forced expiratory lung functions (FVC, PEF) and wet and dry lung weights were measured 48 h after antigen challenge. Ovalbumin challenge reduced FVC (63% reduction) and PEF (33% reduction) and increased wet (65% increase) and dry (51% increase) lung weights. The antigen-induced reduction in FVC and PEF was completely inhibited by oral treatment with betamethasone and partially attenuated by inhibitors of arachidonic acid metabolism including indomethacin (cyclooxygenase inhibitor), 7-TM and MK-7246 (CRTH2 antagonists) and montelukast (CysLT1 receptor antagonist). Antagonists of histamine H1 receptors (mepyramine) and 5-HT receptors (methysergide) had no significant effects indicating that these pre-formed mast cell mediators were not involved. There was a highly significant (P < 0.005) correlation for the inhibition of FVC reduction and increase in wet and dry lung weights by these pharmacological agents. These results strongly support the hypothesis that lung microvascular leakage and the associated lung edema contribute to the reduction in forced expiratory lung functions in antigen-challenged Brown Norway rats and identify an important role for the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in these responses.
    No preview · Article · Mar 2013 · Pulmonary Pharmacology & Therapeutics
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    ABSTRACT: Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist. Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension. The affinity and functional activity of compound B for α2C-adrenoceptors were determined by binding analysis and the ability of compound B to stimulate [(35)S]GTPγS binding to the receptors. Compound B was also tested in a postjunctional α2C-adrenoreceptor bioassay. EFS-induced contractions were partly blocked by the α2-adrenoreceptor antagonist yohimbine (41.1%) and the α2C-adrenoreceptor antagonist JP-1302 had no effect. The α2-adrenoreceptor agonist clonidine, but not compound B, exerted a significant blockade (70.6%). Compound B had high affinity (Ki = 18 nM), produced potent agonist (EC50 = 279 nM) and good efficacy (Emax = 73%) responses at the α2C-adrenoceptors, and displayed good functional agonist potency in the human saphenous vein α2C-adrenoreceptor bioassay (pD2 = 6.2). (1) Neurogenic vasomotor contractility is largely regulated through an α-adrenergic mechanism; (2) pig nasal mucosa possesses post- and prejunctional α2-adrenoceptors; (3) the α2C-adrenoreceptor subtype does not seem to be involved; and (4) compound B is a novel, highly selective, and potent α2C-adrenoreceptor agonist.
    No preview · Article · Mar 2013 · American Journal of Rhinology and Allergy
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    ABSTRACT: A novel series of dual NK1/NK2 receptor antagonists, based on the 2-oxo-(1,4′-bipiperidine) template, has been prepared. Compound 10R is a potent dual NK1/NK2 antagonist and demonstrates excellent in vivo activity and good oral plasma levels in the dog.
    No preview · Article · Dec 2010 · ChemInform
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    ABSTRACT: Mometasone furoate (MF)/formoterol fumarate (F) combination is a new inhaIed corticosteroid/long-acting β₂-adrenergic agonist (ICS/LABA). The purpose of this study was to evaluate the effects of different dose combinations of MF/F on a variety of late-phase responses to aerosolized antigen challenge in ovalbumin sensitized Brown Norway rats. Late-phase responses were assessed by reductions in lung function, measured by forced vital capacity (FVC) and increased numbers of inflammatory cells and pro-inflammatory cytokines in the bronchoalveolar lavage (BAL) fluid of ovalbumin challenged rats. Intratracheal administration of MF/F 5 h before aerosolized ovalbumin challenge inhibited the increase in inflammatory cells, including eosinophils and levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor-α (TNF-α) appearing in the bronchoalveolar lavage fluid 24 h after the antigen challenge. The combination index for inhibition of both inflammatory cells and cytokines was consistently <1 suggesting a synergistic interaction between MF and F. Intratracheal MF/F given 24 h after the aerosolized ovalbumin challenge reversed the reduction in FVC with statistically significant effects seen over a 24 h period after drug whereas MF and F alone reversed the antigen-induced reduction in FVC at selected times only. At 5 h after drug administration, when both MF and F were partially active, the combination index for MF/F was <1 suggesting a synergistic interaction between MF and F for reversal of the lung function. These results demonstrate that MF/F combination inhibits a variety of late-phase responses induced by allergen challenge and it is likely that MF/F will have a significant benefit in clinical asthma to suppress lung inflammation and improve lung function.
    Full-text · Article · Oct 2010 · Pulmonary Pharmacology & Therapeutics
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    ABSTRACT: A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC(50)=70pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.
    Full-text · Article · Sep 2010 · European journal of pharmacology

  • No preview · Conference Paper · May 2010
  • Jonathan E. Phillips · Monika Anand · Richard W. Chapman

    No preview · Conference Paper · May 2010
  • Gissela Lieber · Robbie L. McLeod · Richard W. Chapman · Yanlin Jia

    No preview · Conference Paper · May 2010
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    ABSTRACT: Continuous isometric microfocal X-ray computed tomography (CT) scans were acquired from an AKR/J mouse, Brown-Norway rat, and Hartley guinea pig. The anatomy and volume of the paranasal sinus cavities were defined from 2-dimensional (2-D) and 3-dimensional (3-D) CT images. Realistic 3-D images were reconstructed and used to determine the anterior maxillary, posterior maxillary, and ethmoid sinus cavity airspace volumes (mouse: 0.6, 0.7, and 0.7 mm(3), rat: 8.6, 7.7, and 7.0 mm(3), guinea pig: 63.5, 46.6 mm(3), and no ethmoid cavity, respectively). The mouse paranasal sinus cavities are similar to the corresponding rat cavities, with a reduction in size, while the corresponding maxillary sinus cavities in the guinea pig are different in size, location, and architecture. Also, the ethmoid sinus cavity is connected by a common drainage pathway to the posterior maxillary sinus in mouse and rat while a similar ethmoid sinus was not present in the guinea pig. We conclude that paranasal sinus cavity airspace opacity (2-D) or volume (3-D) determined by micro-CT scanning may be used to conduct longitudinal studies on the patency of the maxillary sinus cavities of rodents. This represents a potentially useful endpoint for developing and testing drugs in a small animal model of sinusitis.
    Full-text · Article · Jul 2009 · Canadian journal of veterinary research = Revue canadienne de recherche vétérinaire
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    ABSTRACT: Manual total and differential leukocyte counting in bronchoalveolar lavage fluids (BALF) by visual microscopy is a standard means of evaluating airway inflammation and the anti-inflammatory properties of therapeutics in various animal models of lung disease. The manual cell counting method derives total leukocyte counts from BALF with a hemocytometer, and cell differentials (mononuclear, neutrophil, eosinophil) are calculated from the percentage of each cell type taken from a count of at least 200 cells on a stained cytocentrifuge preparation of the BALF cells. These manual methods are time-consuming and have inherent error–variability. The ADVIA 120 Hematology System is an automated analyzer designed to perform total and differential leukocyte analysis of blood. With the light scattering, cell lysis resistance, and cytochemical staining data from a BALF sample processed by the ADIVA, a BALF total leukocyte count and differential analysis is provided in approximately 30s. In order to correlate automated BALF leukocyte counting by the ADVIA 120 Hematology System with manual counting, we developed a manual red blood cell lysing and white blood cell staining technique for BALF cells similar to the process used by the ADVIA. Significant correlations for BALF white blood cells were obtained for the manual (microscopic analysis) and the automated (ADVIA) methods. Comparison of manual and automated cell counts also generates the same conclusions about anti-inflammatory drug efficacy. Both manual and automated cell counting methods agree that 3mg/kg orally administered dexamethasone inhibited cigarette-smoke-induced total BALF cell counts by ∼65% in mice and 42μg/kg fluticasone propionate delivered by nose-only inhalation inhibited allergen-induced total BALF cells by 77% in rats. The use of the ADVIA to perform total and differential leukocyte counts in BALF will save time spent manually counting cells and this instrument will standardize the analysis of white blood cells across the laboratories currently using various manual counting preparations and procedures.
    Full-text · Article · May 2009 · Comparative Clinical Pathology
  • Aidan K Curran · Susan Skeans · Devon Landers · Richard W Chapman
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    ABSTRACT: The proximal and distal portions of the lungs may respond differently to antigen challenge and bronchodilator treatment. This difference may contribute to differences in actual and perceived efficacy of therapies. In this study we used the forced oscillation technique (FOT) to measure impedance in the pulmonary system and discern the effects of antigen challenge on proximal (large airway) and distal (small airway and lung parenchyma) portions of the lung. In addition we treated the animals with two i.m. injections of either a saline control or dexamethasone (0.5 mg/kg) 18 and 1 hour(s) before the antigen challenge. The FOT technique was used to measure indices of proximal airway status, Newtonian airway resistance (R(N)), and distal airway status, including tissue damping (G) and tissue elastance (H). Challenging the animals with Ascaris Suum antigen caused a significant increase in both the proximal and distal lung measures. Pretreatment with dexamethasone significantly reduced the peak increase in R(N) but not G or H. In addition, the area under the curve (AUC) of the FOT response over 60 minutes was significantly reduced for the R(N) but again, G and H were not significantly reduced. These data indicate that, using the FOT, we can dissociate the response of proximal and distal airways to an antigen challenge. Moreover, steroid pre-treatment can reduce the bronchoconstrictor response to inhaled antigen but this effect is primarily via effects on the proximal airways with little effect on the distal airways and parenchymal component of pulmonary impedance. These data may help to provide a mechanism for evaluation of novel therapies for small airway dysfunction.
    No preview · Article · Jul 2008 · Journal of Asthma
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    ABSTRACT: PURPOSE: To assess inhibitory effects of mometasone furoate (MF) on allergen-provoked upper and lower airway inflammation, we evaluated inflammatory cell infiltration and reductions in forced vital capacity (FVC) and peak expiratory flow (PEF) in allergen-challenged Brown Norway rats. METHODS: Four experiments were performed on ovalbumin (OVA)-sensitized rats: Group 1) intranasal (i.n.) MF or vehicle given for 3 consecutive days, last treatment dose given 2 hours before i.n. OVA (1%) challenge on last day; Group 2) and Group 3) intratracheal (i.t.) MF or vehicle given 5 hours before aerosolized OVA (1%) challenge; Group 4) nose-only inhalation of dry powder MF, given 5 hours before aerosolized OVA (1%) challenge. In Groups 1 and 2, nasal lavage (NL) and bronchoalveolar lavage (BAL) samples were collected 24 hours after OVA challenge. In Groups 3 and 4, FVC and PEF were assessed 24 hours after OVA challenge. RESULTS: Intranasal MF (0.01-10 ng/ml) reduced number of total inflammatory cells in the NL induced by OVA challenge, with significant effects seen at all doses. Intratracheal MF (0.01-0.3 mg/kg, i.t.) significantly attenuated number of total BAL inflammatory cells. MF (0.1-1 mg/kg, i.t.) also inhibited reductions in FVC and PEF induced by the OVA challenge. MF attenuated reductions in FVC (32%, 45%, and 92% inhibition) and PEF (50%, 59%, and 100% inhibition) when given by nose-only inhalation (estimated pulmonary deposition of MF, 1.4, 4.1, and 13.3 mcg/kg, respectively). CONCLUSION: In these animal models of upper and lower airway inflammation, MF significantly attenuated cellular lung inflammation and normalized lung function following allergen provocation. This study provides insight into the anti-inflammatory properties of the corticosteroid mometasone furoate.
    No preview · Conference Paper · Apr 2008
  • Richard W Chapman
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    ABSTRACT: Dogs have been extensively used to model the important components of asthma and COPD. Many of the key features of human asthma such as reversible airflow obstruction, pulmonary inflammation, airway hyperresponsiveness and cough are demonstrated in dogs after provocation with antigen, following a period of hyperventilation with dry air or after inhalation of ozone. Furthermore, standard anti-asthma drugs such as beta-adrenergic agonists, corticosteroids and leukotriene inhibitors are effective in these models. The pathology and pathophysiology of chronic bronchitis and emphysema can also be demonstrated in dogs after exposure to cigarette smoke, following inhalation of sulfur dioxide and by intra-tracheal or aerosol administration of proteolytic enzymes such as papain. These canine models of COPD have been used to evaluate a variety of new methodologies and treatments before they are tested in humans. This review highlights some of the important features of these canine models and how they have increased our understanding of the pathology, pathophysiology and control of human asthma and COPD.
    No preview · Article · Mar 2008 · Pulmonary Pharmacology & Therapeutics
  • John A. Hey · Maurice Prado · Richard W. Chapman · Jackie Wright
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    ABSTRACT: 1. To characterize pharmacologically the role of the autonomic nerves on the bronchoconstrictor and cardiovascular responses to central nervous medullary stimulation, paralysed, chloralose-anaesthetized guinea-pigs were instrumented for measurement of bronchoconstriction and blood pressure, and for electrical stimulation of the dorsal medulla. 2. Bilaterl medullary stimulation (32 Hz, 1.5 ms pulse, 50-700 μA for 5-10s) elicited intensity-dependent increases in pulmonary insufflation pressure (PIP) and blood pressure (BP). In animals instrumented for the measurement of pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)), medullary stimulation caused intensity-dependent increases in R(L) and decreases in C(Dyn) that paralleled the increases in PIP. Pretreatment with the anticholinergic drug, ipratropium bromide (10 μg kg-1, i.v.) abolished these bronchomotor responses. 3. Administration of the β-blocker, (±)-propranolol (1 mg kg-1, iv), potentiated the bronchoconstrictor and reduced the hypertensive responses to medullary stimulation. The inactive stereoisomer, (+)-propranolol had no effect. 4. Bilateral adrenalectomy potentiated the bronchoconstrictor and reduced the hypertensive responses to medullary stimulation. In adrenalectomized animals, injection of lidocaine into the spinal cord or administration of (±)-propranolol (1 mg kg-1, i.v.) further potentiated the CNS bronchoconstriction. 5. Therefore, stimulation of discrete sites within the dorsal medulla activates both the parasympathetic and the sympathetic nervous systems to produce a vagal, cholinergic bronchospasm that is under the inhibitory influence of sympathetic nerves. The inhibitory influence is probably mediated by β-adrenoceptor stimulation that is produced primarily by adrenal-derived catecholamines and, to a lesser extent, by sympathetic innervation of the lungs.
    No preview · Article · Jan 2008 · Journal of Autonomic Pharmacology
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    ABSTRACT: Orally active phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of asthma and chronic obstructive pulmonary disorders (COPD) although their full development has been limited by adverse side effects. Administration of PDE4 inhibitors by inhalation may improve their therapeutic index, but limited information exists on the efficacy of inhaled PDE4 inhibitors to improve lung function. In this study in ovalbumin-sensitized Brown Norway rats, roflumilast was given either intratracheally or by nose-only inhalation and changes in lung function (forced vital capacity, FVC; peak expiratory flow, PEF) and inflammatory cell influx (total cells, eosinophils and neutrophils) into the bronchoalveolar lavage (BAL) fluid were evaluated 24 h after allergen challenge. Intratracheal roflumilast, given 5 h before antigen challenge, inhibited the antigen-induced reductions in FVC (ED50 = 140 microg/kg, i.t.) and total cells appearing in the bronchoalveolar lavage fluid (ED50 = 50 microg/kg, i.t.). By the nose-only inhalation route, roflumilast reduced the bronchoalveolar lavage fluid total cells (ED50 = 10 microg/kg, estimated pulmonary deposition). Intratracheal roflumilast (600 microg/kg, i.t.) was also given to rats 24 h after the antigen challenge and reversed the antigen-induced reductions of FVC by 38% at 1 h, 54% at 5 h and 71% by 16 h. Intratracheal roflumilast also reduced the number of inflammatory cells in the bronchoalveolar lavage fluid and reduced the interstitial airway edema caused by the antigen challenge. These results support the development of inhaled PDE4 inhibitors for the treatment of asthma and COPD, particularly for the improvement of lung function.
    Full-text · Article · Nov 2007 · European Journal of Pharmacology
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    ABSTRACT: Sch527123 [2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]ben-zamide] is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al., 2007). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, as well as its in vivo activity in models demonstrating prominent pulmonary neutrophilia, goblet cell hyperplasia, and mucus production. Sch527123 bound with high affinity to the CXCR2 receptors of mouse (K(d) = 0.20 nM), rat (K(d) = 0.20 nM), and cynomolgus monkey (K(d) = 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC(50) approximately 3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K(d) = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC(50) approximately 1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED(50) = 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED(50) = 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED(50) =<0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED(50) = 1.3 mg/kg), goblet cell hyperplasia (ED(50) = 0.7 mg/kg), and increase in BAL mucin content (ED(50) = <1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduced the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED(50) = 0.3 mg/kg). Therefore, Sch527123 may offer benefit for the treatment of inflammatory lung disorders in which pulmonary neutrophilia and mucus hypersecretion are important components of the underlying disease pathology.
    Full-text · Article · Aug 2007 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: The Brown-Norway rat is often used to study the allergic pulmonary response. However, relatively little is known about the delayed phase reactions after allergen challenge in this species. To evaluate the temporal changes in lung function and elucidate the mechanisms involved in the delayed phase response, Brown-Norway rats were sensitized and challenged to aerosolized ovalbumin and lung functions were measured by forced expiratory maneuvers and forced oscillation for up to 10 days after a single antigen challenge. Statistically significant (P < 0.05) reductions in inspiratory capacity, forced vital capacity, functional residual capacity, peak expiratory flow and maximum mid-expiratory flow and increases in respiratory system resistance and elastance were seen by 1 to 3 days after ovalbumin challenge that returned to baseline by 10 days. The reductions in lung function after ovalbumin challenge were blocked by the corticosteroid, betamethasone (1 mg/kg, p.o.). Histological evaluation of lung tissue of sensitized rats demonstrated evidence of interstitial pulmonary edema, an increase in tissue eosinophils and an increase in Periodic Acid Schiff-positive cells in the airway epithelium. Bronchoalveolar lavage fluid samples showed large numbers of eosinophils and increased mucin content up to 6 days after antigen challenge. There was also an increase in wet-to-dry lung weight ratio in the lungs of sensitized rats after antigen. These results demonstrate that prolonged reductions in lung function occur after a single antigen challenge in Brown-Norway rats that is probably due to inflammatory processes producing interstitial pulmonary edema, mucus secretion and cellular influx into the lungs.
    No preview · Article · Jul 2006 · European Journal of Pharmacology