Papers by Jennifer Wattie
PubMed, Nov 1, 1996
Cyclopiazonic acid (selective blocker of the internal Ca+2 pump) evoked tonic contraction in cani... more Cyclopiazonic acid (selective blocker of the internal Ca+2 pump) evoked tonic contraction in canine bronchial smooth muscle (BSM) and tracheal smooth muscle. This contraction was biphasic, including an initial component that was relatively insensitive to blockade of Ca+2 influx (e.g., removal of external Ca+2; nifedipine; hyperpolarization using lemakalim) followed by a component that was sensitive to all such interventions. In BSM, but not in tracheal smooth muscle, electrical field stimulation (EFS) evoked relaxations that were not affected by interventions designed to prevent release of autacoids from nerve endings or the epithelium, Na+/Ca+2 exchange or Ca(+2)-ATPase activities (internal or plasmalemmal). EFS evoked little or no relaxant response in carbachol-precontracted BSM in the presence of propranolol. After Ca+2 was replaced with Sr+2, however, carbachol evoked comparable contraction after which EFS evoked non-neurogenic relaxations. We found that the EFS-evoked relaxations were abolished by TEA or high KCI, were reduced significantly by charydotoxin or quinine, were reduced partially by ouabain and were unaffected by removal of external K+, by apamin or by glybenclamide. In addition, the relaxations were reduced significantly by the free radical scavenger N-acetylcysteine, were mimicked by H2O2 but were unaffected by superoxide dismutase or catalase. These observations suggest that the cyclopiazonic acid-evoked contraction involves pharmacomechanical coupling mechanisms (i.e., Ca(+2)-release) initially, followed by electromechanical coupling (i.e., voltage-dependent Ca+2 influx). After depletion of the internal Ca+2 store (e.g., by cyclopiazonic acid or Sr+2), EFS is able to evoke in BSM (but not in tracheal smooth muscle) relaxations that seem to involve opening of K+ channels (including those of the large-conductance Ca(+2)-dependent type) by EFS-liberated free radicals.
The Journal of Allergy and Clinical Immunology, Feb 1, 2006
Since little information is available on eosinophil activation and cytokine response in virus-ind... more Since little information is available on eosinophil activation and cytokine response in virus-induced asthma, we attempted to detect respiratory viruses and measure levels of various serum cytokines/chemokines, and eosinophil cationic protein (ECP) in acute as well as stable asthma. METHODS: We detected viruses in nasal lavage obtained from patients with acute asthma using antigen detection kits or PCR followed by direct DNA sequencing analysis. We also measured peripheral eosinophil counts, concentrations of serum ECP, and 17 types of cytokines/chemokines (IL-1,
European Journal of Pharmacology: Environmental Toxicology and Pharmacology, Oct 1, 1995
Both ozone and allergen inhalation increase the capacity to produce oxygen radicals by bronchoalv... more Both ozone and allergen inhalation increase the capacity to produce oxygen radicals by bronchoalveolar lavage cells in dogs. The purpose of these studies was to determine whether inhaled corticosteroids inhibits these increases in oxygen radical production from bronchoalveolar lavage cells. Six random source dogs were studied after dry air or ozone inhalation (3 ppm, 30 min). Seven random source dogs were studied after diluent or allergen inhalation. The dogs inhaled budesonide (2.74 mg/day) or lactose powder, twice daily for 7 days before ozone and allergen. 90 min after ozone or dry air, and 24 h after Ascaris suum or diluent a bronchoalveolar lavage was carried out. Spontaneous luminol-enhanced chemiluminescence was measured from bronchoalveolar lavage cells (4 x 106 cells) for 10 min, followed by a measurement of phorbol myristate acetate (PMA 2.4/xmol/1) stimulated chemiluminescence for 10 min. Both ozone and allergen inhalation caused an increase in PMA stimulated chemiluminescence (P < 0.05). Budesonide pretreatment inhibited ozone-induced (P < 0.008), but not allergen-induced PMA stimulated chemiluminescence (P > 0.90). Both ozone and allergen inhalation caused an increase in the bronchoalveolar lavage neutrophils. Budesonide pretreatment significantly inhibited the ozone-induced (P = 0.007), but not the ascaris-induced neutrophil influx (P = 0.93). These results demonstrate that ozone, but not allergen, stimulated oxygen radical release and neutrophil influx are attenuated by inhaled corticosteroids. This suggests that luminol-enhanced chemiluminescence from bronchoalveolar lavage cells measures oxygen radicals derived from neutrophils, and that ozone-and allergen-induced bronchoalveolar lavage neutrophilia are caused by different mechanisms.
American Journal of Respiratory Cell and Molecular Biology, Oct 1, 1999
Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced ... more Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced airway hyperresponsiveness and inflammation in asthmatics and dogs. Here, for the first time, we compare the time course of airway hyperresponsiveness, inflammation, and marrow progenitor responses in a mouse model of airway allergen challenge. Sensitized BALB/c mice were studied at 2, 12, 24, 48, and 72 h after intranasal ovalbumin or saline challenges. Outcome measurements included airway responsiveness, airway inflammation as assessed via bronchoalveolar lavage (BAL) and lung tissue sections, and BM eosinophil colony-forming units (Eo-CFU) as enumerated using a semisolid culture assay with optimal concentrations of interleukin-5. We observed significant increases in BAL fluid eosinophils, neutrophils, lymphocytes, and macrophages by 2 h after the second of two intranasal allergen challenges (P Ͻ 0.05). Significant increases in airway responsiveness or BM Eo-CFU were observed at 24 h and persisted until 48 h after the second challenge (P Ͻ 0.05). Airway inflammation, including eosinophils, persisted until at least 72 h (P Ͻ 0.05). We observed that allergen-induced airway eosinophilia is accompanied by increases in BM eosinophil progenitors, indicating that in this model, increased eosinophil production involves an expansion of the relevant stem-cell population. These findings support the use of this model to explore the mechanisms of increased eosinopoiesis observed in human asthma. Inman, M. D., R. Ellis, J. Wattie, J. A. Denburg, and P. M. O'Byrne. 1999. Allergen-induced increase in airway responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice. Am. J. Respir. Cell Mol. Biol. 21:473-479.
American Journal of Physiology-lung Cellular and Molecular Physiology, Dec 1, 1997
American Journal of Physiology-lung Cellular and Molecular Physiology, Feb 1, 1998
To investigate the role of prostaglandin (PG) E 2 in allergen-induced hyperresponsiveness, dogs i... more To investigate the role of prostaglandin (PG) E 2 in allergen-induced hyperresponsiveness, dogs inhaled either the allergen Ascaris suum or vehicle (Sham). Twenty-four hours after inhalation, some animals exposed to allergen demonstrated an increased responsiveness to acetylcholine challenge in vivo (Hyp-Resp), whereas others did not (Non-Resp). Strips of tracheal smooth muscle, either epithelium intact or epithelium denuded, were suspended on stimulating electrodes, and a concentration-response curve to carbachol (10 Ϫ9 to 10 Ϫ5 M) was generated. Tissues received electrical field stimulation, and organ bath fluid was collected to determine PGE 2 content. With the epithelium present, all three groups contracted similarly to 10 Ϫ5 M carbachol, whereas epithelium-denuded tissues from animals that inhaled allergen contracted more than tissues from Sham dogs. In response to electrical field stimulation, Hyp-Resp tissues contracted less than Sham tissues in the presence of epithelium and more than Sham tissues in the absence of epithelium. PGE 2 release in the muscle bath was greater in Non-Resp tissues than in Sham or Hyp-Resp tissues when the epithelium was present. Removal of the epithelium greatly inhibited PGE 2 release. We conclude that tracheal smooth muscle is hyperresponsive in vitro after in vivo allergen exposure only when the modulatory effect of the epithelium, largely through PGE 2 release, is removed.
C33. ANTI-INFLAMMATORY STRATEGIES IN AIRWAYS DISEASE: ANIMAL MODELS, 2010
Genes
Background: The immune response in COVID-19 is characterized by the release of alarmin cytokines,... more Background: The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. Methods: We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. Results: Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs393928...
American Journal of Respiratory and Critical Care Medicine, 1995
Allergen inhalation causes airway hyperresponsiveness and airway inflammation in dogs. The purpos... more Allergen inhalation causes airway hyperresponsiveness and airway inflammation in dogs. The purpose of this study was to determine whether allergen-induced airway hyperresponsiveness is associated with increases in oxygen radical production from bronchoalveolar lavage (BAL) cells. A group of 10 random-source dogs were studied twice, 4 wk apart. On each occasion, acetylcholine (ACh) airway responsiveness was measured before and 24 h after inhalation of Ascaris suum or its diluent, followed by BAL. The response to ACh was expressed as the concentration causing an increase in lung resistance of 5 cm H2/O/L/s above baseline. Spontaneous and phorbol myristate acetate (PMA)-stimulated (2.4 mumol/L) oxygen radical release were measured, for 10 min each, from washed BAL cells (4 x 10(6) cells/ml) by luminol-enhanced chemiluminescence in a luminometer at 37 degrees C. Superoxide anion production was measured using a cytochrome c assay. Allergen inhalation caused bronchoconstriction, airway inflammation, and airway hyperresponsiveness. The acetylcholine provocative concentration fell from 7.47 mg/ml (% SEM 1.61) before to 1.23 mg/ml (% SEM 1.62) after allergen (p &lt; 0.0001). Allergen inhalation significantly increased absolute neutrophil (p = 0.03) and eosinophil (p = 0.02) counts in BAL. Spontaneous (p &lt; 0.0003) and PMA-stimulated (p &lt; 0.0005) chemiluminescence and superoxide anion production (p = 0.039) were increased after allergen inhalation. The allergen-induced increases in chemiluminescence were significantly correlated with the increases in ACh airway hyperresponsiveness (r = 0.75, p &lt; 0.012). These results indicate that inhaled allergen increases oxygen radical release from bronchoalveolar lavage cells and supports the hypothesis that oxygen radicals are important in causing allergen-induced airway hyperresponsiveness.
Rationale: Although corticosteroids are highly effective at prevent- ing allergen-induced increas... more Rationale: Although corticosteroids are highly effective at prevent- ing allergen-induced increases in goblet cell numbers, we observed in unpublished experiments a rebound increase in goblet cell numbersinmiceafterthesimultaneouswithdrawalofcorticosteroid and cessation of exposure to allergen that reached levels greater than those observed in mice exposed to allergen alone, without corticosteroid treatment. Objectives: To formally explore the goblet cell hyperplasia rebound observed after
European Respiratory Journal, 2008
Despite the effectiveness of corticosteroids at resolving airway inflammation, they are only mode... more Despite the effectiveness of corticosteroids at resolving airway inflammation, they are only moderately effective at attenuating airway hyperresponsiveness (AHR). The extent to which corticosteroids are able to reverse or inhibit the development of sustained AHR is not known. The present study aimed to determine whether budesonide can resolve and or prevent the development of sustained AHR in mice. Mice were chronically exposed to allergen and treated with budesonide either: 1) briefly during the final weeks of exposure to allergen; 2) prolonged concurrently throughout exposure to allergen; or 3) delayed following final exposure to allergen. AHR was assessed 24 h (brief treatment) or 4 weeks (prolonged concurrent and delayed treatments) following final exposure to allergen. Brief budesonide intervention significantly attenuated the inflammation-associated AHR assessed immediately following final exposure to allergen. Similarly, prolonged concurrent budesonide treatment prevented the development of sustained AHR. Delayed budesonide intervention, however, did not resolve sustained AHR. In conclusion, the early introduction and, importantly, the persistence of corticosteroid treatment prevented the development of sustained airway hyperresponsiveness; however, the inability of corticosteroids to reverse established airway dysfunction indicates a limitation in their use for the complete, long-term management of airway hyperresponsiveness.
Journal of Allergy and Clinical Immunology, 2007
Background: Pathologic changes, including inflammation and remodeling, occur in the asthmatic air... more Background: Pathologic changes, including inflammation and remodeling, occur in the asthmatic airway. However, their relative contribution to the components of airway hyperresponsiveness (AHR) remains unclear. Objective: Attempting to delineate AHR into discrete immunemediated and structural remodeling components, we performed a detailed time course of the development, progression, and persistence of maximal respiratory system resistance, airway reactivity, and airway sensitivity. Methods: Mice exposed to increasing durations of persistent allergen were assessed for airway function, morphometry, and inflammation. Results: Allergen exposure resulted in increases for all indices of AHR that persisted for at least 4 weeks after chronic allergen exposure (P < .01 for all values). Early increases in AHR were associated with increases in immune-mediated events, including airway eosinophils (P < .01), whereas sustained AHR was associated with structural remodeling events. Increased maximal respiratory system resistance, evident by 6 weeks postallergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, was associated with an increase in collagen deposition (P < .01). Increased airway reactivity and sensitivity, each evident by 1 week after allergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, were associated with an increase in airway smooth muscle area (P < .01). Conclusion: Our novel observation of distinct temporal relationships in the development, progression, and persistence of the individual indices of AHR supports our hypothesis that multiple underlying factors contribute to airway dysfunction. Clinical implications: These findings illustrate the importance of clearly addressing specific components of airway dysfunction to provide greater insight into specific pathophysiologic mechanisms in airway disease. (J Allergy Clin Immunol 2007;119:848-54.)
Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced ... more Increases in bone-marrow (BM) inflammatory cell progenitors are associated with allergen-induced air- way hyperresponsiveness and inflammation in asthmatics and dogs. Here, for the first time, we compare the time course of airway hyperresponsiveness, inflammation, and marrow progenitor responses in a mouse model of airway allergen challenge. Sensitized BALB/c mice were studied at 2, 12, 24, 48, and 72 h after
American journal of respiratory and critical care medicine, Jan 15, 2002
We have previously demonstrated that allergen inhalation induces expansion of bone marrow eosinop... more We have previously demonstrated that allergen inhalation induces expansion of bone marrow eosinophil progenitors in sensitized mice and subjects with asthma and that the inhaled corticosteroid, budesonide, reduced baseline but not allergen-induced increase in bone marrow eosinophil/basophil progenitors (EoB-CFU) in subjects with asthma. Here, we evaluated the effects of intranasal budesonide on allergen-induced increases in interleukin (IL)-5 and eotaxin in the airway and peripheral blood, expansion of bone marrow Eo-CFU and eosinophilia in bone marrow, peripheral blood and airway, as well as airway hyperresponsiveness, in ovalbumin (OVA)-sensitized mice. Budesonide treatment attenuated allergen-induced eosinophilia in bone marrow, peripheral blood, and airways as well as allergen-induced increases in bone marrow eosinophil progenitors but not allergen-induced increases in IL-5 or eotaxin 12 h following the second of two daily exposures to allergen; at later time points treatment wa...
The antibiotic erythromycin has been shown to modulate a variety of electrophysiological and mech... more The antibiotic erythromycin has been shown to modulate a variety of electrophysiological and mechanical responses in many cell types. We investigated whether it did so in airway smooth muscle using standard patch clamp, fura-2 fluorimetric and organ bath techniques. Erythromycin (10(-4) M) evoked a small transient inward current with reversal potential and time-course similar to that of the Ca2+-dependent Cl- currents seen in these cells. Unlike its effects in other cell types, however, it did not alter basal [Ca2+]i, voltage-dependent Ca2+ currents, nor mechanical tone at rest, nor the corresponding responses to cholinergic stimulation (membrane currents; release of internally sequestered Ca2+, nor contractions evoked by neural stimulation or exogenously added cholinergic agonist). In conclusion, erythromycin does exert interesting electrophysiological actions in airway smooth muscle, but does not alter mechanical activity as it has been shown to do elsewhere.
PLoS ONE, 2014
Background: Asthmatic responses involve a systemic component where activation of the bone marrow ... more Background: Asthmatic responses involve a systemic component where activation of the bone marrow leads to mobilization and lung-homing of progenitor cells. This traffic may be driven by stromal cell derived factor-1 (SDF-1), a potent progenitor chemoattractant. We have previously shown that airway angiogenesis, an early remodeling event, can be inhibited by preventing the migration of endothelial progenitor cells (EPC) to the lungs. Given intranasally, AMD3100, a CXCR4 antagonist that inhibits SDF-1 mediated effects, attenuated allergen-induced lung-homing of EPC, vascularization of pulmonary tissue, airway eosinophilia and development of airway hyperresponsiveness. Since SDF-1 is also an eosinophil chemoattractant, we investigated, using a transgenic eosinophil deficient mouse strain (PHIL) whether EPC lung accumulation and lung vascularization in allergic airway responses is dependent on eosinophilic inflammation.
Journal of Allergy and Clinical Immunology, 2015
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Papers by Jennifer Wattie