Effects of IL-13 on airway responses in the guinea pig

2002 ◽  
Vol 282 (1) ◽  
pp. L44-L49 ◽  
Author(s):  
Brian Morse ◽  
Joseph P. Sypek ◽  
Debra D. Donaldson ◽  
Kathleen J. Haley ◽  
Craig M. Lilly
Keyword(s):  
Guinea Pig ◽  
Airway Hyperresponsiveness ◽  
Histological Grade ◽  
Allergen Challenge ◽  
Cell Counts ◽  
Respiratory System Resistance ◽  
Airway Responses ◽  
Necessary And Sufficient ◽  
Eosinophil Accumulation

Levels of interleukin (IL)-13 are increased in asthmatic airways. IL-13 has been shown to be necessary and sufficient for allergen-induced airway hyperresponsiveness and increased inflammatory cell counts in bronchoalveolar lavage (BAL) fluid in a murine model of asthma but is thought to protect against airway inflammation when low doses are provided to the guinea pig lung. To determine the role of IL-13 in the guinea pig, we studied the effects of a 360-μg/kg dose of nebulized IL-13 in naive animals and of IL-13 abrogation after airway challenge of sensitized animals. Nebulized IL-13 significantly decreased the dose of histamine required to double baseline respiratory system resistance (ED100, 22 ± 3 vs. 13 ± 2 nmol/kg; P < 0.05) and was associated with recovery of significantly greater numbers of macrophages, lymphocytes, eosinophils, and neutrophils in BAL fluid. Guinea pigs pretreated with a fusion protein that binds IL-13 [soluble IL-13 receptor α2 (sIL-13Rα2)] were protected from developing antigen-induced airway hyperresponsiveness (ED100, 210 ± 50 vs. 20 ± 10 nmol/kg; P <0.01). sIL-13Rα2 (2 doses of 20 mg/kg) significantly reduced the histological grade of allergen-induced lung eosinophil accumulation, whereas the effects of two doses of 10 mg/kg were not significant. These findings demonstrate that the tissue levels of IL-13 induced by allergen challenge of sensitized animals induce airway hyperresponsiveness and inflammation and that IL-13 is required for the expression of allergen-induced airway hyperresponsiveness in the guinea pig ovalbumin model.

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs

1993 ◽  
Vol 75 (6) ◽  
pp. 2797-2804 ◽  
Author(s):  
A. Garland ◽  
J. E. Jordan ◽  
D. W. Ray ◽  
S. M. Spaethe ◽  
L. Alger ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Quiet Breathing ◽  
Leukotriene D4 ◽  
Mechanically Ventilated ◽  
Respiratory System Resistance ◽  
D4 Receptor ◽  
Airway Responses ◽  
Previous Demonstration

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50–80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

Effect of thromboxane antagonists on ozone-induced airway responses in dogs

1990 ◽  
Vol 69 (3) ◽  
pp. 880-884 ◽  
Author(s):  
G. L. Jones ◽  
C. G. Lane ◽  
P. M. O'Byrne
Keyword(s):  
Airway Hyperresponsiveness ◽  
The Other ◽  
Receptor Antagonists ◽  
Thromboxane Receptor ◽  
Before And After ◽  
The Mean ◽  
Airway Responses ◽  
Control Infusion

Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); on the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.

Protective role of epithelium in the guinea pig airway

1989 ◽  
Vol 66 (4) ◽  
pp. 1547-1552 ◽  
Author(s):  
M. Munakata ◽  
I. Huang ◽  
W. Mitzner ◽  
H. Menkes
Keyword(s):  
Guinea Pig ◽  
Protective Role ◽  
Airway Epithelial ◽  
Serosal Side ◽  
Epithelial Surface ◽  
Airway Responses ◽  
Airway Tone ◽  
Stimulation Of

We developed an in vitro system to assess the role of the epithelium in regulating airway tone using the intact guinea pig trachea (J. Appl. Physiol. 64: 466–471, 1988). This method allows us to study the response of the airway when its inner epithelial surface or its outer serosal surface is stimulated independently. Using this system we evaluated how the presence of intact epithelium can affect pharmacological responsiveness. We first examined responses of tracheae with intact epithelium to histamine, acetylcholine, and hypertonic KCl when stimulated from the epithelial or serosal side. We then examined the effect of epithelial denudation on the responses to these agonists. With an intact epithelium, stimulation of the inner epithelial side always caused significantly smaller changes in diameter than stimulation of the outer serosal side. After mechanical denudation of the epithelium, these differences were almost completely abolished. In the absence of intact epithelium, the trachea was 35-fold more sensitive to histamine and 115-fold more sensitive to acetylcholine when these agents were applied to the inner epithelial side. In addition, the presence of an intact epithelium almost completely inhibited any response to epithelial side challenge with hypertonic KCl. These results indicate that the airway epithelial layer has a potent protective role in airway responses to luminal side stimuli, leading us to speculate that changes in airway reactivity measured in various conditions including asthma may result in part from changes in epithelial function.

Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses toAspergillus fumigatus

2002 ◽  
Vol 283 (1) ◽  
pp. L198-L204 ◽  
Author(s):  
Jane M. Schuh ◽  
Kate Blease ◽  
Steven L. Kunkel ◽  
Cory M. Hogaboam
Keyword(s):  
T Cell ◽  
Airway Hyperresponsiveness ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Th2 Cells ◽  
Wild Type ◽  
Cell Recruitment ◽  
Chronic Model ◽  
Airway Responses

Eotaxin/CCL11 is a major chemoattractant for eosinophils and Th2 cells. As such, it represents an attractive target in the treatment of allergic disease. The present study addresses the role of eotaxin/CCL11 during acute and chronic allergic airway responses to the fungus Aspergillus fumigatus. Mice lacking the eotaxin gene (Eo−/−) and wild-type mice (Eo+/+) were sensitized to A. fumigatus and received either an intratracheal challenge with soluble A. fumigatusantigens (acute model) or an intratracheal challenge with live A. fumigatus spores or conidia (chronic model). Airway hyperresponsiveness and eosinophil, but not T cell, recruitment were significantly decreased at 24 h after the soluble allergen in A. fumigatus-sensitized Eo−/− mice compared with similarly sensitized Eo+/+ mice. In contrast, the development of chronic allergic airway disease due to A. fumigatus conidia was not altered by the lack of eotaxin. Together, these data suggest that eotaxin initiates allergic airway disease due to A. fumigatus, but this chemokine did not appear to contribute to the maintenance of A. fumigatus-induced allergic airway disease.

scholarly journals Exhaled Nitric Oxide is Related to Bronchial Eosinophilia and Airway Hyperresponsiveness to Bradykinin in Allergen-Induced Asthma Exacerbation

2012 ◽  
Vol 25 (1) ◽  
pp. 175-182 ◽  
Author(s):  
F.L.M. Ricciardolo ◽  
A. Di Stefano ◽  
M. Silvestri ◽  
A.M. Van Schadewijk ◽  
M. Malerba ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Airway Hyperresponsiveness ◽  
Allergen Challenge ◽  
Immunohistochemical Analysis ◽  
Allergen Exposure ◽  
Exhaled Nitric Oxide ◽  
Atopic Asthma ◽  
Bronchial Biopsy ◽  
Cell Counts ◽  
Large Project

Exhaled nitric oxide (FeNO) has been associated with bronchial eosinophilia and with airway hyperresponsiveness (AHR) in mild stable asthma. We previously demonstrated in a large project that allergen exposure is able to raise FeNO and to worsen AHR to bradykinin. We postulated that allergen-induced increase in FeNO could be related to heightened mucosal eosinophils and AHR to bradykinin in atopic asthma. We performed a new immunohistochemical analysis on bronchial biopsy specimens, previously obtained from the same large project, in order to assess the number of mucosal eosinophils (EG-2+ cell) and other inflammatory cells at 48 hours after diluent and allergen exposures. Inflammatory cell counts were related to FeNO and AHR to BK (expressed as logPD20 bradykinin). In 10 atopic mild asthmatics, we found that the numbers of EG-2+ and CD4+ cells in bronchial submucosa were significantly increased after allergen compared to the respective counts after diluent (p < 0.01). EG-2+ cells in the bronchial submucosa were negatively correlated with logPD20 bradykinin only after allergen challenge (rho = −0.709, p = 0.027). We also found a positive strong correlation between EG-2+ cells and FeNO values in atopic asthmatics at 48 hours after both diluent (rho = 0.746, p = 0.017) and allergen (rho = 0.644, p = 0.049) challenge. FeNO values negatively correlated with responsiveness to bradykinin only after allergen challenge (rho = −0.675, p = 0.039). This study indicates that after allergen exposure heightened level of exhaled NO may reflect augmented airway eosinophilic inflammation and airway responsiveness to bradykinin indicating loss of asthma control.

scholarly journals Allergen Induced Increase in Nonallergic Airway Responsiveness: A Citation Classic Revisited

2000 ◽  
Vol 7 (2) ◽  
pp. 182-187 ◽  
Author(s):  
Donald W Cockcroft
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Immunoglobulin E ◽  
Allergen Challenge ◽  
Airway Responsiveness ◽  
Forced Expiration ◽  
Citation Classic ◽  
Poor Understanding ◽  
The Times

BACKGROUND:The present paper revisits the 1977 paper by DW Cockcroft, RE Ruffin, the late J Dolovich and FE Hargreave entitled "Allergen-induced increase in nonallergic bronchial reactivity" (Clin Allergy1977;7:503-13) that became a citation classic. Although clinical types of asthma were recognized at the time, there was a poor understanding regarding the role of allergic reactions in causing increases in airway hyperresponsiveness. The objective was to study formally Dr Altounyan's observation that patients with asthma showed increases in airway responsiveness at the times of natural allergen exposure during pollen season. Thirteen atopic patients with asthma were studied over two days, following inhalation of diluent (control) and following doubling amounts of an allergen solution at 10-min intervals until forced expiration volume in 1 s fell by 20%. Methacholine and histamine challenges were performed before, at 8 h, at 32 h and seven days following the inhalations. A significant reduction (reduction of at least one doubling concentration) in the provocative concentration that causes a 20% fall in forced expiration volume in 1 s occurred in seven of 13 patients, and more often in subjects with a late bronchoconstrictor response to allergen challenge.IMPORTANCE:The study showed that large changes in airway responsiveness could occur in patients with asthma and suggested that allergens could cause, rather than trigger, asthma. The study also led to the concept of asthma inducers and inciters -- inducers causing airway inflammation and inciters provoking bronchospasm. The results led to a series of observations that have now implicated immunoglobulin E-mediated airway inflammation as perhaps the most important cause of airway hyperresponsiveness in asthma.

scholarly journals Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation.

1994 ◽  
Vol 179 (3) ◽  
pp. 881-887 ◽  
Author(s):  
P J Jose ◽  
D A Griffiths-Johnson ◽  
P D Collins ◽  
D T Walsh ◽  
R Moqbel ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
High Performance ◽  
Allergen Challenge ◽  
Neutrophil Accumulation ◽  
Platelet Factor ◽  
Inflammatory Reactions ◽  
Eosinophil Accumulation

Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both to generate and assay relevant activity. Bronchoalveolar lavage (BAL) fluid was taken from sensitized guinea pigs at intervals after aerosol challenge with ovalbumin. BAL fluid was injected intradermally in unsensitized assay guinea pigs and the accumulation of intravenously injected 111In-eosinophils was measured. Activity was detected at 30 min after allergen challenge, peaking from 3 to 6 h and declining to low levels by 24 h. 3-h BAL fluid was purified using high performance liquid chromatography techniques in conjunction with the skin assay. Microsequencing revealed a novel protein from the C-C branch of the platelet factor 4 superfamily of chemotactic cytokines. The protein, "eotaxin," exhibits homology of 53% with human MCP-1, 44% with guinea pig MCP-1, 31% with human MIP-1 alpha, and 26% with human RANTES. Laser desorption time of flight mass analysis gave four different signals (8.15, 8.38, 8.81, and 9.03 kD), probably reflecting differential O-glycosylation. Eotaxin was highly potent, inducing substantial 111In-eosinophil accumulation at a 1-2 pmol dose in the skin, but did not induce significant 111In-neutrophil accumulation. Eotaxin was a potent stimulator of both guinea pig and human eosinophils in vitro. Human recombinant RANTES, MIP-1 alpha, and MCP-1 were all inactive in inducing 111In-eosinophil accumulation in guinea pig skin; however, evidence was obtained that eotaxin shares a binding site with RANTES on guinea pig eosinophils. This is the first description of a potent eosinophil chemoattractant cytokine generated in vivo and suggests the possibility that similar molecules may be important in the human asthmatic lung.

Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig

1996 ◽  
Vol 270 (3) ◽  
pp. L368-L375 ◽  
Author(s):  
C. M. Lilly ◽  
R. W. Chapman ◽  
S. J. Sehring ◽  
P. J. Mauser ◽  
R. W. Egan ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Histological Grade ◽  
Platelet Activating Factor ◽  
Inflammatory Cells ◽  
Dependent Manner ◽  
Interleukin 5 ◽  
Dose Dependent

Administration of interleukin 5 (IL-5) to guinea pigs by tracheal injection was associated with increased recovery of eosinophils and neutrophils from bronchoalveolar lavage (BAL) fluid. The number of eosinophils recovered from BAL fluid increased in a dose-dependent manner from 9 +/- 2 X 10(3)/ml to a plateau of 143 +/- 29 X 10(3)/ml after the administration of recombinant human IL-5 (rhIL-5). Tracheal administration of recombinant guinea pig IL-5 (gpIL-5) also increased eosinophil recovery but was less potent than rhIL-5. Histological analysis confirmed the presence of inflammatory cells in the lung; there were higher grades of inflammation in airway than in parenchymal tissue after gpIL-5 administration. In addition, the histological grade of airway inflammation was greater 24 and 72 h after gpIL-5 administration than it was 6 days after administration. Airway hyperresponsiveness is reported to occur in guinea pigs exposed to rhIL-5 by intraperitoneal cellular production. It is surprising that airway infiltration with eosinophils induced by the topical application of IL-5 was not associated with hyperresponsiveness to substance P, histamine, or platelet-activating factor in intact animals or to methacholine in tracheally perfused lungs. Furthermore, the microvascular leakage induced by substance P was not altered by rhIL-5 administration. These findings indicate that the presence of eosinophils alone is not sufficient for the expression of airway hyperresponsiveness. Our ability to separate eosinophil recruitment and retention in the tissues from airway hyperresponsiveness indicates that these two processes are distinct and that the presence of eosinophils in lung tissue, by itself, is not sufficient to alter airway contractile responses.

Sign in / Sign up

Export Citation Format

Share Document