Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs

1985 ◽  
Vol 59 (6) ◽  
pp. 1918-1923 ◽  
Author(s):  
H. Aizawa ◽  
K. F. Chung ◽  
G. D. Leikauf ◽  
I. Ueki ◽  
R. A. Bethel ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Thromboxane A2 ◽  
Lavage Fluid ◽  
Airway Epithelial Cells ◽  
Airway Responsiveness ◽  
Base Line ◽  
Airway Epithelial ◽  
Pulmonary Resistance ◽  
Fourfold Increase ◽  
Synthase Inhibitor

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.

Leukotriene B4 induces airway hyperresponsiveness in dogs

1985 ◽  
Vol 59 (6) ◽  
pp. 1941-1946 ◽  
Author(s):  
P. M. O'Byrne ◽  
G. D. Leikauf ◽  
H. Aizawa ◽  
R. A. Bethel ◽  
I. F. Ueki ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Leukotriene B4 ◽  
Airway Responsiveness ◽  
Thromboxane B2 ◽  
Neutrophil Chemotaxis ◽  
Pulmonary Resistance ◽  
Thromboxane Synthase Inhibitor ◽  
Synthase Inhibitor ◽  
Cellular Components

We studied the effect of leukotriene B4 aerosols on airway responsiveness to inhaled acetylcholine aerosols and on the cellular components and cyclooxygenase metabolites in bronchoalveolar lavage fluid in dogs. Inhalation of leukotriene B4 aerosols had no effect on resting total pulmonary resistance but increased airway responsiveness, an effect that was maximum in 3 h and that returned to control levels within 1 wk. Three hours after leukotriene B4, the number of neutrophils and the concentration of thromboxane B2 recovered in lavage fluid increased markedly. Pretreatment with the thromboxane synthase inhibitor OKY-046 prevented the increases in airway responsiveness and in thromboxane B2 but did not alter neutrophil chemotaxis. Thus we speculate that leukotriene B4 causes neutrophil chemotaxis and release of thromboxane B2, which increases airway responsiveness.

scholarly journals S100A9 in adult asthmatic patients: a biomarker for neutrophilic asthma

2021 ◽  
Author(s):  
Quang Luu Quoc ◽  
Youngwoo Choi ◽  
Tra Cao Thi Bich ◽  
Eun-Mi Yang ◽  
Yoo Seob Shin ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Macrophage Polarization ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Airway Epithelial Cells ◽  
Neutrophil Activation ◽  
Neutrophil Extracellular Trap ◽  
Airway Epithelial ◽  
Asthmatic Patients ◽  
M1 Macrophage

AbstractThe biomarkers and therapeutic targets of neutrophilic asthma (NA) are poorly understood. Although S100 calcium-binding protein A9 (S100A9) has been shown to correlate with neutrophil activation, its role in asthma pathogenesis has not been clarified. This study investigated the mechanism by which S100A9 is involved in neutrophil activation, neutrophil extracellular trap (NET)-induced airway inflammation, and macrophage polarization in NA. The S100A9 levels (by ELISA) in sera/culture supernatant of peripheral blood neutrophils (PBNs) and M0 macrophages from asthmatic patients were measured and compared to those of healthy controls (HCs). The function of S100A9 was evaluated using airway epithelial cells (AECs) and PBNs/M0 macrophages from asthmatic patients, as well as a mouse asthma model. The serum levels of S100A9 were higher in NA patients than in non-NA patients, and there was a positive correlation between serum S100A9 levels and sputum neutrophil counts (r = 0.340, P = 0.005). Asthmatic patients with higher S100A9 levels had lower PC20 methacholine values and a higher prevalence of severe asthma (SA) (P < .050). PBNs/M0 macrophages from SA released more S100A9 than those from non-SA patients. PBNs from asthmatic patients induced S100A9 production by AECs, which further activated AECs via the extracellular signal-regulated kinase (ERK) pathway, stimulated NET formation, and induced M1 macrophage polarization. Higher S100A9 levels in sera, bronchoalveolar lavage fluid, and lung tissues were observed in the mouse model of NA but not in the other mouse models. These results suggest that S100A9 is a potential serum biomarker and therapeutic target for NA.

Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

2000 ◽  
Vol 279 (2) ◽  
pp. L379-L389 ◽  
Author(s):  
Dennis W. McGraw ◽  
Susan L. Forbes ◽  
Judith C. W. Mak ◽  
David P. Witte ◽  
Patricia E. Carrigan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Adrenergic Receptors ◽  
Airway Epithelial Cells ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Clara Cell ◽  
Whole Body ◽  
Airway Epithelial

Airway epithelial cells express β2-adrenergic receptors (β2-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of β2-ARs to airway epithelium of transgenic (CCSP-β2-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that β2-AR density in CCSP-β2-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED200) was greater for CCSP-β2-AR than for NTG mice (345 ± 34 vs. 157 ± 14 mg/ml; P < 0.01). CCSP-β2-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline ( P < 0.05) but remained unchanged in the CCSP-β2-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED200for ozone-exposed CCSP-β2-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell β2-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of β-agonists results from activation of receptors on both epithelial and smooth muscle cells.

scholarly journals Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

2014 ◽  
Vol 82 (9) ◽  
pp. 3531-3541 ◽  
Author(s):  
Claire Legendre ◽  
F. Jerry Reen ◽  
David F. Woods ◽  
Marlies J. Mooij ◽  
Claire Adams ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Immune Response ◽  
Bile Acids ◽  
Respiratory Disease ◽  
Hypoxia Inducible Factor ◽  
Lavage Fluid ◽  
Airway Epithelial Cells ◽  
26S Proteasome ◽  
Specific Response ◽  
Airway Epithelial

ABSTRACTGastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1α (HIF-1α) protein, an emerging master regulator in response to infection and inflammation. HIF-1α repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1α repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1α, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation.

scholarly journals IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response

2012 ◽  
Vol 303 (5) ◽  
pp. L382-L390 ◽  
Author(s):  
Maureen B. Josephson ◽  
Junfang Jiao ◽  
Shuyun Xu ◽  
Aihua Hu ◽  
Chinmay Paranjape ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Hyperresponsiveness ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Pulmonary Epithelium ◽  
Lung Fluid ◽  
Peripheral Lung ◽  
Induced Changes ◽  
Fluid Levels ◽  
Glucocorticoid Metabolism

Endogenous glucocorticoid (GC) activation is regulated by the intracellular GC-activating and -inactivating enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD)1 and 11β-HSD2, respectively, that catalyze interconversion of inert cortisone and its bioactive metabolite cortisol. Because endogenous GCs are critically implicated in suppressing the asthmatic state, this study examined the roles of the 11β-HSD enzymes in regulating GC activation and bronchoprotection during proasthmatic stimulation. Airway hyperresponsiveness to methacholine and inflammation were assessed in rabbits following inhalation of the proasthmatic/proinflammatory cytokine IL-13 with and without pretreatment with the 11β-HSD inhibitor carbenoxolone (CBX). Additionally, IL-13-induced changes in 11β-HSD isozyme expression and GC metabolism were examined in epithelium-intact and -denuded tracheal segments and peripheral lung tissues. Finally, the effects of pretreatment with CBX or 11β-HSD2-targeted siRNAs were investigated with respect to cortisol prevention of IL-13-induced airway constrictor hyperresponsiveness and eotaxin-3 production by airway epithelial cells. IL-13-exposed rabbits exhibited airway hyperresponsiveness, inflammation, and elevated bronchoalveolar lung fluid levels of eotaxin-3. These responses were inhibited by pretreatment with CBX, suggesting a permissive proasthmatic role for 11β-HSD2. Supporting this concept, extended studies demonstrated that 1) IL-13-treated tracheal epithelium and peripheral lung tissues exhibit upregulated 11β-HSD2 activity, 2) the latter impairs cortisone-induced cortisol accumulation and the ability of administered cortisol to prevent both IL-13-induced heightened airway contractility and eotaxin-3 release from epithelial cells, and 3) these proasthmatic responses are prevented by cortisol administration in the presence of 11β-HSD2 inhibition. Collectively, these data demonstrate that the proasthmatic effects of IL-13 are enabled by impaired endogenous GC activation in the lung that is attributed to upregulation of 11β-HSD2 in the pulmonary epithelium.

A PAF antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep

1989 ◽  
Vol 67 (1) ◽  
pp. 406-413 ◽  
Author(s):  
M. Soler ◽  
M. W. Sielczak ◽  
W. M. Abraham
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Indirect Evidence ◽  
Airway Responsiveness ◽  
Antigen Challenge ◽  
Base Line ◽  
Response Curves ◽  
Challenge Control ◽  
Web 2086

We studied the effects of WEB-2086, a specific antagonist of platelet-activating factor (PAF), on the development of antigen-induced airway hyperresponsiveness and inflammation in sheep (n = 8). For these studies, airway responsiveness was determined from slopes of carbachol dose-response curves (DRC) performed at base line (prechallenge) and 2 h after Ascaris suum antigen challenges in the following three protocols: 1) antigen challenge alone (control trial), 2) WEB-2086 (1 mg/kg iv) given 30 min before antigen challenge (WEB pretreatment), and 3) WEB-2086 given 2 h after antigen challenge, immediately before the postchallenge DRC (WEB posttreatment). Airway inflammation was assessed by bronchoalveolar lavage (BAL) before antigen challenge and after the postchallenge DRC for each trial. A. suum challenge resulted in acute increases in specific lung resistance that were not different among the three trials. Antigen challenge (control trial) caused a 93% increase (P less than 0.05) in the slope of the carbachol DRC when compared with the prechallenge value. WEB pretreatment (1 mg/kg) reduced (P less than 0.05) this antigen-induced hyperresponsiveness, whereas pretreatment with a 3-mg/kg dose completely prevented it. WEB posttreatment was ineffective in blocking this hyperresponsiveness. BAL neutrophils increased after antigen challenge in the control trial and when WEB-2086 was given after antigen challenge (P less than 0.05). Pretreatment with WEB-2086 (1 or 3 mg/kg) prevented this neutrophilia. This study provides indirect evidence for antigen-induced PAF release in vivo and for a role of endogenous PAF in the modulation of airway responsiveness and airway inflammation after antigen-induced bronchoconstriction in sheep.

O3-induced change in bronchial reactivity to methacholine and airway inflammation in humans

1986 ◽  
Vol 60 (4) ◽  
pp. 1321-1326 ◽  
Author(s):  
J. Seltzer ◽  
B. G. Bigby ◽  
M. Stulbarg ◽  
M. J. Holtzman ◽  
J. A. Nadel ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Bronchoalveolar Lavage ◽  
Airway Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Human Subjects ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Airway Epithelial ◽  
Healthy Human ◽  
Before And After

The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.

Histamine release and circulating cells after antigen inhalation in allergic dogs

1987 ◽  
Vol 62 (1) ◽  
pp. 253-258 ◽  
Author(s):  
K. F. Chung ◽  
M. L. Osborne ◽  
R. J. Corrales ◽  
T. W. Evans ◽  
L. McCabe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mast Cells ◽  
Time Course ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Antigen Challenge ◽  
Base Line ◽  
Plasma Histamine ◽  
Pulmonary Resistance ◽  
Circulating Cells

Histamine can be recovered from the blood of ragweed-sensitized dogs after aerosol antigen challenge, although its source is unknown. Neutrophils and eosinophils have been recovered from bronchoalveolar lavage fluid (BALF) obtained under identical conditions. We investigated the time course of changes in histamine levels in plasma and BALF taken from ragweed-sensitized dogs after aerosol challenge. Changes in the numbers of circulating neutrophils, eosinophils, lymphocytes, monocytes, and platelets were also studied. After 3 min, total pulmonary resistance (RL) was maximally increased and systolic blood pressure was maximally decreased. Histamine levels in plasma and BALF were increased and circulating eosinophils and neutrophils were decreased. After 15 min, platelet numbers were reduced. By 90 min, changes in RL, blood pressure, plasma and BALF histamine concentrations, and circulating neutrophils and eosinophils had returned to base-line values, but platelet numbers remained significantly decreased. Sham challenge caused no significant changes in any of these variables. Intravenous administration of histamine in doses large enough to attain plasma levels comparable with those achieved after aerosol antigen challenge resulted in no concomitant rise in BALF histamine levels. We conclude that antigen challenge in sensitized dogs causes increases in BALF and plasma histamine levels and is associated with a reduction in circulating neutrophils, eosinophils, and platelets. It is likely that antigen causes airway mast cells to release mediators that move down a concentration gradient from the airways to the pulmonary circulation.

Sign in / Sign up

Export Citation Format

Share Document