![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina
Received May 20, 2004; accepted December 21, 2004.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
). Many other studies have also demonstrated that the acute inflammatory component of asthma can be characterized by the recruitment of eosinophils to the lungs (Spruntulis and Broadley, 2001). This recruitment of eosinophils to the lungs has been postulated to be the result of mast cell degranulation.
Adenosine, an endogenous purine nucleoside, acts as a mediator of asthma and can cause bronchoconstriction in asthmatics but not in normal subjects (Cushley et al., 1983). Adenosine acts on four extracellular G-protein-coupled adenosine receptors: A1,A2A,A2B, and A3. Through their ability to promote or enhance mediator release from mast cells, these receptors have been shown to have a contributory role in inflammation and are important in the etiology of asthma and chronic obstructive pulmonary disease. Blackburn et al. (2000) have demonstrated that knocking out the gene for adenosine deaminase results in adenosine accumulation in the lungs. The deleterious effects of adenosine accumulation in the lungs include extensive mast cell degranulation, eosinophilia, increased airway responsiveness, and mucus secretion (Blackburn et al., 2000; Zhong et al., 2001, 2003).
Current research supports that activation of adenosine receptors potentiates mast cell mediator release after being induced by allergen challenge (Church et al., 1983; Fozard and Hannon, 2000; Meade et al., 2001). Activation of the A1 adenosine receptor has been shown to cause bronchoconstriction in rabbit airway smooth muscle (Ali et al., 1994). The A2B and A3 receptors have been shown to be responsible for initiating mast cell degranulation (Feoktistov and Biaggioni, 1995; Zhong et al., 2003) and airway reactivity (Fan et al., 2003). Little is known about the effects of A2A adenosine receptor activation in the development of asthma and inflammation, but it has been postulated that it is not involved in adenosine-induced bronchoconstriction in rats (Pauwels and Joos, 1995). Ohta and Sitkovsky (2001) recently reported that activation of the A2A adenosine receptor is a critical part of the negative feedback mechanism for limitation and termination of both tissue-specific and systemic inflammatory responses.
Allergen induced activation of lung mast cells leads to the release of histamine (Polosa et al., 1995; Forsythe et al., 1999), adenosine (Forsythe et al., 1999), 5-hydroxytryptamine (Fozard and Hannon, 2000), and a myriad of other mediators. Bronchial constriction (Polosa et al., 1995), increased mucus secretion (Sommerhoff et al., 1989), and increases in the localization of inflammatory cells to the airways (Forsythe and Ennis, 1999) are hallmark signs of allergic asthma. Our laboratory has shown that allergen challenge in allergic mice leads to increased airway reactivity and inflammation (Fan and Mustafa, 2002; Fan et al., 2003). Adenosine-induced bronchoconstriction is also associated with increased levels of histamine, prostaglandin D2, and tryptase (Fozard and Hannon, 2000). It has been shown that pretreatment with disodium cromoglycate and nedocromil sodium (Phillips et al., 1989) will attenuate adenosine-induced bronchoconstriction by inhibiting mast cell mediator release through the inhibition of degranulation (Eady and Norris, 1997).
Therefore, to study the role of the mast cell in airway constriction and inflammation, the mast cell degranulating agent, compound 48/80 (C48/80) was administered to ragweed sensitized and control mice. We hypothesized that the chronic degranulation of mast cells would result in attenuation of adenosine-mediated airway constriction and a decreased recruitment of eosinophils to the lungs. We sought to test this hypothesis through the use of the nonspecific adenosine receptor agonist NECA to obtain dose-responsiveness for bronchoconstriction and by performing cell differentials on the cells obtained from the bronchoalveolar lavage fluid (BALF) from each group of mice.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The sensitization was performed according to previously described methods, including the one from this laboratory (Sommerhoff et al., 1989; Fan and Mustafa, 2002). In short, mice were sensitized by i.p. injections of 200 µg of short ragweed (Greer Laboratories, Lenoir, NC) adsorbed to 200 µl of Imject alum (Pierce Chemical, Rockford, IL) per dose on days 1 and 6. On days 11 to 13, the mice were placed in a Plexiglas chamber and challenged with an aerosolized 1% ragweed solution via an ultrasonic nebulizer (DeVilbiss, Somerset, PA) for 20 min in the morning and afternoon. The control animals received i.p. injections of alum only (same volume as sensitized mice) on days 1 and 6 and were subjected to a 0.9% saline aerosolization on days 11 to 13 in the morning and afternoon.
The following groups of mice were used in this study: sensitized, mice sensitized to ragweed and treated with methacholine (MCh) or NECA (0.9% saline was used in place of NECA as a sensitized control); sensitized with C48/80 pretreatment, mice sensitized to ragweed and treated with MCh or NECA; sensitized + saline, mice sensitized to ragweed but treated with saline in place of MCh or NECA; control, mice with no ragweed exposure and treated with MCh or NECA; and control with C48/80 pretreatment, mice with no ragweed exposure and treated with MCh or NECA.
Experimental Protocol
Compound 48/80 Treatments. BALB/c mice were injected chronically to deplete mast cells of their granular contents. This protocol is modified from previous work by Karadag et al. (2000). C48/80 was injected i.p. twice daily as follows: 0.5 mg/kg on day 9, 1.0 mg/kg on day 10, 2.0 mg/kg on day 11, 3.0 mg/kg on day 12, and 4.0 mg/kg on day 13. Groups of mice not receiving C48/80 were given i.p. injections of 0.9% saline twice daily in the same manner.
Airway Responsiveness to NECA and Methacholine. The airway responsiveness was assessed by unrestrained whole-body plethysmography (Max II; Buxco, Troy, NY). The Buxco system uses a dimensionless parameter known as enhanced pause (Penh) to estimate the total pulmonary airflow. This parameter has been shown to correlate with direct invasive measures of airway obstruction, primarily airway resistance and dynamic compliance (Justice et al., 2001). Twelve hours after the last i.p. injection of C48/80, the mice were placed in separate Plexiglas chambers and allowed 10 min to accommodate to their surroundings. After the accommodation period, the mice were exposed to either MCh or the nonselective adenosine receptor agonist (NECA) via the Buxco aerosol delivery system (version 1.5; Buxco, Sharon, CT). Drug was aerosolized for 2.0 min with increasing concentrations (1.5–48.0 mg/ml MCh; 23.44–375.0 µg/ml NECA) to establish a dose-response relationship. Readings were taken for 5 min immediately following drug aerosolization. Each consecutive dose was not administered until the mice returned to baseline Penh levels. Airway responsiveness (Penh values) were normalized to the vehicle values and then expressed as a percentage increase in Penh compared with vehicle.
Bronchoalveolar Lavage. Twenty-four hours after exposure to NECA, the mice were euthanized by i.p. injection of 100 mg/kg sodium pentobarbital, and the bronchoalveolar lavage was performed according to established protocols (Sur et al., 1996; Fan and Mustafa, 2002). In brief, the trachea was exposed and cannulated. Three washings, each consisting of 1.0 ml of phosphate-buffered saline, were introduced into the lungs via the cannula, and the fluid was withdrawn to collect the cells. The pooled lavage fluid was placed in tubes on ice. The collected BALF was then centrifuged at 1600 rpm for 7 min at 4°C (model TJ-6 centrifuge; Beckman Coulter, Fullerton, CA). After removing the supernatant, the cells were resuspended in 0.5 ml of phosphate-buffered saline. Total cell numbers were counted on a hemocytometer (Fisher Scientific Co., Pittsburgh, PA) and 1 to 5 x 103 cells were spun onto glass microscope slides (cytospin 3; Shandon Scientific, Cheshire, England, UK). The cell slides were air dried for 24 to 36 h, then fixed and stained with a Diff-Quik stain set (Dade Behring, Newark, DE). A differential cell count of at least 300 cells per slide was made according to morphologic criteria. The number of cells recovered was calculated and expressed as a percentage of total cells.
Chemicals. Acetyl-
-MCh, NECA, compound 48/80, and sodium pentobarbital were purchased from Sigma-Aldrich (St. Louis, MO). Diff-Quik stain set was purchased from Dade Behring.
Statistical Analysis. All experimental data are expressed as means ± S.E.M. Data were plotted using GraphPad Prism 3.0 (GraphPad Software Inc., San Diego, CA), and the average Penh between different groups was analyzed by analysis of variance followed by Bonferroni's post hoc analysis for multiple comparisons. This test was used to determine the level of significance between all treatment groups. Probability levels less than 0.05 were considered to be statistically significant.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
Airway Responsiveness to NECA. We examined baseline lung function and assessed airway responsiveness to the inhaled nonspecific adenosine receptor agonist, NECA. Baseline Penh values between control, control + C48/80, sensitized, and sensitized + C48/80 groups of mice are comparable, and no significant differences were found (0.6073 ± 0.0219, 0.6862 ± 0.0299, 0.7079 ± 0.0330, and 0.7461 ± 0.0497, respectively). These values were similar to the baseline values with MCh administration. Administration of NECA caused a dose-dependent increase in bronchoconstrictor responsiveness in all groups of mice with the sensitized group being significantly higher. Figure 2 shows the dose-responsiveness of sensitized and control BALB/c mice after exposure to aerosolized NECA. The sensitized group was significantly different (p < 0.05) from all other groups at the 187.5- and 375.0-µg/ml dose. No significant differences were observed between the sensitized + C48/80, control, and control + C48/80 groups. These data show that C48/80 treatment caused a dose-dependent attenuation in Penh when compared with sensitized control mice but did not cause a further attenuation in Penh in control mice. These data illustrate that degranulation of mast cells results in a dose-dependent attenuation in Penh in sensitized mice with NECA.
|
Bronchoalveolar Cellularity. BALF was collected to determine whether chronic pretreatment with C48/80 had effects on cell recruitment. The sensitized mice showed significant (p < 0.05) increases in total cell number when compared with the other groups of mice (Fig. 3). These data demonstrate that chronic depletion of the granular contents of mast cells result in attenuation of inflammatory cell recruitment to the lungs mediated by the activation of adenosine receptors by NECA.
|
The sensitization and challenge protocol with ragweed had an effect on the composition of inflammatory cells collected in the BALF. The cell differentials of the sensitized, sensitized + C48/80, control, and control + C48/80 groups of mice are shown in Fig. 4. Macrophage cells were the primary observed cell type in the control and control + C48/80 groups, and very little inflammation was evident in these groups. The sensitized group showed a significant (p < 0.05) increase in eosinophil recruitment to the lungs, comprising roughly 65% of the cells in that group. This increased eosinophil recruitment is a key hallmark of asthma and correlates with the increase in airway responsiveness observed in these mice. The proportion of macrophages decreased (p < 0.05) in the sensitized mice when compared with the other groups. Neutrophils were also increased in the BALF of the sensitized mice. The lymphocyte component of BALF was not different between groups. Sensitized mice aerosolized with saline showed a significant (p < 0.05) decrease in the proportion of macrophages and a significant (p < 0.05) increase in eosinophil recruitment to the lung when compared with the control and control + C48/80 groups of mice. The saline aerosolized group showed significantly (p < 0.05) more macrophage and significantly (p < 0.05) less eosinophils than the sensitized group treated with NECA. Based on these data, it is evident that NECA is involved in the recruitment of inflammatory cells to the lung.
|
The BALF from the sensitized + C48/80 group showed significantly (p < 0.05) fewer macrophages than the control and control + C48/80 groups but showed significantly (p < 0.05) more macrophage cells than the sensitized-only group (Fig. 4). The sensitized + C48/80 group had (p < 0.05) more neutrophils than the control groups but had less neutrophils (p < 0.05) than the sensitized-only group. Eosinophil numbers for the sensitized + C48/80 group were increased significantly when compared with the control and control + C48/80 groups (p < 0.05), but when compared with the sensitized-only group, the sensitized + C48/80 group contained significantly (p < 0.05) fewer eosinophils. Chronic treatment with C48/80 had anti-inflammatory effects, as observed by an approximate 66% decrease in eosinophils when compared with the sensitized group. From these data, it can be concluded that mast cells indeed have a definitive role in this murine model of lung inflammation due to NECA activation as is observed in allergic asthma.
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Forsythe and Ennis, 1999; Polosa, 2002). Adenosine has many inflammatory effects, such as modulating histamine release from mast cells, influencing eosinophil function, and stimulating mucus secretion in the airways (Blackburn et al., 2000; Polosa et al., 2002). The data presented in this study show that a nonselective adenosine analog, NECA, can cause the degranulation of mast cells, which in turn results in increased airway responsiveness and inflammation. Our data show that the adenosine agonist NECA has a significant effect on airway reactivity as demonstrated by the increased Penh response to NECA in the sensitized mice. Also, the data show that chronic treatment with C48/80 results in a significant attenuation of Penh in sensitized mice. Moreover, our data demonstrate that inflammatory cells, including mast cells, have an important role in the bronchoactive response to the adenosine agonist, NECA.
Chronic treatment with C48/80 has been shown to deplete mast cells of their granular contents (Jaffery et al., 1994; Karadag et al., 2000). Adenosine is involved in asthma through its ability to promote or enhance mediator release from mast cells (Peachell et al., 1988; Jacobson and Bai, 1997). The depletion of mast cells leads to the release of mediators such as histamine, tryptase, chemokines, and interleukins, all of which are important in the etiology of asthma (Forsythe et al., 1999; Polosa et al., 2002).
In vivo studies by various groups (Tilley et al., 2000; Zhong et al., 2003) have shown that adenosine is a potent activator of mast cell degranulation. In contrast to this, in vitro studies of mast cells have shown adenosine to elicit only a minimal level of mast cell degranulation (Ramkumar et al., 1993). This suggests that the mast cell response and the participation of adenosine receptors may be different when grown in culture.
Our data illustrate that Penh measurements in conscious unrestrained mice confirm previous observations in anesthetized animals that allergen challenge enhances airway responsiveness (Fozard and Hannon, 2000; Fan and Mustafa, 2002). Previous data from this laboratory demonstrated that ragweed sensitization results in increased IgE levels (Oldenburg and Mustafa, 2003). These increased levels of IgE may perhaps allow mast cells to become more susceptible to activation by adenosine and its analogs as confirmed by the increased airway responsiveness of the sensitized mice to NECA observed in this study. Treatment with C48/80 resulted in the activation of mast cells, which may predispose them to become less susceptible to the effect of the adenosine analog, which is made evident by the attenuation in the Penh response to NECA (Fig. 2). We feel that this phenomenon was most likely the result of the mast cell activation. Control mice that were not sensitized to ragweed still showed a modest response to NECA. This we believe is due to a direct activation of adenosine receptors located on airway smooth muscle. Data from this laboratory (Fan and Mustafa, 2002) have also shown that treatment with theophylline, a nonspecific adenosine receptor antagonist, will not block the hyperreactivity effects of MCh. Our laboratory has also reported that the airway hyperreactivity to NECA can be attenuated with specific adenosine receptor antagonists (Fan et al., 2003). This, therefore, shows that NECA is acting through specific adenosine receptors. Previous data from this laboratory have shown that adenosine when acting directly on its receptors on airway smooth muscle will lead to bronchoconstriction in a rabbit model of adenosine-mediated bronchoconstriction (Ali et al., 1994).
Inflammation is a key hallmark of asthma. Fan et al. (2003) have shown that aerosolized adenosine potentiates the infiltration of inflammatory cells induced by allergen challenge into the lungs. The data presented in this study support these findings because significant potentiation of neutrophils and eosinophils was observed in the BALF of both sensitized and the sensitized + C48/80 groups of mice (Fig. 4). We observed nearly a 70% increase in eosinophils in the sensitized mice over the control mice and an approximate 20% eosinophil increase in the sensitized + C48/80 group when compared with control groups (Fig. 4). This leads us to speculate that degranulating mast cells through treatment with C48/80 may result in an anti-inflammatory effect of decreasing eosinophil and neutrophil recruitment to the lungs after exposure to NECA. It may also be feasible that the inhibition of release of mast cell mediators may in turn be leading to an inhibition of inflammatory cell recruitment with C48/80 pretreatment. NECA challenge may, in addition, cause recruitment of inflammatory cells independent of mast cells into the lungs.
We also observed a decrease in the proportion of macrophage cells upon NECA challenge (Fig. 4), which was not expected, although clinical studies have found that macrophage numbers in BALF of humans are also decreased in asthma (Ndukwu et al., 1999). The mechanism for this decrease in alveolar macrophages needs further investigation. No change was observed in the cellularity of the control mice BALF possibly due to the absence of allergen to potentiate IgE levels and increase the adenosine response. The results support a role for mast cell activation (or the release of mast cell mediators) in inflammation after exposure to an adenosine receptor agonist.
The recruitment of eosinophils to the lungs is the direct result of mast cell activation caused by adenosine receptor stimulation. We speculate that this recruitment is caused by the collective action of multiple mediators released from mast cells, including cytokines and interleukins. Recent studies have shown a role for IL-13 in airway inflammation (Wills-Karp et al., 1998; Zhu et al., 1999). These studies have demonstrated that inflammation can be blocked through concurrent treatment with IL-13 inhibitors. It is likely that the potent eosinophil chemoattractant IL-13 is involved in inflammation.
With all that is known about the role of adenosine and its effects in asthma, including increased production during periods of hypoxia, its ability to induce bronchoconstriction in asthmatics, but not normal individuals, and the elevation of adenosine in the BALF of asthmatics (Driver et al., 1993; Fozard, 2003), the specific adenosine receptor responsible for degranulation of mast cells in humans remains elusive. This may be due to the fact that each species is different and has a different adenosine receptor expression profile. Feoktistov et al. have recently shown in an HMC-1 mast cell line the presence of A2A, A2B, and A3 receptors, with only the A2B receptor being functionally coupled to stimulation of phospholipase C (Feoktistov and Biaggioni, 1995; Forsythe and Ennis, 1999). Ramkumar et al. (1993) have shown in the RBL-2H3 mast cell line that the A3 receptor is the primary receptor involved in mast cell activation, whereas in canine BR mastocytoma cells, Marquardt et al. (1994) have shown that the A2B receptor is the primary activator of mast cells. Murine mast cells express the A2A, A2B, and A3 adenosine receptors (Marquardt et al., 1994; Forsythe and Ennis, 1999; Salvatore et al., 2000; Zhong et al., 2003) and lack the A1 adenosine receptor (Marquardt, 1997). Zhong et al. (2003) have recently shown large transcript levels of the A3 adenosine receptor through the use of reverse transcription-polymerase chain reaction techniques in murine primary lung mast cells. It can therefore be speculated that mast cell degranulation in the murine model of asthma is most probably due to activation of the A3 adenosine receptor (Salvatore et al., 2000; Tilley et al., 2000; Zhong et al., 2003).
The involvement of the A3 adenosine receptor may be critical to the degranulation of murine mast cells. A recent report by Tilley et al. (2003) using mice genetically deficient in A3 adenosine receptors showed a significant attenuation in the degranulation of mast cells in vivo. In their study, airway responses were also measured by whole-body plethysmography, and the A3 receptor knockout mice had decreased Penh levels consistent with the attenuation caused by C48/80 treatment reported in the present study. Activation of adenosine A3 receptors by selective A3 receptor agonists has recently been shown to activate cultured murine mast cells, resulting in the release of histamine and other mast cell mediators (Zhong et al., 2003). These findings suggest an important role for the A3 adenosine receptor and mast cells in adenosine-induced bronchoconstriction and inflammation.
In conclusion, the data presented here strongly implicate a role for adenosine in initiating the degranulation of mast cells and their involvement in bronchoconstriction and inflammation, which occurs in the pathophysiology of asthma. However, the identification of the adenosine receptor subtype responsible for this effect in our model is not known, and further studies are needed.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: C48/80, compound 48/80; NECA, 5'-N-ethylcarboxamidoadenosine; BALF, bronchoalveolar lavage fluid: MCh, methacholine; Penh, enhanced pause; IL-13, interleukin 13.
Address correspondence to: Dr. S. Jamal Mustafa, Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. E-mail: mustafas{at}mail.ecu.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Ali S, Mustafa SJ, and Metzger WJ (1994) Adenosine receptor-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbit model. Am J Physiol 266: L271-L277.
Blackburn MR, Volmer JB, Thrasher JL, Zhong H, Crosby JR, Lee JJ, and Kellems RE (2000) Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation and airway obstruction. J Exp Med 192: 159-170.
Church MK, Holgate ST, and Hughes PJ (1983) Adenosine inhibits and potentiates IgE-dependent histamine release from human basophils by an A2-receptor mediated mechanism. Br J Pharmacol 80: 719-726.[Medline]
Cushley MJ, Tattersfield AE, and Holgate ST (1983) Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 15: 161-165.[Medline]
Driver AG, Kukoly CA, Ali S, and Mustafa SJ (1993) Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 148: 91-97.[Medline]
Eady R and Norris A (1997) Nedocromil sodium and sodium cromoglycate: pharmacology and putative modes of action, in Allergy and Allergic Diseases (Kay AB ed) pp 584-595, Blackwell Scientific, Oxford, UK.
Fan M and Mustafa SJ (2002) Adenosine-mediated bronchoconstriction and lung inflammation in an allergic mouse model. Pulm Pharmacol Ther 15: 147-155.[CrossRef][Medline]
Fan M, Qin W, and Mustafa SJ (2003) Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model. Am J Physiol Lung Cell Mol Physiol 284: L1012-L1019.
Feoktistov I and Biaggioni I (1995) Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells: an enprofylline-sensitive mechanism with implications for asthma. J Clin Investig 96: 1979-1986.
Forsythe P and Ennis M (1999) Adenosine, mast cells and asthma. Inflamm Res 48: 301-307.[CrossRef][Medline]
Forsythe P, McGarvey LP, Heaney LG, MacMahon J, and Ennis M (1999) Adenosine induces histamine release from human bronchoalveolar lavage mast cells. Clin Sci (Lond) 96: 349-355.[Medline]
Fozard JR (2003) The case for a role for adenosine in asthma: almost convincing? Curr Opin Pharmacol 3: 264-269.[CrossRef][Medline]
Fozard JR and Hannon JP (2000) Species differences in adenosine receptor-mediated bronchoconstrictor responses. Clin Exp Allergy 30: 1213-1220.[CrossRef][Medline]
Jacobson M and Bai T (1997) The role of adenosine in asthma, in Purinergic Approaches in Experimental Therapeutics (Jacobson K and Jarvia M eds), Wiley-Liss, Inc., Danvers, MA.
Jaffery G, Coleman JW, Huntley J, and Bell EB (1994) Mast cell recovery following chronic treatment with compound 48/80. Int Arch Allergy Immunol 105: 274-280.[Medline]
Justice JP, Shibata Y, Sur S, Mustafa J, Fan M, and Van Scott MR (2001) IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice. Am J Physiol Lung Cell Mol Physiol 280: L363-L368.
Karadag CH, Dokmeci D, Dost T, Ulugol A, and Dokmeci I (2000) Compound 48/80, a histamine-depleting agent, blocks the protective effect of morphine against electroconvulsive shock in mice. Braz J Med Biol Res 33: 327-330.[Medline]
Marquardt D (1997) Adenosine, in Asthma (Barnes P, Grunstein M, Leff A, and Woolcock A eds) pp 585-591, Lippencourt-Raven, Philadelphia, PA.
Marquardt DL, Walker LL, and Heinemann S (1994) Cloning of two adenosine receptor subtypes from mouse bone marrow-derived mast cells. J Immunol 152: 4508-4515.[Abstract]
Meade CJ, Dumont I, and Worrall L (2001) Why do asthmatic subjects respond so strongly to inhaled adenosine? Life Sci 69: 1225-1240.[CrossRef][Medline]
Ndukwu IM, Naureckas ET, Maxwell C, Waldman M, and Leff AR (1999) Relationship of cellular transmigration and airway response after allergen challenge. Am J Respir Crit Care Med 160: 1516-1524.
Ohta A and Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature (Lond) 414: 916-920.[CrossRef][Medline]
Oldenburg P and Mustafa SJ (2003) Immunization with and subsequent challenges with ragweed or ovalbumin induces bronchial hyperresponsiveness in allergic mice. Am J Crit Care Med 165: A694.
Pauwels RA and Joos GF (1995) Characterization of the adenosine receptors in the airways. Arch Int Pharmacodyn Ther 329: 151-160.[Medline]
Peachell PT, Columbo M, Kagey-Sobotka A, Lichtenstein LM, and Marone G (1988) Adenosine potentiates mediator release from human lung mast cells. Am Rev Respir Dis 138: 1143-1151.[Medline]
Phillips GD, Scott VL, Richards R, and Holgate ST (1989) Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5'-monophosphate. Eur Respir J 2: 210-217.[Abstract]
Polosa R (2002) Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease. Eur Respir J 20: 488-496.
Polosa R, Ng WH, Crimi N, Vancheri C, Holgate ST, Church MK, and Mistretta A (1995) Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med 151: 624-629.[Abstract]
Polosa R, Rorke S, and Holgate ST (2002) Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Thorax 57: 649-654.
Ramkumar V, Stiles GL, Beaven MA, and Ali H (1993) The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J Biol Chem 268: 16887-16890.
Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH, and Jacobson MA (2000) Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275: 4429-4434.
Sommerhoff CP, Caughey GH, Finkbeiner WE, Lazarus SC, Basbaum CB, and Nadel JA (1989) Mast cell chymase: a potent secretagogue for airway gland serous cells. J Immunol 142: 2450-2456.[Abstract]
Spruntulis LM and Broadley KJ (2001) A3 receptors mediate rapid inflammatory cell influx into the lungs of sensitized guinea-pigs. Clin Exp Allergy 31: 943-951.[CrossRef][Medline]
Sur S, Lam J, Bouchard P, Sigounas A, Holbert D, and Metzger WJ (1996) Immunomodulatory effects of IL-12 on allergic lung inflammation depend on timing of doses. J Immunol 157: 4173-4180.[Abstract]
Tilley SL, Tsai M, Williams CM, Wang ZS, Erikson CJ, Galli SJ, and Koller BH (2003) Identification of A3 receptor- and mast cell-dependent and -independent components of adenosine-mediated airway responsiveness in mice. J Immunol 171: 331-337.
Tilley SL, Wagoner VA, Salvatore CA, Jacobson MA, and Koller BH (2000) Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells. J Clin Investig 105: 361-367.[Medline]
Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, and Donaldson DD (1998) Interleukin-13: central mediator of allergic asthma. Science (Wash DC) 282: 2258-2261.
Zhong H, Chunn JL, Volmer JB, Fozard JR, and Blackburn MR (2001) Adenosine-mediated mast cell degranulation in adenosine deaminase-deficient mice. J Pharmacol Exp Ther 298: 433-440.
Zhong H, Shlykov SG, Molina JG, Sanborn BM, Jacobson MA, Tilley SL, and Blackburn MR (2003) Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol 171: 338-345.
Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, and Elias JA (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities and eotaxin production. J Clin Investig 103: 779-788.[Medline]
This article has been cited by other articles:
|
|
 |
|
  P. J. Oldenburg, T. A. Wyatt, P. H. Factor, and J. H. Sisson Alcohol feeding blocks methacholine-induced airway responsiveness in mice Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L109 - L114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Ponnoth, A. Nadeem, and S. J. Mustafa Adenosine-mediated alteration of vascular reactivity and inflammation in a murine model of asthma Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2158 - H2165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Blackburn A role for neural pathways in adenosine-induced bronchoconstriction Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L22 - L24. [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Mustafa, A. Nadeem, M. Fan, H. Zhong, L. Belardinelli, and D. Zeng Effect of a Specific and Selective A2B Adenosine Receptor Antagonist on Adenosine Agonist AMP and Allergen-Induced Airway Responsiveness and Cellular Influx in a Mouse Model of Asthma J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1246 - 1251. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
