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• W2079231364 abstract "Asthma may be triggered by multiple mediators, including allergen-IgE cross-linking and non-IgE mechanisms. Several clinical studies have shown acute ethanol consumption exacerbates asthma, yet no animal model exists to study this process. We developed a model of ethanol-triggered asthma in allergen-sensitized mice to evaluate the mechanisms of ethanol inducing asthma-like responses. Outbred mice were exposed to cockroach allergens on Days 0 and 14; and on Day 21, mice received ethanol by oral gavage. Tracer studies confirmed alcohol aspiration did not occur. Within 30 minutes, alcohol induced degranulation of over 74% of mast cells, and multiple parameters of asthma-like pulmonary inflammation were triggered. Ethanol-gavaged mice had a fivefold increased production of eotaxin-2 (534 pg/mL) and a sevenfold increase in bronchoalveolar eosinophils (70,080 cells). Ethanol induced a 10-fold increase in IL-13, from 84 pg/mL in sensitized mice to 845 pg/mL in ethanol-gavaged sensitized mice. In cockroach allergen–sensitized mice, ethanol triggered asthma-like changes in respiratory physiology and a significant fivefold increase in airway mucin production. Importantly, none of these asthmatic exacerbations were observed in normal mice gavaged with ethanol. Cromolyn sodium effectively stabilized mast cells, yet increased mucin production and bronchoalveolar eosinophil recruitment. Together, these data show a single oral alcohol exposure will trigger asthma-like pulmonary inflammation in allergen-sensitized mice, providing a novel asthma model. Asthma may be triggered by multiple mediators, including allergen-IgE cross-linking and non-IgE mechanisms. Several clinical studies have shown acute ethanol consumption exacerbates asthma, yet no animal model exists to study this process. We developed a model of ethanol-triggered asthma in allergen-sensitized mice to evaluate the mechanisms of ethanol inducing asthma-like responses. Outbred mice were exposed to cockroach allergens on Days 0 and 14; and on Day 21, mice received ethanol by oral gavage. Tracer studies confirmed alcohol aspiration did not occur. Within 30 minutes, alcohol induced degranulation of over 74% of mast cells, and multiple parameters of asthma-like pulmonary inflammation were triggered. Ethanol-gavaged mice had a fivefold increased production of eotaxin-2 (534 pg/mL) and a sevenfold increase in bronchoalveolar eosinophils (70,080 cells). Ethanol induced a 10-fold increase in IL-13, from 84 pg/mL in sensitized mice to 845 pg/mL in ethanol-gavaged sensitized mice. In cockroach allergen–sensitized mice, ethanol triggered asthma-like changes in respiratory physiology and a significant fivefold increase in airway mucin production. Importantly, none of these asthmatic exacerbations were observed in normal mice gavaged with ethanol. Cromolyn sodium effectively stabilized mast cells, yet increased mucin production and bronchoalveolar eosinophil recruitment. Together, these data show a single oral alcohol exposure will trigger asthma-like pulmonary inflammation in allergen-sensitized mice, providing a novel asthma model. Asthma is one of the most common chronic diseases, with increasing prevalence, affecting nearly 25 million people in the United States alone and 300 million worldwide.1Global Initiative for AsthmaPocket Guide for Asthma Management and Prevention. Global Initiative for Asthma, National Heart, Lung, and Blood Institute, Bethesda, MD2010Google Scholar One in 10 children and nearly 1 in 12 adults have asthma.2Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005–2009.Natl Health Stat Report. 2011, Jan 12; : 1-14PubMed Google Scholar There are multiple triggers for asthma, including airway irritants, allergens, respiratory infections, aspirin, cold, and exercise.3Goksel O. Celik G.E. Erkekol F.O. Gullu E. Mungan D. Misirligil Z. Triggers in adult asthma: are patients aware of triggers and doing right?.Allergol Immunopathol (Madr). 2009; 37: 122-128Crossref PubMed Scopus (13) Google Scholar Despite recognition of asthma triggers and availability of a myriad of therapeutic options, in many patients, the etiology is undefined, suggesting other triggers and disease mechanisms have yet to be identified. Recent increases in other health issues have been noted in teens and young adults, the age group also highly affected by asthma, including an increase in binge drinking.4Jackson J.E. Doescher M.P. Hart L.G. Problem drinking: rural and urban trends in America, 1995/1997 to 2003.Prev Med. 2006; 43: 122-124Crossref PubMed Scopus (31) Google Scholar, 5Serdula M.K. Brewer R.D. Gillespie C. Denny C.H. Mokdad A. Trends in alcohol use and binge drinking, 1985-1999: results of a multi-state survey.Am J Prev Med. 2004; 26: 294-298Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Currently, over half of American adults are regular drinkers, with even higher prevalence rates in high school and college-aged students.5Serdula M.K. Brewer R.D. Gillespie C. Denny C.H. Mokdad A. Trends in alcohol use and binge drinking, 1985-1999: results of a multi-state survey.Am J Prev Med. 2004; 26: 294-298Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 6Naimi T.S. Brewer R.D. Mokdad A. Denny C. Serdula M.K. Marks J.S. Binge drinking among US adults.JAMA. 2003; 289: 70-75Crossref PubMed Scopus (786) Google Scholar In the young adults that do drink, the majority of the drinking is in the form of binge drinking.7NIAAA Council approves definition of binge drinking.in: NIAAA Newsletter. 2004 Winter: 3Google Scholar, 8Courtney K.E. Polich J. Binge drinking in young adults: data, definitions, and determinants.Psych Bul. 2009; 135: 142-156Crossref PubMed Scopus (495) Google Scholar Although the incidences of asthma and binge drinking are both on the rise, their interactions remain relatively unexplored. Multiple clinical studies have clearly shown that ethanol exacerbates asthma.9Ayres J.G. Alcohol-induced bronchial asthma.J Allergy Clin Immunol. 1997; 99: 860Abstract Full Text PDF PubMed Google Scholar, 10Harada S. Agarwal D.P. Goedde H.W. Mechanism of alcohol sensitivity and disulfiram-ethanol reaction.Subst Alcohol Actions Misuse. 1982; 3: 107-115PubMed Google Scholar, 11Vally H. de Klerk N. Thompson P.J. Alcoholic drinks: important triggers for asthma.J Allergy Clin Immunol. 2000; 105: 462-467Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 12Zellweger J.P. Alcohol-induced asthma: not only in Asians.J Allergy Clin Immunol. 1997; 99: 860Abstract Full Text PDF PubMed Google Scholar Although a recent publication showed that chronic alcohol exposure would reduce inflammation in ovalbumin-induced murine asthma,13Oldenburg P.J. Poole J.A. Sisson J.H. Alcohol reduces airway hyperresponsiveness (AHR) and allergic airway inflammation in mice.Am J Physiol Lung Cell Mol Physiol. 2012; 302: L308-L315Crossref PubMed Scopus (18) Google Scholar our studies focused on whether acute alcohol exposure can trigger atopic asthma in a sensitized animal. The allergen dose administered was carefully chosen to produce sensitized mice with the capacity to exhibit asthmatic responses following cockroach allergen (CRA) exposure, but that do not display chronic inflammation in the absence of a stimulus. This “sensitized, but asymptomatic” model was designed to mimic the majority of human asthmatics, who are allergen sensitized and primed to respond to provocation, but who do not display outright asthmatic inflammation and respiratory distress in the absence of a stimulus.14Koh M.S. Irving L.B. Evidence-based pharmacologic treatment for mild asthma.Int J Clin Pract. 2007; 61: 1375-1379Crossref PubMed Scopus (7) Google Scholar Furthermore, this model of asthma allows the investigation of asthma triggers in a sensitized, but otherwise asymptomatic, host. The data presented here demonstrate a novel mechanism for triggering asthma by showing that a single instance of acute ethanol exposure can trigger multiple asthmatic symptoms in cockroach allergen–sensitized mice. Female, outbred Hsd:ICR 18- to 20-g mice were used exclusively for these experiments (Harlan Laboratories, Indianapolis, IN). Mice were housed in a temperature-controlled room with 12-hour light/dark cycles and unrestricted access to food and water. All experiments were reviewed and approved by the Institutional Animal Care and Use Committee (Boston University). Previous reports demonstrated that intratracheal sensitization with CRA, without the use of adjuvants, was sufficient to induce a robust asthmatic response.15Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Inbred and outbred mice have equivalent variability in a cockroach allergen-induced model of asthma.Comp Med. 2010; 60: 420-426PubMed Google Scholar, 16Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Assessing pulmonary pathology by detailed examination of respiratory function.Am J Pathol. 2010; 177: 1861-1869Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 17Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study.Respir Res. 2010; 11: 160Crossref PubMed Scopus (14) Google Scholar In the current study, the CRA dose was approximately 10-fold lower to develop a model of allergen sensitization. CRA was purchased from Greer Laboratories (Lenoir, NC) as a lyophilized extract and diluted in sterile Hanks' balanced salt solution to yield a combined dose of 100 ng of the allergens Blag1 and Blag2, and 30 ng of lipopolysaccharide per 50-μL dose. Allergen sensitization (Day 0) and challenge (Day 14) were given via intratracheal instillation as described.17Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study.Respir Res. 2010; 11: 160Crossref PubMed Scopus (14) Google Scholar One week after the last CRA challenge, mice underwent food deprivation for 2 hours before water or ethanol administration by oral gavage. Absolute 200 proof ethanol (Sigma-Aldrich, St. Louis, MO) was diluted to 32%, 10.7%, or 3.2% (v/v) in water for blood ethanol concentration kinetics, and the 32% dose (approximately 3 g/kg) for all other experiments. Gavage was performed under light isoflurane anesthesia by administering 300 μL of water or ethanol to the stomach with an 18 ga × 51 mm gastric feeding tube (Instech Solomon, Plymouth Meeting, PA). Oral gavage was chosen as the physiologically relevant route for ethanol dosing,18Lim Jr., R.T. Gentry R.T. Ito D. Yokoyama H. Baraona E. Lieber C.S. First-pass metabolism of ethanol is predominantly gastric.Alcohol Clin Exp Res. 1993; 17: 1337-1344Crossref PubMed Scopus (86) Google Scholar, 19Elgebaly S.A. Kozol R.A. Kreutzer D.L. Alcohol and immune system: role of gastric tissue.Prog Clin Biol Res. 1990; 325: 75-78PubMed Google Scholar and mice were lightly anesthetized during the gavage procedure to reduce unnecessary stress-related immune modulation.20Plackett T.P. Kovacs E.J. Acute models of ethanol exposure to mice.Methods Mol Biol. 2008; 447: 3-9Crossref PubMed Scopus (10) Google Scholar In separate experiments, additional CRA-sensitized mice were given 200 μL of water or 32% ethanol by intraperitoneal (i.p.) injection to induce similar blood ethanol kinetics. To rule out potential aspiration during the gavage procedure, ethanol was measured in bronchoalveolar lavage (BAL) samples. In a separate study, naive food-deprived mice were gavaged with 300 μL of 32% ethanol containing 1 mg/mL methylene blue tracer dye.21Fergani A. Oudart H. Gonzalez De Aguilar J.L. Fricker B. Rene F. Hocquette J.F. Meininger V. Dupuis L. Loeffler J.P. Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis.J Lipid Res. 2007; 48: 1571-1580Crossref PubMed Scopus (95) Google Scholar Immediately following gavage, the stomach and lungs were resected and homogenized in 0.1 mol/L sodium hydroxide, and the presence of dye assayed by optical density at 665 nm. For blood ethanol concentration kinetic measurements, naive mice were gavaged with 300 μL of 32%, 10.7%, or 3.2% ethanol, and 20-μL blood samples were obtained from the submandibular vein at designated time points. Plasma and BAL ethanol concentrations were determined using the alcohol dehydrogenase–based Ethanol-L3K Assay (Genzyme Diagnostics P.E.I., Charlottetown, PE Canada). E-Mitter Transmitters (Mini Mitter Co., Bend, OR) were used as previously described.22Remick D.G. Bolgos G. Copeland S. Siddiqui J. Role of interleukin-6 in mortality from and physiologic response to sepsis.Infect Immun. 2005; 73: 2751-2757Crossref PubMed Scopus (167) Google Scholar In brief, transmitters were placed subcutaneously 3 days before ethanol or water gavage. Mice were food deprived for 2 hours then gavaged with 300 μL of water or 32% ethanol. Movement was monitored continuously for 10 hours starting 3 hours before gavage. As a cross-over study, the day after the first gavage, mice were gavaged with water if gavaged with ethanol and vice versa, and the movement results combined. Movement counts (centimeters moved) were measured every 15 minutes. Mice from 0.5 or 2 hours postgavage, or 0.5 hours after i.p. injection, were anesthetized with an intraperitoneal ketamine/xylazine injection at 87 and 13 μg/g body weight, respectively, bled retro-orbitally, and sacrificed by cervical dislocation. Twenty microliters of blood were analyzed with a Hemavet hematology system for blood cell counts (Drew Scientific, Oxford, CT), and the remaining blood sample was spun to collect plasma. BAL was performed as previously described.17Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study.Respir Res. 2010; 11: 160Crossref PubMed Scopus (14) Google Scholar Total cell counts were performed on a Coulter particle counter. Cells were then spun onto a glass slide, stained with Diff-Quik Stain Set (Siemens, Newark, DE), and cell differentials were performed under a light microscope. Plasma and BAL cell methodology was repeated for naive (normal) mice and CRA-sensitized mice before gavage (sensitized). Sterile saline was used to perfuse heart and lungs followed by ethanol fixation and paraffin embedding of a single lobe. To test whether using ethanol as a fixative was having a confounding effect on the histology results, studies were performed that fixed paired lung sections in both 70% ethanol and 10% buffered formalin. The comparisons showed no significant differences in mucin staining and exhibited similar trends when comparing mast cell numbers between groups; thus 70% ethanol was used as fixative for all further experiments. Lung sections taken 0.5 or 2 hours postgavage were sectioned and stained with periodic acid-Schiff (PAS) for mucus analysis and quantified as previously described.16Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Assessing pulmonary pathology by detailed examination of respiratory function.Am J Pathol. 2010; 177: 1861-1869Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Additional slides were also stained with toluidine blue for mast cell identification and quantified as previously described.23de Waal Malefyt R. Figdor C.G. Huijbens R. Mohan-Peterson S. Bennett B. Culpepper J. Dang W. Zurawski G. de Vries J.E. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes Comparison with IL-4 and modulation by IFN-gamma or IL-10.J Immunol. 1993; 151: 6370-6381PubMed Google Scholar The remainder of the unfixed lung was homogenized as described24Natarajan S. Kim J. Bouchard J. Cruikshank W. Remick D.G. Reducing LPS content in cockroach allergens increases pulmonary cytokine production without increasing inflammation: a randomized laboratory study.BMC Pulm Med. 2011; 11: 12Crossref PubMed Scopus (11) Google Scholar for tryptase, chemokine, and cytokine measurements. The lung processing protocol should not disrupt intact mast cell granules since this lung homogenization protocol did not include harsh detergents or sonication steps; therefore, lung homogenate tryptase levels represent tryptase released by the mast cells. Lung histology methodology was repeated for naive (normal) mice and CRA-sensitized mice before gavage (sensitized). Lung homogenate supernatants from lungs collected 30 minutes postgavage were diluted 1:10 for chemokine and cytokine measurements as described.25Nemzek J.A. Siddiqui J. Remick D.G. Development and optimization of cytokine ELISAs using commercial antibody pairs.J Immunol Methods. 2001; 255: 149-157Crossref PubMed Scopus (93) Google Scholar Tryptase was measured by coating the BAL or lung homogenate on a 96-well plate overnight at 4°C. After blocking with casein, tryptase was detected with rat anti-mouse tryptase-β1 (R&D Systems, Minneapolis, MN) and developed with mouse anti-rat IgG coupled to horseradish peroxidase. Recombinant mouse tryptase β-1 was used as a standard (R&D Systems). Cytokine measurements were repeated for naive (normal) mice and CRA-sensitized mice before gavage (sensitized). Measurements were performed as previously described.24Natarajan S. Kim J. Bouchard J. Cruikshank W. Remick D.G. Reducing LPS content in cockroach allergens increases pulmonary cytokine production without increasing inflammation: a randomized laboratory study.BMC Pulm Med. 2011; 11: 12Crossref PubMed Scopus (11) Google Scholar A 96-well plate was coated overnight at 4°C with 50 μL per well of a CRA solution diluted to 5 μg/mL Blag2 allergen concentration in phosphate-buffered saline (PBS). Plates were blocked with Casein Blocker (Thermo Scientific, Waltham, MA) for 2.5 hours and then 50 μL of 1:10 diluted plasma, collected from each mouse 30 minutes postgavage, and was incubated overnight. IgE bound to CRA-coated plate was detected using goat-anti-mouse IgE–horseradish peroxide (Bethyl Laboratories, Montgomery, TX) and assay developed with tetramethylbenzidine. CRA-specific IgE measurements were repeated for naive (normal) mice and CRA-sensitized mice before gavage (sensitized). Respiratory function was evaluated using unrestrained whole-body plethysmography (Buxco Research Systems, Wilmington, NC). Select groups of mice receiving gavage (water or ethanol) were assayed either 30 minutes or 1 hour postgavage on Day 21 of immunization protocol. Other nongavaged mice (normal and sensitized) were assayed at arbitrary times on Day 21. All mice were acclimated 5 minutes in plethysmography chambers, then baseline respiratory physiology was recorded before aerosol exposures. Aerosol challenges of PBS, 25 mg/mL methacholine, and 50 mg/mL methacholine were given after baseline measurements were taken. Each parameter measured per mouse was z-score normalized using the average and SD of all available data for that parameter as previously described.16Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Assessing pulmonary pathology by detailed examination of respiratory function.Am J Pathol. 2010; 177: 1861-1869Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Z-scores were averaged per group and loaded into MultiExperiment Viewer freeware (MeV; , last accessed October 16, 2011), and unsupervised hierarchical clustering was performed. Detailed descriptions of each parameter are listed in Supplemental Table S1, available at . The mast cell stabilizer, cromolyn sodium (Enzo Life Sciences, Exeter, UK), proven effective at stabilizing mast cells in other studies,26Santone D.J. Shahani R. Rubin B.B. Romaschin A.D. Lindsay T.F. Mast cell stabilization improves cardiac contractile function following hemorrhagic shock and resuscitation.Am J Physiol Heart Circ Physiol. 2008; 294: H2456-H2464Crossref PubMed Scopus (16) Google Scholar, 27Holgate S.T. Peters-Golden M. Panettieri R.A. Henderson Jr., W.R. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling.J Allergy Clin Immunol. 2003; 111 (discussion S34-S36): S18-S34Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholarwas used in ethanol-gavaged CRA-sensitized mice. Cromolyn sodium was given intratracheally once a day for 3 days before ethanol gavage (Days 18, 19, and 20) and once on Day 21, 1 hour before gavage. Each instillation was given as 30 mg/kg cromolyn in two 25-μL aliquots in saline (vehicle). Mice were sacrificed 30 minutes after ethanol gavage. Asthmatic responses for all mast cell stabilizer–treated mice were measured as described above. Statistical analysis was performed using Graphpad Prism 5.02 (GraphPad Software, La Jolla, CA). All data are presented as mean ± SEM. Significance was achieved if P < 0.05 using unpaired two-tailed Student's t-tests, one-way or two-way analysis of variance with a Bonferroni posttest with a confidence interval of 95%, or by χ2 analysis for comparisons with values below detection limits. Respiratory physiology was analyzed by two-way analysis of variance separately for normal (normal, normal + water, normal + ethanol) and for sensitized (sensitized, sensitized + water, sensitized + ethanol) mice. To assess the effects of alcohol consumption in our asthmatic mice, we first needed to design an acute ethanol exposure model to reproduce acute alcohol intoxication rather than chronic alcoholism. The model was developed because previous reports indicate that in humans, acute ethanol intoxication will induce clinical symptoms of asthma in sensitized individuals.11Vally H. de Klerk N. Thompson P.J. Alcoholic drinks: important triggers for asthma.J Allergy Clin Immunol. 2000; 105: 462-467Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 28Ayres J.G. Clark T.J. Alcoholic drinks and asthma: a survey.Br J Dis Chest. 1983; 77: 370-375Abstract Full Text PDF PubMed Scopus (34) Google Scholar, 29Shimoda T. Kohno S. Takao A. Fujiwara C. Matsuse H. Sakai H. Watanabe T. Hara K. Asai S. Investigation of the mechanism of alcohol-induced bronchial asthma.J Allergy Clin Immunol. 1996; 97: 74-84Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Blood alcohol pharmacokinetics were determined by gavaging normal mice with various concentrations of ethanol and withdrawing serial blood samples from the same mouse. There was a clear dose-response effect on blood ethanol concentration (BEC) (Figure 1A), and the high-dose ethanol (32%; approximately 3g/kg) induced a peak BEC of 37 mmol/L (0.17%) at 1 hour postgavage, a level easily achieved by binge-drinking humans.30Urso T. Gavaler J.S. Van Thiel D.H. Blood ethanol levels in sober alcohol users seen in an emergency room.Life Sci. 1981; 28: 1053-1056Crossref PubMed Scopus (210) Google Scholar To most closely correlate ethanol-induced behavioral changes and BEC to human intoxication, the 32% ethanol dose was selected for all subsequent studies. Additional experiments using i.p. injection of alcohol achieved similar blood ethanol kinetics with 200 μL administration (data not shown). To address the possibility of pulmonary aspiration of gavaged liquid, two separate methods were used. Ethanol was measured in the BAL obtained 30 minutes after gavage and found to be below detection limits (Figure 1B). Additional studies done by gavaging with a methylene blue tracer demonstrated that none of the tracer was detected in the lungs (Figure 1C). Both of these experiments demonstrated that no pulmonary aspiration occurred during the ethanol gavage procedure. Although these additional experiments were performed to confirm that substantial alcohol aspiration did not occur during gavage procedures, the presence of alcohol in the lung cannot be completely ruled out. Bronchial circulation and the volatile nature of alcohol allow for the vaporization of alcohol directly into the conducting airways to allow lung exposure to ethanol,31Sisson J.H. Alcohol and airways function in health and disease.Alcohol. 2007; 41: 293-307Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar hence the basis behind the breathalyzer test.32Hlastala M.P. The alcohol breath test: a review.J Appl Physiol. 1998; 84: 401-408Crossref PubMed Scopus (13) Google Scholar Ethanol-gavaged mice showed mild ataxia similar to other murine binge drinking models.33Carson E.J. Pruett S.B. Development and characterization of a binge drinking model in mice for evaluation of the immunological effects of ethanol.Alcohol Clin Exp Res. 1996; 20: 132-138Crossref PubMed Scopus (134) Google Scholar To rule out severe ataxia and a gross loss/gain of locomotor activity, we measured movement using a subcutaneously implanted radiotransmitter (Figure 1D). There were no differences in locomotor movements between the water- and ethanol-gavaged groups at any time point. Intestinal histology showed no ethanol-induced damage or induction of mucin (data not shown). These results indicate that our model is representative of mild acute alcohol intoxication. A murine asthma model previously described in our lab15Vaickus L.J. Bouchard J. Kim J. Natarajan S. Remick D.G. Inbred and outbred mice have equivalent variability in a cockroach allergen-induced model of asthma.Comp Med. 2010; 60: 420-426PubMed Google Scholar used 10-fold higher allergen concentrations and investigated asthmatic responses induced after a third allergen exposure on Day 21. The current study used a lower allergen concentration and only two pulmonary exposures to allergens (Days 0 and 14). The purpose of lowering the dose and number of exposures was to elicit sensitization without sustained asthma-like pulmonary inflammation, to allow the evaluation of whether ethanol could trigger asthma-like pulmonary inflammation in a symptomless, but sensitized, host. Even though we used a lower dose of allergen, there was still a clear asthmatic phenotype in our allergen-sensitized mice compared to normal mice, including increases in cockroach allergen–specific IgE, a 5-fold increase in circulating eosinophils, a 20-fold increase in BAL eosinophils, increased mucin production, and respiratory exacerbations as represented by increases in enhanced pause (PenH) in response to methacholine (Table 1). Allergen sensitization increased the numbers of lung mast cells approximately 10-fold compared to normal mice, consistent with previous publications showing increased lung mast cells in allergen-sensitized34Di Santo E. Meazza C. Sironi M. Fruscella P. Mantovani A. Sipe J.D. Ghezzi P. IL-13 inhibits TNF production but potentiates that of IL-6 in vivo and ex vivo in mice.J Immunol. 1997; 159: 379-382PubMed Google Scholar and asthmatic35Muchamuel T. Menon S. Pisacane P. Howard M.C. Cockayne D.A. IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-alpha, IFN-gamma, and IL-12 production.J Immunol. 1997; 158: 2898-2903PubMed Google Scholar individuals.Table 1Comparison of Asthmatic Parameters in Normal (Naive) and CRA-Sensitized MiceParameterNormalSensitizedP valueCRA-specific IgE (OD)0.223 ± 0.0110.288 ± 0.0150.007Eosinophils (per mL blood)5 ± 224 ± 100.126BAL eosinophils (per mouse)386 ± 967746 ± 22920.023Mast cells (per 10 lung slices)2.5 ± 2.522.5 ± 6.20.053Mucus (mean gray area × 1000)28 ± 9125 ± 300.020PenH (25 mg/mL methacholine)0.436 ± 0.0170.620 ± 0.0510.028Sensitized mice were immunized with cockroach allergens on Days 0 and 14 and then studied on Day 21, ie, 7 days after the last exposure to allergen. The final allergen exposure typically given on Day 21 was not administered.OD, optical density. Open table in a new tab Sensitized mice were immunized with cockroach allergens on Days 0 and 14 and then studied on Day 21, ie, 7 days after the last exposure to allergen. The final allergen exposure typically given on Day 21 was not administered. OD, optical density. Traditionally, allergic-type inflammatory events are potentiated by repeat antigen exposure, subsequent IgE cross-linking, and mast cell degranulation.36Hamelmann E. Gelfand E.W. IL-5-induced airway eosinophilia: the key to asthma?.Immunol Rev. 2001; 179: 182-191Crossref PubMed Scopus (178) Google Scholar Because antigens were not administered during the time of ethanol gavage in our model, we investigated whether mast cell degranulation was indeed involved, potentially through another mechanism. Acetaldehyde, the first metabolite of ethanol catabolism, is elevated immediately on ethanol ingestion in mice37Park H.M. Eo Y.W. Cha K.S. Kim Y.M. Lee K.B. Determination of free acetaldehyde in total blood for investigating the effect of aspartate on metabolism of alcohol in mice.J Chromatogr B Biomed Sci Appl. 1998; 719: 217-221Crossref PubMed Scopus (7) Google Scholar and will induce mast cell degranulation in vivo.38Kawano T. Matsuse H. Kondo Y. Machida I. Saeki S. Tomari S. Mitsuta K. Obase Y. Fukushima C. Shimoda T. Kohno S. Acetaldehyde induces histamine release from human airway mast cells to cause bronchoconstriction.Int Arch Allergy Immunol. 2004; 134: 233-239Crossref PubMed Scopus (31) Google Scholar To test whether ethanol exposure caused mast cell degranulation in our allergen-sensitized mice, we used two independent methods. First, we measured tryptase, one of the abundant proteins in mast cell granules, in lung homogenates 30 minutes postgavage (Figure 2A). Within 30 minutes, ethanol gavage [sensitized + ethanol gavage (S+E)] significantly increased tryptase release into the lung tissue in CRA-sensitized mice compared to water-gavaged controls [sensitized + water gavage (S+W)]. To confirm mast cell degranulation, lung sections from the same mice used for tryptase measurements were stained" @default.
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• W2079231364 date "2012-09-01" @default.
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• W2079231364 title "Acute Oral Ethanol Exposure Triggers Asthma In Cockroach Allergen–Sensitized Mice" @default.
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