Body Mass Index (BMI) in Asthmatics is Associated with Airway Neutrophil Response to Inhaled Endotoxin: A Role for Atopic Inflammation

24-36 months (OR 6.8 [2.2-21]). In contrast, neither BMI at age 24 nor 36 months was associated with wheeze in the preceding 12 months (adjusted OR 1.3 [0.66-2.6] and 1.0 [0.50-2.1], respectively). CONCLUSIONS: In this inner-city cohort, elevated BMI at age 36 months predicted wheeze at age 5, independent of wheeze earlier in life. This result suggests that obesity precedes the development of asthma symptoms in young children. Funding: NIH NIEHS Body Mass Index (BMI) in Asthmatics is Associated with Airway Neutrophil Response to Inhaled Endotoxin: A Role for Atopic Inflammation N. E. Alexis1,2, M. Almond1,2, D. B. Peden1,2; 1Pediatrics, Center Environmental Med Asthma & Lung Biology, Chapel Hill, NC, 2UNC Chapel Hill, Chapel Hill, NC. RATIONALE: Asthmatics show elevated airway neutrophils following inhaled challenge with endotoxin/LPS. Increased BMI has been associated with asthma prevalence, severity (airway hyper-responsiveness) and atopy (skin test reactivity), and mouse models of obesity show enhanced airway responses to ozone air pollution. We investigated whether BMI in asthmatics was associated with airway neutrophil response (PMNs/mg) to inhaled endotoxin. METHODS: BMI (kg/m2) was calculated from measured height and weight and assessed in N=22 mild - moderate atopic asthmatics and N=25 non-asthmatic controls, all of whom underwent controlled inhalation challenge with LPS (20,000-30,000 EU). Markers of airways inflammation were assessed 6h later by induced sputum. RESULTS: Following inhaled LPS challenge, BMI was positively correlated with the PMN response (R = 0.7, p=0.0003) and IL-8 (pg/ml) levels (R = 0.6, p = 0.03) in asthmatics, but not in healthy non-asthmatics. In a sub-group of asthmatics on whom cytokines were measured, BMI was strongly associated with baseline GM-CSF (pg/ml) (R = 0.7, p = 0.03) and post-LPS ECP levels (R = 0.9, p = 0.0003). CONCLUSIONS: BMI may play a role in the sensitivity of asthmatics to inhaled endotoxin, a ubiquitous gram negative bacteria associated with asthma exacerbation at occupational levels and increased responsiveness to inhaled allergen at lower levels. In asthmatics, Th-2 type airways inflammation may be enhanced by elevated BMI and in this way potentially contribute to increased responsiveness to airborne irritants. Funding: NIH

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Mast Cell Carboxypeptidase as a New Clinical Marker for Anaphylaxis X. Zhou1, M. G. Buckley1, L. C. Lau1, C. Summers2, R. S. H. Pumphrey2, A. F. Walls1; 1Immunopharmacology Group, University of Southampton, Southampton, UNITED KINGDOM, 2Department of Immunology, St Mary’s Hospital, Manchester, UNITED KINGDOM. RATIONALE: Assays for tryptase have proved useful in the laboratory diagnosis of anaphylaxis, but in a substantial number of cases increased circulating concentrations of this mast cell product are not detected. The measurement of levels of mast cell carboxypeptidase, a protease coreleased with tryptase, could provide information useful in diagnosis.

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METHODS: A sandwich-based ELISA procedure with specific monoclonal antibodies has been developed and validated for the measurement of carboxypeptidase. This assay has allowed the release of carboxypeptidase to be detected in supernatants from experimentally activated mast cells. It has been adapted and applied to determine concentrations in serum and plasma from cases of suspected anaphylaxis (n=181), systemic mastocytosis (30), and from control groups consisting of healthy blood donors (209) or subjects with bronchial asthma (15). RESULTS: Carboxypeptidase levels in serum or plasma collected within 8h of the onset of an allergic reaction were significantly greater than in those of either of the control groups (p<0.0001). In some cases the concentrations were more than 100-fold greater. Levels in the mastocytosis group were also greater than in the control groups (p<0.001). There was no significant difference between the two control groups. In 83% of anaphylaxis cases with an elevated tryptase concentration there were carboxypeptidase levels greater than the normal range, though concentrations of these mast cell proteases were not correlated with each other. Out of 110 cases of suspected anaphylaxis that were tryptase negative, there was an elevated concentration of carboxypeptidase in 77 (70%). CONCLUSIONS: Mast cell carboxypeptidase should be a valuable serum marker for anaphylaxis. Funding: Thrasher Research Fund and London Law Trust Sublingual Epinephrine Tablets Versus EpiPen: Dose Equivalence for Potential First-Aid Treatment of Anaphylaxis M. M. Rawas-Qalaji1, F. E. R. Simons2, K. J. Simons1; 1Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, CANADA, 2Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, CANADA. RATIONALE: Self-injectable epinephrine (E) is underutilized in the firstaid treatment of anaphylaxis in the community. We hypothesized that sublingual E from novel fast-disintegrating tablets would result in E plasma concentrations (EPC) similar to those obtained after E 0.3 mg IM injection. METHODS: In a cross-over study, sublingual tablets containing E 0, 10, 20, and 40 mg, and EpiPen® (E 0.3 mg) were compared in a validated rabbit model. Sublingual tablets were retained under the tongue for 5 min. EpiPen® was injected in the thigh. Blood was collected before dosing and 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 min afterwards. EPC were measured using HPLC-EC. Data were analysed using repeated measures ANOVA and Tukey-Kramer tests, NCSS program (p< 0.05). RESULTS: The area under the plasma concentration versus time curves (AUC) of tablets containing E 0 mg (AUC=547 ng/ml/min), E 10 mg (AUC=335 ng/ml/min), and E 20 mg (AUC=801 ng/ml/min) did not differ significantly from each other, but were significantly lower (p<0.05) than the AUC after E 40 mg (AUC=1,861 ng/ml/min) and after EpiPen® (AUC=2,431 ng/ml/min). The AUC, maximum plasma concentration (Cmax), and time of maximum plasma concentration (Tmax) after E 40 mg (AUC=1,861 ng/ml/min, Cmax =27.5 ng/ml, and Tmax=15 min) and EpiPen® (AUC=2,431 ng/ml/min, Cmax=29.0 ng/ml, and Tmax=10 min) did not differ significantly from each other. CONCLUSIONS: In this model, sublingual administration of E 40 mg resulted in EPC similar to those obtained after E 0.3 mg IM injection in the thigh. Funding: Manitoba Institute of Child Health

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Abstracts S85

J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2