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Susceptibility to asthma phenotype in human airway smooth muscle mannose receptor (huASM-MR) transgenic mice
S186 Abstracts
642
Susceptibility to Asthma Phenotype in Human Airway Smooth Muscle Mannose Receptor (huASM-MR) Transgenic Mice
MONDAY
W. Robinson, Jr.1, C. Michael1, T. Overbeck1, F. Kirkland1, E. Bonten2, A. d’Azzo1, B. Lew1; 1Pediatrics, University of Tennessee, Memphis, TN, 2Genetics, St Jude Research Children’s Hospital, Memphis, TN. RATIONALE: We have previously reported that lysosomal hydrolases such as b-hexosaminidase (Hex), via the ASM-MR, promote mitogenesis in the inflamed airways. Studies were conducted to demonstrate the importance of the lysosomal hydrolases and ASM-MR system in the development of airway hyperreactivity. METHODS: Wild type naïve FVB/N mice received aerosolized Hex A (1 mg) or vehicle, either daily or every other day for 2 weeks. Transgenic (Tg) strain was developed by transfection of human ASM-MR linked to SM22 promotor. These Tg (+), Tg (-) littermates or wild type FVB/N mice were ovalbumin sensitized (i.p. injection on day 0, 14 and 21) and challenged for three consecutive days (days 28-30, via aerosol). Lung physiology was non-invasively assessed by methacholine challenge and changes in pulmonary resistance (pause enhancement, Penh) on day 31. RESULTS: After Hex treatment, naïve wild type mice showed increase in Penh at 25mg/ml methacholine concentration: 790 + 225% of control (Hex) vs. 423 + 124% of control (vehicle), respectively, n=3). Aerosolized yeast mannan, a mannose receptor blocker, inhibited Penh (>75% inhibition, n=3) in ovalbumin-sensitized FVB/N mice. The ovalbumin-sensitized and -challenged huASM-MR Tg (+) mice showed both hypersensitivity and hypereactivity to methacholine compared to Tg (-) littermate controls (n=4, p<0.05). CONCLUSIONS: The huASM-MR transgenic mouse model was more susceptible to allergic asthma phenotype than the Tg (-) littermate controls. Airway changes mediated via lysosomal hydrolases and ASM-MR may be important in the development of airway hyperreactivity characteristic of asthma. Funding: NIH
J ALLERGY CLIN IMMUNOL FEBRUARY 2004
642
Susceptibility to Asthma Phenotype in Human Airway Smooth Muscle Mannose Receptor (huASM-MR) Transgenic Mice
MONDAY
W. Robinson, Jr.1, C. Michael1, T. Overbeck1, F. Kirkland1, E. Bonten2, A. d’Azzo1, B. Lew1; 1Pediatrics, University of Tennessee, Memphis, TN, 2Genetics, St Jude Research Children’s Hospital, Memphis, TN. RATIONALE: We have previously reported that lysosomal hydrolases such as b-hexosaminidase (Hex), via the ASM-MR, promote mitogenesis in the inflamed airways. Studies were conducted to demonstrate the importance of the lysosomal hydrolases and ASM-MR system in the development of airway hyperreactivity. METHODS: Wild type naïve FVB/N mice received aerosolized Hex A (1 mg) or vehicle, either daily or every other day for 2 weeks. Transgenic (Tg) strain was developed by transfection of human ASM-MR linked to SM22 promotor. These Tg (+), Tg (-) littermates or wild type FVB/N mice were ovalbumin sensitized (i.p. injection on day 0, 14 and 21) and challenged for three consecutive days (days 28-30, via aerosol). Lung physiology was non-invasively assessed by methacholine challenge and changes in pulmonary resistance (pause enhancement, Penh) on day 31. RESULTS: After Hex treatment, naïve wild type mice showed increase in Penh at 25mg/ml methacholine concentration: 790 + 225% of control (Hex) vs. 423 + 124% of control (vehicle), respectively, n=3). Aerosolized yeast mannan, a mannose receptor blocker, inhibited Penh (>75% inhibition, n=3) in ovalbumin-sensitized FVB/N mice. The ovalbumin-sensitized and -challenged huASM-MR Tg (+) mice showed both hypersensitivity and hypereactivity to methacholine compared to Tg (-) littermate controls (n=4, p<0.05). CONCLUSIONS: The huASM-MR transgenic mouse model was more susceptible to allergic asthma phenotype than the Tg (-) littermate controls. Airway changes mediated via lysosomal hydrolases and ASM-MR may be important in the development of airway hyperreactivity characteristic of asthma. Funding: NIH
J ALLERGY CLIN IMMUNOL FEBRUARY 2004