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Intrapulmonary Human Airway Smooth Muscle Tissues Are Hyperreactive and Hyposensitive in Asthma

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A2739 - Intrapulmonary Human Airway Smooth Muscle Tissues Are Hyperreactive and Hyposensitive in Asthma
Author Block: G. Ijpma1, L. Kachmar1, A. L. Panariti2, O. S. Matusovsky1, A. Lauzon3; 1Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada, 2Faculty of Medicine, McGill University, Montreal, QC, Canada, 3Meakins Christie Laboratories, McGill University, Montreal, QC, Canada.
RATIONALE: Excessive bronchoconstriction plays a central role in airway hyperresponsiveness in asthma, but it is unclear whether the airway smooth muscle (ASM) per se is altered and whether any changes are permanent or transient. Whereas the trachealis muscle is not altered in asthma compared to controls, we previously reported that in a spontaneously occurring horse model of asthma, intrapulmonary ASM did show altered mechanics despite a lack of changes in trachealis ASM. In the current study we aimed to investigated whether in humans, like in horses, the intrapulmonary airways show altered ASM contractile properties.
METHODS: Asthmatic and control airways from the 3rd-5th generations as well as trachealis ASM strips were dissected from transplant grade lungs within 24h of cross-clamp. The airways were dissected free from parenchyma, cartilage, connective tissues and epithelium. The ASM tissues were then placed in force-length tissue baths (Aurora Scientific) in which we measured Force-Velocity curves during both Electrical Field Stimulation (EFS) and 10-5 M methacholine (MCh) exposure, MCh and Isoproterenol (Iso) dose response and stiffness. To calculate maximum stress, the ASM area in the tissues was determined from histological analysis.
RESULTS: Asthmatic peripheral ASM showed a significantly greater maximum stress response to MCh than control (84%, p=0.003) but also a significantly increased EC50 (10-5.55 M to 10-6.08 M, p=0.02), the dose at which 50% of the maximum stress is generated. No differences were found in Iso dose response. Force velocity curves showed no difference between controls and asthmatics, both for EFS and MCh activated muscle. We found no difference in tissue stiffness when normalized to contractile force.
CONCLUSION: Our data show two seemingly contradictory changes in ASM of asthmatic intrapulmonary airways: hyperreactivity coupled with hyposensitivity. This could be explained by a contrast between transient and permanent changes in the muscle. Intrapulmonary ASM in asthma may be desensitized between asthmatic attacks, but hypersensitive during periods of excessive inflammation. Meanwhile the contractile machinery itself may be more permanently altered. The lack of changes at the tracheal level probably results from reduced exposure to inflammation.
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