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Efficacy of Mucolytic Treatment in Decreasing Airway Resistance and Increasing Mucus Clearance in a Mouse Model of Allergic Asthma

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A7187 - Efficacy of Mucolytic Treatment in Decreasing Airway Resistance and Increasing Mucus Clearance in a Mouse Model of Allergic Asthma
Author Block: L. Morgan, D. Raclawska, C. M. Evans; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver School of Medicine, Aurora, CO, United States.
ABSTRACT
Rationale
Presently, treatments for asthma target controlling smooth muscle contraction and reducing inflammation. Mucin overproduction is another prominent feature of asthma, with airway mucus plugging being long recognized as prominent in fatal asthma. Mucin hypersecretion is also prominent in mild to moderate disease, but its role in non-fatal asthma exacerbations is less clear. To begin to clarify the impact of mucin production and secretion in asthma, we generated mice deficient in the gene encoding the polymeric mucin Muc5ac. In mouse models of allergic asthma, Muc5ac was required for airway hyperresponsiveness (AHR), a pathophysiological readout of the asthma phenotype. In the present studies, we sought to determine crucial biochemical mechanisms for mucin mediated AHR by determining whether a compound that disrupts mucin glycoprotein polymers can prevent AHR.
Methods
A mouse model of allergic asthma was created using BALB/cJ wild type (WT), and Muc5ac knockout (Muc5ac -/-) mice challenged with Aspergillus oryzae extract (AOE). Mice were ventilated, and respiratory system resistance (Rrs) was measured at baseline and in response to methacholine (MCh)-induced smooth muscle contraction and mucin secretion. Polymeric mucins are assembled via end-to-end disulfide bonds. To test the requirement for disulfide-mediated polymerization in AHR, AOE challenged WT mice were treated with aerosolized tris(2-carboxyethyl)phosphine (TCEP), a reducing agent. Mucus occlusion was calculated using stereology, and disruption of mucin polymers was assessed with Western blots.
Results
Rrs increased eight-fold in AOE challenged WT mice compared to unchallenged non-allergic WT mice, and increased three-fold compared to the AOE challenged Muc5ac -/- mice. AOE challenged WT mice treated with TCEP also showed significantly lower changes in Rrs in response to IV MCh compared to the AOE challenged, non-mucolytic treated WT mice. TCEP-treated mice had identical dose response curves to those of AOE challenged Muc5ac -/- mice. Western blots confirmed that TCEP treatment disrupted mucin polymers, and histology showed that the volume of mucus in the airways of AOE challenged WT mice was significantly reduced in mucolytic treated allergic mice compared to AOE challenged untreated animals (p = 0.00952). Collectively, these data demonstrate that acute disruption of mucins with a mucolytic compound was as effective as genetic prevention in the Muc5ac -/- mice.
Conclusions
In summary, by demonstrating that TCEP is capable of reversing AHR and mucus plugging in mice via disruption of mucin polymers, we have shown that acutely reversing mucus hypersecretion is a potential therapeutic strategy for allergic asthma.
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