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Title: Cellular interactions of airway smooth muscle and human lung mast cells
Author: Woodman, Lucy
ISNI:       0000 0004 2683 2956
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2009
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Asthma is characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), inflammation and remodeling. Mast cells (MC) co-localise to airway structures such as epithelium and airway smooth muscle (ASM) - the latter is a key determinant of AHR. Our group has reported that the CXCL10/CXCR3 axis is important in MC migration towards ASM, MCs adhere to ASM predominately via CADM-1 and this interaction promotes MC survival and proliferation. Whether there are other important mechanisms driving MC localization, ASM migration, and how MCs affect ASM differentiation is uncertain. We sought to examine i) chemokine concentrations in airway secretions in eosinophilic bronchitis (EB), and asthma, and their effects on MC migration ii) CCR3 mediated ASM migration, iii) effects of MC–ASM co-culture on ASM differentiation. Bronchoalveolar lavage (BAL) CXCL10 and CXCL8 concentrations were increased in subjects with EB compared to asthmatics and controls; were chemotactic for MCs and was attenuated by CXCR1 or CXCR3 inhibition. CCL11 mediated ASM migration and wound healing, but had no effect on proliferation or survival. Co-culture with β-tryptase or MCs degraded CCL11, and inhibited CCL11-mediated ASM migration. In vitro co-culture of ASM cells with β-tryptase or MCs increased ASM-derived TGF-β1 secretion, α-smooth muscle actin (α-SMA) expression and agonist-provoked contraction. Promotion to a more contractile phenotype was inhibited by leupeptin and TGF-β1 neutralization, suggesting ASM differentiation was driven by the autocrine release of TGF-β1 in response to β-tryptase. Importantly, in vivo, in asthmatic bronchial biopsies, intensity of α-SMA expression was strongly related to the number of MCs within or adjacent to ASM bundles. In conclusion, CXCL8 and CXCL10 are important in MC migration to the epithelium, but CCL11 is unlikely to be important in ASM migration. MCs drive ASM differentiation to a more contractile phenotype via autocrine release of TGF-β1, which may contribute to the disordered airway physiology in asthma.
Supervisor: Brightling, C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available