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Title: Collectins and innate immunity in the lung : therapeutic potential of a recombinant fragment of surfactant protein D in lung disease
Author: Clark, Howard W.
ISNI:       0000 0001 3554 0742
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2003
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This thesis examines the role played by the lung collectins, surfactant proteins A and D (SP-A and SP-D) in innate immunity in the lung. The generation of SP-A and SP-D deficient mice has confirmed the important part played by these innate immune molecules in the defence of the lung against infection and in the control of inflammation. SP-A deficient mice are susceptible to infection with a range of microbes. The critical role played by SP-D in controlling inflammation in the lung has been convincingly demonstrated in the SP-D deficient mouse which shows a chronic low grade lung inflammation and the spontaneous development of emphysema. The thesis examines the in vivo activity of recombinant forms of surfactant proteins, in particular a recombinant fragment of surfactant protein D, in the control of lung inflammation using SP-D deficient mice as a model of emphysema. Murine models of allergic inflammation to fungal and common house dust mite allergens were employed to assess the efficacy of recombinant collectins in modulating allergic processes in vivo. The animal models employed and the generation and structural characterisation of recombinant SP-Dare described in the first sections of the thesis. SP-A and SP-D are known to bind to fungal aeroallergens and to allergens of the common house dust mite. Therapeutic testing of the recombinant fragment of surfactant protein D was carried out in mouse models of allergy against allergens of the common house dust mite Dermatophagoides pterynossinus and those of the fungus Aspergillus fumigatus. Exogenously administered collectin reduced serum eosinophilia, IgE and specific IgG 1 levels as well as airway hyperresponsiveness to challenge with both fungal and house dust mite allergens. Further characterisation of the lung phenotype of the SP-D deficient mouse and the use of replacement therapy in correcting the phenotype revealed that SP-D deficient mice have an increased burden of apoptotic and necrotic inflammatory cells in the alveolar space. Treatment of these mice with a recombinant fragment of surfactant protein D led to a marked reduction of the number of apoptotic and necrotic alveolar macrophages in the alveolar space and a partial resolution of the inflammation and excess production of surfactant phospholipids. These results indicate the critical role played by SP-D in regulating inflammation in the lung and the efficacy of a recombinant fragment of SP-D in reducing inflammation in the SP-D deficient lung. Finally the results of a pilot investigation into the levels of SP-Din a population of intubated neonates is presented. The clinical implications of the findings of the thesis are discussed in chapter four, focussing on the therapeutic potential of the recombinant fragment of SP-D to reduce inflammation in neonatal chronic lung disease, cystic fibrosis and adult emphysema.
Supervisor: Reid, Kenneth B. M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Lungs ; Collectins ; Natural immunity