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Activation and inactivation of the complement anaphylatoxins during chronic neutrophilic inflammation of the cystic fibrosis airway

Stott, Matthew 2018. Activation and inactivation of the complement anaphylatoxins during chronic neutrophilic inflammation of the cystic fibrosis airway. PhD Thesis, Cardiff University.
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Abstract

Cystic fibrosis (CF) is a fatal genetic disease that affects 1/2500 people in the UK. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause dehydration of mucosal membranes, leading to mucus obstruction of the small airways. The CF lungs are susceptible to recurrent infection promoting chronic neutrophilic inflammation. Neutrophils recruited to the CF lungs become dysfunctional and are ineffective at clearing pathogens, perpetuating inflammation. Neutrophil serine proteases (NSPs) released by neutrophils collaterally remodel the airway, reducing lung function and causing mortality. The complement anaphylatoxins (C5a and C3a) are important mediators of inflammation. C5a and C3a are chemotactic for monocytes and granulocytes, they also stimulate degranulation and the generation of reactive oxygen species (ROS). C5a is particularly potent towards neutrophils and is critical for orchestrating their response towards pathogens. C5a and C3a are elevated in the CF airway. Furthermore, in addition to complement activation these anaphylatoxins can be generated by non-complement proteases including NSPs. The mechanisms by which C5a and C3a promote chronic neutrophilic inflammation in the CF airways are not fully understood. In my study I show that C5a and C3a correlate with markers of neutrophilic inflammation (neutrophil count and CXCL8) in bronchoalveolar lavage (BAL) fluid from paediatric CF patients. I further characterise the generation of functionally active C5a-like and C3a-like forms by NSPs. Moreover, I demonstrate that atypical C5a production by NSPs cannot be prevented by therapeutic complement inhibitors. I show for the first time that NSP-generated C5a-like fragments are resistant to inactivation by carboxypeptidase B, an important regulator of C5a activity. I also further characterise the interaction between C5a and soluble glycosaminoglycans (GAGs), these are abundant during chronic neutrophilic inflammation of the CF airway. Additionally, I show that GAG interaction influences C5a activity. In conclusion, the CF airway environment modifies C5a function; these mechanisms could promote chronic neutrophilic inflammation.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Funders: Alexion Pharmateuticals
Date of First Compliant Deposit: 22 January 2019
Last Modified: 22 Jan 2019 11:08
URI: http://orca.cf.ac.uk/id/eprint/118523

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