On Mechanisms Impairing Airway Host Defence in Cystic Fibrosis

Sammanfattning: Cystic fibrosis is an inherited disease, caused by mutations of the cystic fibrosis transmembrane conductance regulator gene. The gene codes for a protein that serve as chloride channel. In cystic fibrosis, this protein is lacking or has a defect function resulting in a thick and sticky mucus of the airways. The altered airway environment promotes mucus and growth of pathogenic bacteria. A common pathogen is Pseudomonas aeruginosa that often colonizes the lungs of adult cystic fibrosis patients and is associated with a poor diagnosis. The host defense fails to eradicate the bacteria and instead a prolonged inflammatory response, including excessive recruitment of neutrophils, confers damage to the lungs. To date, several theories exist of why there is an impaired bacterial clearance in the airways of cystic fibrosis patients. Increased salt concentration, reduced depth and pH of the thin fluid lining the epithelial cells are examples. In this thesis, we have examined different mechanisms impairing the host defense in cystic fibrosis. First, we describe that the growth factor midkine is expressed in the airways of cystic fibrosis patients and that it has antibacterial activity against P. aeruginosa. However, both salt and pH alterations reduced the antibacterial activity of midkine. It was also cleaved into smaller fragments by elastases from neutrophils and P. aeruginosa. In a second study, we show that the chemokine MIG/CXCL9 is expressed in the airways of cystic fibrosis patients and that it has antibacterial activity against P. aeruginosa. MIG/CXCL9 was cleaved into three smaller fragments by elastase of P. aeruginosa, that all had reduced antibacterial activity against P. aeruginosa. The degradation also resulted in a reduced recruitment of other immune cells that are involved in eliminating P. aeruginosa. In a third study, we showed that the negatively charged protein, osteopontin is expressed in the airways of cystic fibrosis patients. Interestingly, osteopontin binds to and inhibits the antibacterial activity and receptor activating properties of several ELR-negative CXC chemokines. This is not the case for the neutrophil recruiting ELR-positive CXC chemokines. These interactions can result in an accumulation of neutrophils in the airways and also a reduced antibacterial activity. Lastly, we showed that the neutrophil recruiting chemokine GCP-2/CXCL6 is expressed in the airways of cystic fibrosis patients. GCP-2/CXCL6 binds to free DNA but, its antibacterial activity and receptor activating properties were not affected by this interaction, while the chemotactic properties were slightly decreased. Taken together, this thesis demonstrates several novel mechanisms that explain how the airway immune system is compromised in cystic fibrosis.