Blood coagulation in cystic fibrosis: modulating inflammation?

Abstract

Cystic fibrosis (CF) is a devastating chronic inflammatory disease caused by a mutation in the gene encoding cystic fibrosis transmembrane regulator (CFTR), which is a chloride channel in epithelia cell membranes [1]. The phenotype is dominated by pathological changes occurring in organs that express CFTR, particularly the airways, where infection contributes to severe chronic pulmonary disease. The still unavoidable result is a markedly reduced life expectancy (median age of survival 32 years in 2000). Chronic infection is a hallmark of this disease, so that the question whether infection elicits inflammation or vice versa has never been answered unequivocally. Colonization with specific pathogens, particularly Pseudomonas aeruginosa ,o ccurs in about 100% of cases. Contributing factors are reduced interleukin-10 production in the lungs and reduced sialysation of glycoconjugates on epithelial cell membranes. CFTR specifically acts as receptor for P. aeruginosa, facilitating its clearance by internalization under normal conditions. The F508-deleted CFTR cannot bind this bacterium and impaired clearance is the result. Finally, epithelial cells produce defensins which are only partially active in a high salt milieu which is typical of CF, diminishing the antimicrobial barrier [1]. All these factors probably contribute to the chronic infection in CF. The resulting inflammatory state triggers a host response reaction, which also involves the blood coagulation system. In past decades much attention has been given to the possible role that blood coagulation might play in the inflammatory response, as an integral part of the innate immune system [2]. In experimental models of sepsis it has been demonstrated that proinflammatory mediators including tumor necrosis factor (TNF)-a, interleukin (IL)-1 and interleukin (IL)-6 induce tissue factor expression and subsequent thrombin generation. TNF-a impairs fibrinolytic activity by inducing plasminogen activator inhibitor-1 (PAI-1), while the same mediators downregulate the level of expression of natural