The role of the contact system in pneumonia-derived sepsis

The overall aim of this thesis is to investigate the role of the CAS in pneumonia derived sepsis. To this end, we performed studies in mice in which components of the CAS were deleted or inhibited. In most experiments we used K. pneumoniae to induce pneumonia and subsequent sepsis; in one study we also used Streptococcus (S.) pneumoniae, the most common cause of community-acquired pneumonia, as infecting agent. The studies are presented in the following chapters:
In Chapter 2 we studied the role of FXII and FXI in the host response to K. pneumoniae and S. pneumoniae induced pneumosepsis by infecting FXII and FXI deficient mice with these pathogens via the airways. In Chapter 3 we used the Klebsiella model to study the role of kininogen in pneumonia and sepsis by infecting mice in which kininogen was either deficient (by gene deletion) or inhibited (by treatment with an antisense oligonucleotide). Chapter 4 describes experiments in which the role of B1/B2 receptors were studied by using B1/B2 deficient mice and B1 and B2 antagonists. In Chapter 5 we investigated the role of prekallikrein in K. pneumoniae induced sepsis by inhibiting its production by administration of a specific antisense oligonucleotide. In Chapter 6 antisense oligonucleotides targeting either FXII or FVII were administered to study the roles of the intrinsic and extrinsic routes of coagulation respectively in K. pneumoniae induced pneumonia. Finally, in Chapter 7 we studied the role of neutrophils in systemic coagulation and inflammation induced by LPS.