Modulation of innate immunity during endotoxemia and gram-negative infection

Lower respiratory tract infection is the fourth most common cause of death in the world. Pneumonia can result in sepsis, which is a major cause or morbidity and mortality worldwide. The research described in this thesis focuses on the innate immune response during gram-negative (bacterial) infection, particularly pneumonia and sepsis. For this we made use of established human (endotoxemia) and mouse models (bacterial pneumonia and sepsis).
We first studied the role of mesenchymal stem cells (MSCs) as potential new sepsis therapy. We used adipose-derived mesenchymal stem cells (ASCs) in a randomized placebo controlled endotoxemia trial. We found that ASC infusion was well tolerated and resulted in mixed proinflammatory and anti-inflammatory responses. In addition, ASC infusion resulted in a transient systemic procoagulant effect. In a murine model of Klebsiella pneumoniae derived pneumosepsis, we show that treatment with human ASCs resulted in immune modulatory effects in the lung, associated with less bacterial outgrowth and reduced lung inflammation. We furthermore found that ASCs express tissue factor dependent procoagulant activity.
To gain more knowledge on the pathophysiology we studied two important mediatiors of innate immunity, MMP-8 and caspase-11. Using MMP-8 and caspase-11 knock-out mice respectively, we were able to show their effects in a murine model of pneumosepsis. We show a limited role for MMP-8 in the host response. Caspase-11 deficiency was associated with less fibrin formation and more bacterial outgrowth in the lungs.