On Neutrophil and Platelet Adhesive Interactions in Septic Lung Injury

Sepsis induced by intestinal perforation is a life-threatening illness and is a frequent cause of leukocyte-mediated lung injury. Although antimicrobial therapy has been the central clinical strategy for these patients, the survival rates in such patients are still very low because of their impaired host defense mechanisms. Therefore, control of amplified leukocyte recruitment in the lung may be a potential target to treat septic patients. The aim of the thesis was to define the role of p38 mitogen activated protein kinase (MAPK) signaling pathway and the role LFA-1, Mac-1 and PSGL-1 as well as the role of platelets in septic lung injury. Accumulation of water in lung, infiltration of leukocytes in bronchoalveolar space, levels of myeloperoxidase and CXC chemokines were measured after cecal ligation and puncture (CLP). Animals were treated with the specific p38 MAPK inhibitors, SB 239063 and SKF 86002, corresponding blocking antibodies to LFA-1, Mac-1 or PSGL-1 and plateletes were depleted with an antibody directed against GP1b-alpha from the circulation prior to CLP induction. Clear-cut damage in the lung tissue was observed in CLP animals which was characterized by edema formation, excessive leukocyte accumulation and increased levels of CXC chemokines in the tissue. CLP induced phosphorylation and activity of p38 MAPK in lung which was markedly inhibited by using SB 239063. Moreover, functional inhibition of p38 MAPK signaling reduced CLP-induced formation of CXC chemokines, leukocyte recruitment and protected against septic lung injury. In addition, the results showed that both LFA-1, Mac-1 play important roles in leukocyte recruitment and fluid accumulation in the bronchoalveolar space although the tissue production of CXC chemokines was unaffected by antibody treatments in abdominal sepsis. Notably, inhibition of PSGL-1 reduced CLP-induced leukocyte recruitment and lung injury in a platelet-independent manner. Platelet depletion decreased Mac-1 upregulation on leukocytes as well as the accumulation of leukocyte in septic lung injury. This effect of platelet was independent of platelet-leukocyte aggregate formation. Thus, this work delineates new mechanisms regulating pathological inflammation in the lung during abdominal sepsis