Mechanisms for LPS induced fibroblast apoptosis

PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.Thesis (D.Sc.)--Boston University; Henry Goldman School of Graduate Dentistry, 2004.Includes bibliography (leaves 102-122).Following Gram-negative bacterial infection there is a reduction in matrix producing cells. The goal of the present study was to examine the apoptotic effects of lipopolysaccharide (LPS) on fibroblastic cells and to investigate the role that the host response plays in this reaction. This was accomplished in vivo by subcutaneou s inoculation of LPS in wild type, TNFR 1-1-R2 -t- 1, TNFR 1-1- and TNFRT '- mice . The direct effects of LPS on fibroblast apoptosis was studied in vitro with normal diploid human fibroblasts. In vitro studies demonstrated that LPS did not induce apoptosis of fibroblasts whereas TNF did. Histological studies indicated that LPS in vivo induced apoptosis of fibroblasts. Similar results were obtained by subcutaneou s injection of TNF-a in wild type mice. Histological studies on TNFR 1-1-R2-1- mice demonstrated that LPS-induced fibroblast apoptosis was largely dependent on TNF-a. Fluorometric studies demonstrated that LPS in vivo significantly increased caspase-8 and caspase-3 activity and by use of specific inhibitors, the activation of caspase-3 was shown to be initiated by caspase-8. [TRUNCATED