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Inflammation is the body's innate immune response to the damage caused to its cells and vascularised tissue, either by injury or microbial pathogens. Although these processes cause pain, swelling, redness and an increase in body temperature, inflammation is generally a beneficial salutary response. Since the 1940's glucocorticoids have been widely prescribed in treating inflammatory diseases, e. g. for inflammatory bowel disease and anaphylactic shock hydrocortisone is prescribed, whereas for asthma and rheumatic disease, betametasone and prednisolone are the drugs of choice. During the late 1970's and early 1980's a novel glucocorticoid regulated protein, termed annexin Al, was identified. This protein mediates and shares many of the anti-inflammatory and prostaglandin suppressive properties with glucocorticoids. More recently annexin Al has been shown to be an endogenous ligand for the fMLP receptor, termed the FPR. This thesis questions the fundamental basis of annexin Al leukocyte biology by examining the behaviour of neutrophils and macrophages collected from mice lacking either the protein or its receptor. The major finding in this thesis can be divided into two sections, focusing on the neutrophil activation or the macrophage phagocytosis. Neutrophils from FPR deficient mice could be activated at high concentrations with fMLP, and pre-incubating cells with either the annexin Al mimetic or the FPR antagonist Boc 2 abrogates these effects. Blood neutrophils purified from annexin Al null mice were more susceptible to inflammatory stimuli, causing an excessive increase in cell adhesion molecule expression, chemotaxis and ROS production, compared to littermate (wild type) controls. In contrast neutrophils over expressing this protein exhibited an attenuated degree of activation. Annexin Al null peritoneal macrophages exhibited defects in phagocytosis in a stimulus-specific manner. Annexin Al null macrophages incubated with non-opsonised zymosan, Neisseria or opsonised sheep red blood cells exhibited a grossly impaired uptake of particles. This was further confirmed by electron and confocal microscopy analysis. Furthermore, specific alterations in annexin Al null macrophage plasma 2 membrane CD1lb and F4/80 expression was observed in macrophages lacking this protein. Upon activation these macrophages synthesised an augmented concentration of proinflammatory cytokines. Annexin Al null macrophages were resistant to glucocorticoid inhibition during phagocytosis. These results suggest that the participation of endogenous annexin Al during phagocytosis is critical. In summary, this thesis has investigated for the first time in genetically modified mice the potential effects that the lack of annexin Al may have on specific cellular functions with a major impact on the inflammatory response, finding that indeed this protein exerts a tonic inhibitory action, in a stimulus- and cell-specific fashion, on leukocyte biology.

Copies of author's previously published articles inserted. / Includes bibliographical references. / vii, 39 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Shows that the cytokine tumour necrosis factor [alpha] (TNF-[alpha]) enhances the adhesion of neutrophils to the endothelium by an action both on the neutrophil and on the endothelial cell. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1995?

De nombreuses études soulignent une relation directe entre la prévalence de la fibrillation auriculaire (FA) et le vieillissement. La senescence cellulaire et le phénotype sécrétoire associé semblent jouer un rôle central dans le développement de l'inflammation auriculaire. Cette inflammation est à l’origine d’un remodelage auriculaire délétère (stress oxydant, fibrose) favorable à la perpétuation et au maintien de la FA. Par ailleurs, il est connu que la FA favorise la coagulation locale et systémique. Cependant, l'impact des facteurs de la coagulation, notamment la thrombine, sur la FA est peu connu. L’objectif de cette étude était de déterminer le lien entre la sénescence des cellules endothéliales atriales et le phénotype pro-inflammatoire et pro-adhésif, la fibrose et le remodelage auriculaire tout en évaluant l’impact de la coagulation, et en particulier le rôle de la thrombine. / Many studies documented strong relationship between ageing and development of atrial fibrillation (AF). Moreover, it has been found that senescence and senescence-associated- secretory-phenotype play an important role in development of overall atrial inflammation which can ultimately ends up in atrial structural remodeling paving the way to AF perpetuation and maintenance. Moreover, it has been known for decades that AF has been associated with the activation of local and circulating coagulation factors. However, little is known about the impact of coagulation-derived factors, in particular thrombin, on the onset of AF. The aim of the present study was to determine the link between atrial endothelial cells (AECs) senescence and the induction of pro-inflammatory, pro-adhesive, pro-fibrotic and pro-remodelling AECs patterns and also to evaluate the contribution of coagulation derived-factors such as thrombin.