Multiple Organ Dysfunction Syndrome (MODS) is the leading cause of mortality in Intensive Care Unit (ICU) patients. Although essential for host defense, the polymorphonuclear neutrophil (PMN) contributes to endothelial cell and end organ injury in disease states such as MODS. PMN chemotaxis and apoptosis are principally involved in neutrophil delivery and clearance, and their evaluation is performed with the goal of developing effective therapeutic intervention that would attenuate neutrophil mediated host injury. / To investigate the role of neutrophil membrane receptor expression in the regulation of neutrophil apoptosis and chemotaxis, human circulating PMN (venipuncture, healthy controls), exudate PMN (skin window skin blister) and septic PMN (venipuncture, patients with sepsis) were evaluated for apoptosis rates (flow cytometry), chemotactic function (Boyden chambers), and receptor expression (flow cytometry - Fas, FasL, TNFRI, TNFRII, IL-8RA, IL-8RB, C5aR). Experiments were coupled with a theoretical evaluation of the assumptions and clinical implications inherent to analytical research of the host response. / Following transmigration, exudate neutrophils demonstrate delayed constitutive and induced (TNF-alpha & Fas Ab) apoptosis. Decreased binding to TNF-alpha (not receptor expression) was found in association with decreased TNF-alpha induced apoptosis in exudate PMN. In contrast to circulating PMN, inhibition of protein synthesis in exudate PMN does not augment apoptosis; NF-kappaB does not mediate this effect as inhibition of NF-kappaB augments apoptosis in circulating and exudate PMN. Evaluation of chemoattractant receptors and chemotactic function revealed the following: exudate PMN displayed increased C5a receptors & C5a chemotaxis and reduced Interleukin-8 receptors (both IL-8RA & IL-8RB) & IL-8 chemotaxis. Septic PMN displayed reduced C5a & IL-8 receptors, and decreased C5a chemotaxis. These results suggest that alteration in chemoattractant receptor expression serves to regulate PMN chemotaxis in vivo, exudate PMN chemotaxis depends more on C5a than IL-8, and diminished chemoattractant receptors and chemotaxis in septic PMN may explain decreased PMN delivery in these patients. / Therapeutic interventions for patients with complex inflammatory disease states such as MODS remains elusive despite immense growth in understanding the mechanisms involved in the host response. To complement analytical research, the systemic host response to trauma, shock or sepsis may be evaluated as a complex system. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38518 |
| Date | January 2002 |
| Creators | Seely, Andrew J. E. |
| Contributors | Christou, Nicolas V. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Surgical Research.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001945044, proquestno: NQ85741, Theses scanned by UMI/ProQuest. |
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