The Topham-Stafforini Lab has examined the role of a family of phospholipids that initiate inflammation and allergy. The lab showed that when endothelial cells are activated by a variety of inflammatory mediators, their cell surface changes to one that is adhesive for leukocytes. This finding explained how the inflammatory response could be localized to an appropriate area and not result in a systemic response. Further studies uncovered a novel, multi-step mechanism: endothelial cells translocate a protein, P-selectin, to their surface and this protein "tethers" leukocytes to the endothelial cells, but does not fully activate them. Simultaneously, the endothelial cells synthesize a lipid mediator, platelet-activating factor (PAF), which completes the activation of the leukocyte. This mechanism provides an editing mechanism that prevents the inappropriate activation or recruitment of leukocytes since all the components must be present to achieve a complete response.
The Topham-Stafforini Lab and others have shown that this sequence of events is a critical component of inflammation and a potential target for therapeutic intervention. Topham and Stafforini's work has shown that this regulated process can be mimicked by a non-enzymatic pathway that results from the production of oxidized phospholipids that can bind to the PAF receptor and reproduce its actions. The Topham-Stafforini group carried out detailed chemical analysis of the structure of these phospholipids, which have been shown to occur in inflammatory syndromes and in atherosclerosis.
Diana M. Stafforini, PhD, an investigator at Huntsman Cancer Institute, research associate professor in the Department of Medicine at the University of Utah School of Medicine, is interested in the role of inflammation in human disease. Stafforini, a native of Buenos Aires, Argentina, moved to the United States to complete her PhD in biochemistry at the University of Utah. Stafforini and her colleagues defined how PAF and the oxidized phospholipids are degraded, resulting in a termination of the inflammation signal. Their group purified and characterized a specific phospholipase in plasma and showed that it is synthesized and secreted by macrophages. This led to the cloning of the cDNA and production of recombinant enzyme, which they showed to have marked anti-inflammatory properties in animal models. They defined the regulation of the gene by hormones and cytokines that alter inflammation.
In association with investigators at the University of Utah and at ICOS Corporation, Stafforini conducted studies aimed at establishing the role of this enzyme in vascular and pulmonary diseases. These studies provided a foundation for currently ongoing clinical trials focused on discovering the suitability of PAF-AH as a treatment for diseases with inflammatory components such as acute respiratory distress syndrome (ARDS), asthma, and sepsis. In addition to these studies, Stafforini discovered a human mutation that results in the lack of PAF-AH activity. She established that individuals who have this mutation have a tendency to develop severe inflammation. These studies have contributed greatly to basic understanding of how the inflammatory response is controlled and have identified a promising treatment for severe syndromes of inflammation.
