The participation of Polymorphonuclear neutrophils (PMN) in the inflammatory response provides a first line of defense against invading organisms. However, inflammation has been called """"""""double edged sword"""""""" as PMN can cause damage to surrounding tissues and a prolonged inflammatory response can contribute to a variety of pathological conditions. The recruitment of circulating PMN to inflammatory sites requires the stimulated adhesion of PMN to the endothelium followed by their extravasation and chemotaxis. The beta2 integrins, alpha-L beta-2 and alpha-M beta-2 mediate the tight adhesion of PMN to the endothelial cells required for subsequent extravasation. Although the beta2 integrins have been widely studied, the focus has been on identifying conformational changes necessary for adhesion while the cellular signaling pathways responsible for regulating beta2 mediated adhesion of PMN remain poorly understood. We have identified a signaling pathway associated with PMN apoptosis that attenuates the beta2 mediated adhesion of PMN to pulmonary microvascular endothelial cells. Stimulation of the PMN Fas """"""""death"""""""" receptor results in a reduction of PMN adhesion to pulmonary microvascular endothelial cells. Preliminary data indicates that the loss of adhesion is a very early event in the Fas/Ceramide/Protein Kinase Cdelta (PKCdelta) pathway that contributes to PMN apoptosis. Specifically, Fas activation increases PMN ceramide concentration and causes the cytosolic localization of PKCdelta. We propose that the cytosolic localization of PKCdelta could reduce adhesion because it opposes the membrane localization of PKCdelta that is necessary for beta2 mediated adhesion.
Aim 1 examines the two beta2 integrin receptors on PMN, alpha-L beta-2 and alphaM beta2, that mediate endothelial cell adhesion to determine which of the beta2 receptors are affected by Fas activation.
Aim 2 determines the effect of Fas activation on PKCdelta and manipulates the cellular localization of PKCdelta to determine its effects on the beta2 integrins and adhesion.
Aim 3 examines the effects of Fas on ceramide to confirm that ceramide increases mediate Fas effects on PKCdelta, beta2 integrins, and adhesion.
Aim 4 determines if reducing adhesion by manipulating the Fas/ceramide/PKCdelta pathway can also reduce ischemia/reperfusion-induced injury in an ex-vivo rat lung. An understanding of this pathway would provide novel targets for the control of inflammation.
| Desai Bradaric, Brinda; Patel, Aditiben; Schneider, Julie A et al. (2012) Evidence for angiogenesis in Parkinson's disease, incidental Lewy body disease, and progressive supranuclear palsy. J Neural Transm (Vienna) 119:59-71 |
| Desai, Brinda S; Schneider, Julie A; Li, Jia-Liang et al. (2009) Evidence of angiogenic vessels in Alzheimer's disease. J Neural Transm (Vienna) 116:587-97 |
| Carvey, Paul M; Hendey, Bill; Monahan, Angela J (2009) The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 111:291-314 |
| Desai, Brinda S; Monahan, Angela J; Carvey, Paul M et al. (2007) Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy. Cell Transplant 16:285-99 |
