(601d) Development of a Mathematical Model to Describe the Transport of Monocyte Chemoattractant Protein-1 through a Three-Dimensional Collagen Matrix

Cellular adhesion molecules and inflammatory cytokines are critical participants in the vascular dysfunction and tissue injury associated with a wide variety of inflammatory and cardiovascular diseases, including atherosclerosis. Atherosclerosis is an inflammatory disease in which its initiation involves with the subendothelial accumulation of lipid substances, and the transendothelial migration of monocytes in an artery. Eventually, the monocytes differentiate into cholesterol-engorged macrophages called ?foam cells? that result in the atherosclerotic plaque formation. Having a better understanding of the underlying mechanisms and identifying potential pro-atherogenic markers will help to target these adhesion molecules or cytokines with highly specific therapeutic strategies. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) is a chemokine that is expressed highly in atherosclerotic lesions. The key function of MCP-1 in the formation and progression of the disease is to recruit monocytes to a lesion area. Results of many studies have shown that monocyte transmigration is directed by the soluble gradient of MCP-1. In this study, a 3D in vitro human vascular tissue model, consisting of a collagen matrix, to mimic the subendothelial extracellular matrix (ECM), was introduced to investigate the formation of MCP-1 gradients in the ECM. The 3D tissue model provides the added dimension that is important for the creation of concentration gradients, along with cellular movement and interactions created by such gradients. The main objective of the study is to develop a mathematical model to determine the MCP-1 concentration in the collagen matrix of the tissue model. Both the unsteady-state mass transfer and the kinetics of MCP-1 in the collagen matrix were included in the mathematical model. To characterize the kinetic part of the model, experiments were performed to examine the stability of MCP-1 and the binding reaction between MCP-1 and the collagen matrix. Experimental results show that MCP-1 is stable at standard cell culture conditions (37°C, humidified atmosphere of 5% CO2 and 95% air) for at least 24 hours, and it does bind with the collagen matrix. These findings were taken into account in the development of the mathematical model. Results from the model suggest that not only the soluble gradient of MCP-1 is formed in the collagen matrix, but a static gradient (the gradient of collagen-bound MCP-1) appears in the matrix as well. The static gradient may be another factor that controls the migration of monocytes into the lesion area.