title: Adhesive dynamics simulation of neutrophil arrest with deterministic activation.
abstract: The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and beta2 -integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade. To study the possible mechanism by which neutrophil arrest could occur, we created an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the timescale of neutrophil activation, adhesion, and diapedesis.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Krasik
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hammer
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008954:Models, Biological; D018375:Neutrophil Activation / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*
chemical_list: D016207:Cytokines