Emigration of leukocytes into ischemic and reperfused myocardium occurs rapidly following reperfusion. In animal models, myocardial tissue injury is reduced significantly by experimental therapies that limit the accumulation and/or activation of neutrophils. Experiments proposed in this application will use in vitro models with canine and murine cells to define adhesive mechanisms necessary for the transition of neutrophils from resting cells in the circulation to cells capable of adherence- dependent damage to cardiac myocytes. This transition occurs in vivo as neutrophils migrate through vessel walls into myocardial tissue.
The Specific Aims will address experimentally distinct stages in this transition define, 1) the molecular mechanisms that allow neutrophils to stop on endothelium under conditions of flow with shear stresses in the venular range, 2) the adhesive mechanisms that allow neutrophils to migrate through vessel wall structures and attach to cardiac myocytes, and 3) the adhesive determinants for neutrophil production of reactive oxygen, cytokines (IL-1beta, TNFalpha, and IL-6) and chemokines (IL-8 and MCP-1). Two general experimental strategies will be used -- i) to isolate a known adhesive mechanism (e.g., by using recombinant adhesion molecules) in order to determine if it can support or influence leukocyte functions in these 3 stages, and ii) to determine the relative contributions of each adhesive mechanisms to these functions as leukocytes interact with cytokine-stimulated endothelial cells, extracellular surfaces, and cytokine-stimulated cardiac myocytes. The latter studies will use monoclonal antibodies to block specific adhesive functions, or cells from mice genetically engineered to be deficient in specific adhesion molecules. The focus of these studies will be on CD 18 integrins and stimuli (IL-8 and platelet activating factor) that upregulate the function of two members of this family (CD11b/CD18 and CD11a/CD18), ICAM-1 (CD54) on endothelium and myocytes, members of the selectin family (CD62L and CD62P), and an undefined adhesive mechanism that accounts for primary adhesion of neutrophils 24 hours after stimulation of endothelial cells with IL-1. We will also evaluate the adhesive steps that allow canine monocyte to stop on endothelial cells under conditions of flow, and that influence production of the above cytokines and chemokines. These studies will focus on two adhesion molecules in addition to those cited above, the beta1 integrin, VLA4 (CD49d/CD29), and VCAM-1 (CD106). Intravital microscopy in canine and murine models will also be used to assess some of the concepts resulting from the data obtained in vitro. These studies will enhance understanding of the critical sequential adhesive steps necessary for the emigration and activation of neutrophils and monocytes in the context of myocardial reperfusion injury.
| Mann, Douglas L (2014) Colchicine and the failing heart: a ""FINER"" anti-inflammatory agent? JACC Heart Fail 2:138-40 |
| Burns, Alan R; Phillips, Sharon C; Sokoya, Elke M (2012) Pannexin protein expression in the rat middle cerebral artery. J Vasc Res 49:101-10 |
| Mann, Douglas L (2012) Sphingosine 1-phosphate as a therapeutic target in heart failure: more questions than answers. Circulation 125:2692-4 |
| Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2011) Doppler velocity measurements from large and small arteries of mice. Am J Physiol Heart Circ Physiol 301:H269-78 |
| Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2010) Feasibility of dual Doppler velocity measurements to estimate volume pulsations of an arterial segment. Ultrasound Med Biol 36:1169-75 |
| Haudek, Sandra B; Gupta, Damon; Dewald, Oliver et al. (2009) Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovasc Res 83:511-8 |
| Reddy, Anilkumar K; Namiranian, Khodidad; Lloyd, Eric E et al. (2009) Effect of isoflurane on aortic impedance in mice. Conf Proc IEEE Eng Med Biol Soc 2009:1104-5 |
| Divakaran, Vijay; Adrogue, Julia; Ishiyama, Masakuni et al. (2009) Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading. Circ Heart Fail 2:633-42 |
| Wu, Huaizhu; Gower, R Michael; Wang, Hong et al. (2009) Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 119:2708-17 |
| Liu, Xiuping; Zuo, Yumei; Zhang, Weina et al. (2009) Expression of interleukin-15 and its receptor on the surface of stimulated human umbilical vein endothelial cells. J Huazhong Univ Sci Technolog Med Sci 29:527-34 |
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