The cellular dysfunction that occurs when ischemic skeletal muscle is reperfused is becoming increasingly recognized as one form of acute inflammation in which both chemotactic mediators are released and in which activated neutrophils play a key role. Recent studies from our laboratory indicate that neutrophil adherence to vascular endothelium is required to produce microvascular dysfunction in postischemic skeletal muscle. In vitro evidence indicates that the establishment of adhesive interactions between granulocytes and vascular endothelium is a very complex process that involves a highly coordinated and dynamic interplay among several different adhesion molecules expressed both by the endothelium (eg, ICAM-1 and ELAM-1) and the granulocyte (eg, CD11/CD18 and LAM-1). The overall goal of the projects outlined in this application is to determine the role of those molecular determinants of neutrophil/endothelial cell adhesion in the genesis of microvascular dysfunction induced by ischemia/reperfusion (I/R) in skeletal muscle. These studies will utilize evaluation of vascular permeability and the no-reflow phenomenon as indices of microvascular dysfunction and intravital microscopic techniques to monitor neutrophil/endothelial cell interactions in vivo. In addition, the effect of I/R on cell surface expression of ICAM-1 and ELAM-1 will be evaluated. Immunofluorescence flow cytometry will be used to quantitate changes in surface expression of the leukocyte adhesion molecules, CD11a/CD18,CD11b/CD18, and LAM-1, on neutrophils obtained after I/R relative to control (no ischemia). We propose to determine: (1) the role of the leukocyte adherence molecules CD11a/CD18(LFA-1)CD11b/CD18(Mac-1), and LAM-1 (MEL-14 antigen or LEC- CAM-1) in the increased microvascular permeability and neutrophil infiltration induced by I/R; (2) whether administration of monoclonal antibodies to the endothelial cell adhesive molecules ICAM-1 and ELAM-1 will attenuate postischemic neutrophil infiltration and increased microvascular permeability; (3) the role of neutrophil/endothelial cell adherence reactions in the genesis of the no-reflow phenomenon in postischemic skeletal muscle; and (4) the molecular basis for ischemia/reperfusion-induced leukocyte adherence and emigration in skeletal muscle. These studies should improve our understanding of the role of neutrophil adhesion in the pathogenesis of I/R-induced microvascular dysfunction in skeletal muscle.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048646-02
Application #
3367775
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Korthuis, R J; Gute, D C; Blecha, F et al. (1999) PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction. Am J Physiol 277:H1007-13
Kong, L; Korthuis, R J (1997) Melanoma cell adhesion to injured arterioles: mechanisms of stabilized tethering. Clin Exp Metastasis 15:426-31
Rubin, B B; Romaschin, A; Walker, P M et al. (1996) Mechanisms of postischemic injury in skeletal muscle: intervention strategies. J Appl Physiol 80:369-87
Akimitsu, T; Gute, D C; Korthuis, R J (1996) Ischemic preconditioning attenuates postischemic leukocyte adhesion and emigration. Am J Physiol 271:H2052-9
Kong, L; Dunn, G D; Keefer, L K et al. (1996) Nitric oxide reduces tumor cell adhesion to isolated rat postcapillary venules. Clin Exp Metastasis 14:335-43
Jerome, S N; Akimitsu, T; Gute, D C et al. (1995) Ischemic preconditioning attenuates capillary no-reflow induced by prolonged ischemia and reperfusion. Am J Physiol 268:H2063-7
Akimitsu, T; Gute, D C; Korthuis, R J (1995) Leukocyte adhesion induced by inhibition of nitric oxide production in skeletal muscle. J Appl Physiol 78:1725-32
Jerome, S N; Dore, M; Paulson, J C et al. (1994) P-selectin and ICAM-1-dependent adherence reactions: role in the genesis of postischemic no-reflow. Am J Physiol 266:H1316-21
Jerome, S N; Kong, L; Korthuis, R J (1994) Microvascular dysfunction in postischemic skeletal muscle. J Invest Surg 7:3-16
Korthuis, R J; Anderson, D C; Granger, D N (1994) Role of neutrophil-endothelial cell adhesion in inflammatory disorders. J Crit Care 9:47-71

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