Accumulating evidence implicates the neutrophil as playing an important role in myocardial injury following coronary artery occlusion and reperfusion. Although there are several mechanisms by which the neutrophil can produce myocardial damage, including mechanical plugging and release of oxidants, relatively little attention has been focused on the role of neutrophil-derived proteolytic enzymes in this tissue damage. There is abundant in-vitro evidence and accumulating data in other in-vivo organ systems to support the importance of this proteolytic enzyme mechanism. Moreover, recent data which demonstrates that neutrophil-derived oxidants can both inactivate antiproteinases responsible for regulating toxic proteinase and activate tissue-destructive metalloproteinases, suggest that the role of oxidants in myocardial damage may be more complex than originally considered. Accordingly, we will examine the broad hypothesis that the proteolytic enzymes released from triggered neutrophils contribute to myocardial injury following coronary occlusion and reperfusion. We will systemically investigate the role of neutrophil-derived proteolytic enzymes in myocardial injury by using synthetic or recombinant proteinase inhibitors directed against the four proteolytic enzymes most commonly implicated in tissue damage; namely, the serine proteinase, elastase and cathepsin G, and the metalloproteinases, collagenase and gelatinase. In addition, we will examine the role of the cytokine, interleukin-1 (IL-1), since the cytokine system has been implicated in mediating this proteolytic injury. Initial in-vitro analysis of canine neutrophil proteolytic potential and the inhibitory effect of each of the inhibitors will be carefully examined. Individual protocols will be designed to study each of: a specific elastase inhibitor; 2) a recombinant secretory leukoproteinase inhibitor (rSLPI); 3) collagenase and gelatinase inhibitors, and 4) IL-1 inhibitor. Following these in-vitro analyses to characterize the specific proteolytic mechanisms involved, a series of in-vivo studies will be performed in acute and chronic canine models of coronary occlusion and reperfusion. Experiments will designed: 1) to study the effects of a synthetic elastase inhibitor on myocardial damage and functional recovery following ischemia and reperfusion; 2) to examine the effects of rSLPI, a small molecular weight elastase and cathepsin G inhibitor; 3) to investigate the effects of metalloproteinase inhibitors, and 4) to examine the cardioprotection provided by a recombinant IL-1 receptor antagonist. End points for analysis in these experiments will include infarct size, ventricular function, tissue edema, and histopathologic tissue analysis. An understanding of the mechanisms of neutrophil-mediated myocardial injury will not only provide specific information concerning the pathogenesis of ischemic and reperfusion damage but may also point towards therapeutic interventions which may prove to be important adjuncts to thrombolytic therapy in man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034691-08
Application #
2217625
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1986-12-01
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1996-08-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Lockyer, J M; Colladay, J S; Alperin-Lea, W L et al. (1998) Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circ Res 82:314-20
Tenaglia, A N; Buda, A J; Wilkins, R G et al. (1997) Levels of expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris. Am J Cardiol 79:742-7
Lefer, D J; Flynn, D M; Buda, A J (1996) Effects of a monoclonal antibody directed against P-selectin after myocardial ischemia and reperfusion. Am J Physiol 270:H88-98
Lefer, D J; Flynn, D M; Anderson, D C et al. (1996) Combined inhibition of P-selectin and ICAM-1 reduces myocardial injury following ischemia and reperfusion. Am J Physiol 271:H2421-9
Pabla, R; Buda, A J; Flynn, D M et al. (1995) Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function. Am J Physiol 269:H1113-21
Wood, J C; Barry, D T (1994) Quantification of first heart sound frequency dynamics across the human chest wall. Med Biol Eng Comput 32:S71-8
Wood, J C; Festen, M P; Lim, M J et al. (1994) Regional effects of myocardial ischemia on epicardially recorded canine first heart sounds. J Appl Physiol 76:291-302
Lefer, D J; Flynn, D M; Phillips, M L et al. (1994) A novel sialyl LewisX analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion. Circulation 90:2390-401
Wood, J C; Buda, A J; Barry, D T (1992) Time-frequency transforms: a new approach to first heart sound frequency dynamics. IEEE Trans Biomed Eng 39:730-40
Lim, M J; Karolle, B L; Wood, J C et al. (1992) Ischemic expansion during acute myocardial infarction and reversal by coronary reperfusion. Am Heart J 123:1456-63

Showing the most recent 10 out of 28 publications