Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury.

K. A. Youker, H. K. Hawkins, G. L. Kukielka, J. L. Perrard, L. H. Michael, C. M. Ballantyne, C. W. Smith, M. L. Entman

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Abstract

Acute inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking monoclonal antibodies to either ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential ICAM-1 induction as a function of time of reperfusion, degree of ischemia, and viability of myocardial cells. Our evidence suggests that ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover, ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1 mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of ICAM-1 and the influx of neutrophils (presumably activated by the chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.

Original languageEnglish (US)
Pages (from-to)145-154
Number of pages10
JournalTransactions of the Association of American Physicians
Volume106
StatePublished - 1993
Externally publishedYes

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Intercellular Adhesion Molecule-1
Reperfusion Injury
Reperfusion
Neutrophils
Myocardium
Wounds and Injuries
Cardiac Myocytes
Messenger RNA
Blocking Antibodies
Chemotactic Factors
Extracellular Fluid
Lymph
Muscle Cells
Myocardial Ischemia
Cell Survival
Myocardial Infarction
Monoclonal Antibodies
Dogs
Cytokines
Inflammation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Youker, K. A., Hawkins, H. K., Kukielka, G. L., Perrard, J. L., Michael, L. H., Ballantyne, C. M., ... Entman, M. L. (1993). Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury. Transactions of the Association of American Physicians, 106, 145-154.

Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury. / Youker, K. A.; Hawkins, H. K.; Kukielka, G. L.; Perrard, J. L.; Michael, L. H.; Ballantyne, C. M.; Smith, C. W.; Entman, M. L.

In: Transactions of the Association of American Physicians, Vol. 106, 1993, p. 145-154.

Research output: Contribution to journalArticle

Youker, KA, Hawkins, HK, Kukielka, GL, Perrard, JL, Michael, LH, Ballantyne, CM, Smith, CW & Entman, ML 1993, 'Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury.', Transactions of the Association of American Physicians, vol. 106, pp. 145-154.
Youker KA, Hawkins HK, Kukielka GL, Perrard JL, Michael LH, Ballantyne CM et al. Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury. Transactions of the Association of American Physicians. 1993;106:145-154.
Youker, K. A. ; Hawkins, H. K. ; Kukielka, G. L. ; Perrard, J. L. ; Michael, L. H. ; Ballantyne, C. M. ; Smith, C. W. ; Entman, M. L. / Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury. In: Transactions of the Association of American Physicians. 1993 ; Vol. 106. pp. 145-154.
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abstract = "Acute inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking monoclonal antibodies to either ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential ICAM-1 induction as a function of time of reperfusion, degree of ischemia, and viability of myocardial cells. Our evidence suggests that ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover, ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1 mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of ICAM-1 and the influx of neutrophils (presumably activated by the chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.",
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AU - Kukielka, G. L.

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AU - Michael, L. H.

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