From the Section of Cardiovascular Sciences, Department of Medicine, The
Methodist Hospital and the DeBakey Heart Center, the Department of
Microbiology and Immunology, the Speros P. Martel Laboratory, Section of
Leukocyte Biology, Department of Pediatrics and Texas Children's
Hospital, Baylor College of Medicine, Houston, Tex, and the Department of
Pathology (R.N.S.), State University of New York at Buffalo.
Correspondence to Mark L. Entman, MD, Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza, M/S F-602, Houston, TX 77030-3498. E-mail mentman{at}bcm.tmc.edu
Background—Neutrophil-induced
cardiomyocyte injury requires the expression of myocyte
intercellular adhesion molecule (ICAM)-1 and ICAM-1–CD11b/CD18
adhesion. We have previously demonstrated interleukin (IL)-6 activity
in postischemic cardiac lymph; IL-6 is the primary stimulus
for myocyte ICAM-1 induction. Furthermore, we found that induction of
IL-6 mRNA occurred very early on reperfusion of the infarcted
myocardium. We hypothesized that the release of a preformed
upstream cytokine induced IL-6 in leukocytes infiltrating on
reperfusion.
Methods and Results—Constitutive expression of TNF-
Conclusions—Cardiac mast cells degranulate after myocardial
ischemia, releasing preformed mediators, such as histamine and
TNF-
© 1998 American Heart Association, Inc.
Basic Science Reports
Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-
, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion
and not
IL-1ß was demonstrated in the normal canine myocardium
and was localized predominantly in cardiac mast cells. Mast cell
degranulation in the ischemic myocardium was
documented by demonstration of a rapid release of histamine and TNF-
in the cardiac lymph after myocardial ischemia. Histochemical
studies with FITC-labeled avidin demonstrated degranulating mast cells
only in ischemic samples of canine myocardium.
Immunohistochemistry suggested that degranulating mast cells were the
primary source of TNF- in the ischemic
myocardium. In situ hybridization studies of reperfused
myocardium localized IL-6 mRNA in infiltrating mononuclear
cells and in mononuclear cells appearing in the
postischemic cardiac lymph within the first 15 minutes of
reperfusion. Furthermore, isolated canine mononuclear cells incubated
with postischemic cardiac lymph demonstrated significant
induction of IL-6 mRNA, which was partially blocked with a neutralizing
antibody to TNF-. . We suggest that mast cell–derived TNF- may be a crucial
factor in upregulating IL-6 in infiltrating leukocytes and initiating
the cytokine cascade responsible for myocyte ICAM-1 induction
and subsequent neutrophil-induced injury.
Key Words: cells • ischemia • reperfusion • myocardial infarction • cytokines
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L. Lu, Z. Gunja-Smith, J. F. Woessner, P. C. Ursell, T. Nissen, R. E. Galardy, Y. Xu, P. Zhu, and G. G. Schwartz Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H601 - H609. [Abstract] [Full Text] [PDF]
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 P. J. Wolters, M. Laig-Webster, and G. H. Caughey Dipeptidyl Peptidase I Cleaves Matrix-Associated Proteins and Is Expressed Mainly by Mast Cells in Normal Dog Airways Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 183 - 190. [Abstract] [Full Text]
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S. Belosjorow, R. Schulz, H. Dorge, F. U. Schade, and G. Heusch Endotoxin and ischemic preconditioning: TNF-alpha concentration and myocardial infarct development in rabbits Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2470 - H2475. [Abstract] [Full Text] [PDF]
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 K.-H. Chen, C.-C. Wu, S. Roy, S.-M. Lee, and J.-H. Liu Increased Interleukin-6 in Aqueous Humor of Neovascular Glaucoma Invest. Ophthalmol. Vis. Sci., October 1, 1999; 40(11): 2627 - 2632. [Abstract] [Full Text] [PDF]
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 S. Wan and A. P.C. Yim Cytokines in myocardial injury: impact on cardiac surgical approach Eur. J. Cardiothorac. Surg., September 1, 1999; 16(suppl_1): S107 - S111. [Abstract] [Full Text] [PDF]
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K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
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L. H. Michael, C. M. Ballantyne, J. P. Zachariah, K. E. Gould, J. S. Pocius, G. E. Taffet, C. J. Hartley, T. T. Pham, S. L. Daniel, E. Funk, et al. Myocardial infarction and remodeling in mice: effect of reperfusion Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H660 - H668. [Abstract] [Full Text] [PDF]
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J.L Mehta and D.Y Li Inflammation in ischemic heart disease: Response to tissue injury or a pathogenetic villain? Cardiovasc Res, August 1, 1999; 43(2): 291 - 299. [Full Text] [PDF]
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M. Gwechenberger, L. H. Mendoza, K. A. Youker, N. G. Frangogiannis, C. W. Smith, L. H. Michael, and M. L. Entman Cardiac Myocytes Produce Interleukin-6 in Culture and in Viable Border Zone of Reperfused Infarctions Circulation, February 2, 1999; 99(4): 546 - 551. [Abstract] [Full Text] [PDF]
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N. G. Frangogiannis, J. L. Perrard, L. H. Mendoza, A. R. Burns, M. L. Lindsey, C. M. Ballantyne, L. H. Michael, C. W. Smith, and M. L. Entman Stem Cell Factor Induction Is Associated With Mast Cell Accumulation After Canine Myocardial Ischemia and Reperfusion Circulation, August 18, 1998; 98(7): 687 - 698. [Abstract] [Full Text] [PDF]
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Z. Yang, R. J. Cerniway, A. M. Byford, S. S. Berr, B. A. French, and G. P. Matherne Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H949 - H955. [Abstract] [Full Text] [PDF]
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