Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction.
To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (P<0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-alpha was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-alpha index in cardiomyocytes (r=0.08, P = 0.37), suggesting that TNF-alpha does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-alpha produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.
Akasaka
Yoshikiyo
Y
Department of Pathology, School of Medicine, Toho University, Ohta City, Tokyo, Japan. akasakay@med.toho-u.ac.jp
Morimoto
Noriko
N
Ishikawa
Yukio
Y
Fujita
Kazuko
K
Ito
Kinji
K
Kimura-Matsumoto
Masayo
M
Ishiguro
Shigeki
S
Morita
Hiroshi
H
Kobayashi
Yoshiro
Y
Ishii
Toshiharu
T
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000473:pathology; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D016753:Interleukin-10; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule