@article{3139248,
    title = "Apoptotic Death of Renal Tubular Cells in Experimental Sepsis",
    author = "Messaris, Evangelos and Memos, Nikolaos and Chatzigianni, Emmy and and Kataki, Agapi and Nikolopoulou, Marilena and Manouras, Andreas and and Albanopoulos, Konstadinos and Konstadoulakis, Manousos M. and Bramis, and John",
    journal = "Surgical Infections",
    year = "2008",
    volume = "9",
    number = "3",
    pages = "377-388",
    publisher = "MARY ANN LIEBERT INC PUBL",
    issn = "1096-2964, 1557-8674",
    doi = "10.1089/sur.2006.018",
    abstract = "Background and Purpose: Renal dysfunction attributable to sepsis was
long considered a result of hemodynamic instability and subsequent local
ischemia. Recent data show that apoptosis may be implicated also. The
purpose of this study was to evaluate the role of apoptosis and the
expression of the bax, bcl-2, caspase-8, and cytochrome c proteins in
the renal parenchymal cells of rats with sepsis.
Methods: Sepsis was induced using cecal ligation and puncture (CLP) in
62 male Wistar rats, which were euthanized 6, 12, 24, 36, 48, or 60 h
later. Ten sham-treated animals served as a control group. Another group
of 50 animals were subjected to CLP and then supervised for 60 h. Renal
apoptosis was evaluated using light and transmission electron
microscopy, in situ nick-end labeling (TUNEL), and flow cytometry using
7-amino-actinomycin D (7-AAD). Caspase-mediated apoptosis was assessed
using M30 antibody. The expression of the apoptosis-regulator proteins
B-cell lymphoma 2 (bcl-2), bcl-2-associated x protein (bax), caspase-8,
and cytochrome c was detected immunohistochemically.
Results: Sepsis increased inflammatory infiltration (p < 0.001) and
necrosis (p < 0.001) in renal parenchyma. Apoptosis was significantly
more common than in the kidneys of control animals (p = 0.02). Nuclei
stained by the TUNEL technique were predominant in the tubular cells of
non-survivors (p = 0.05). The time distribution of all types of cell
death was increased significantly 6 h after the induction of sepsis, and
declined subsequently. Caspase-generated cytokeratin 18 (CK18) new
epitope (M30) was significantly more abundant in the kidneys of animals
with sepsis than in control rats, with peaks at 6 h and 60 h
post-procedure (p < 0.001). In addition, cells initiating apoptosis were
significantly more common at 6 h than at 48 h post-CLP (p = 0.014).
Caspase-8 protein immunodetection followed the same time pattern as cell
death, increasing as early as 6 h post-CLP and decreasing thereafter (p
= 0.013). Bax protein expression was elevated significantly early in the
course of sepsis (p = 0.037), whereas the other members of the
mitochondrial-dependent pathway remained constant. Animals dying from
sepsis had a significantly greater prevalence of bax- (p = 0.037) and
caspase-8- (p = 0.031) immunoreactive renal cells.
Conclusion: Apoptosis in renal tissue was significantly more common in
animals with sepsis than in controls. The time distribution of cell
death markers showed a consistent pattern, making early sepsis the
likely initiator of the apoptotic events."
}