경희대학교
의과대학 의과학교실 응급의학과* 및 일반외과,
병리학교실**.
생화학교실***. 동수원병원 일반외과****
김명천*·이석환·이상목·고영관*·고석환·홍성화·
윤
충,김윤화**·백형환***·조용호***·변영훈****
A
Study of Antioxidant Effect of Melatonin on the Animal Sepsis Model
Myung
Chun Kim, M.D*, Seok Hwan Lee, M.D., Sang Mok Lee, M.D., Young Gwan Ko* M.D.*, Sung
Wha Hong, M.D., Choong Yoon, M.D., Youn Hwa Kim, M.D.**, Hyung Hwan Haik,
M.D.***, Yong Ho Cho, M.D.***, Young Hoon Byon. M.D.***
Department
of Emergency Medicine*, General Surgery, Pathology** and
Biochemistry***, School of Medicine, Kyung Hee University, Department
of General Surgery, Dongsoowon Hospital****
Despite
the major advances in the management of critically ill patients, septic shock and
ensuing MODS continue to be the most common causes of death in the surgical intensive
care unit. Endotoxin in sepsis stimulates macrophages and immune cells, and these
stimulated cells secrete multiple cytokines such as TNF-α, IL-1β, and INF-γ and
these in tum stimulate polymorphonuclear leukocytes(PMNs). The stimulated PMNs easily
adhere to the vascular endothelial wall and secrete free oxygen radicals, which
destroy cell function by cellular membrane lipid peroxidation. The consecutive reactions
are responsible for the pathophysiologic consequences of septic shock.
Melatonin,
the major endocrine product of the pineal gland, was found to be an effective free
radical scavenger and antioxidant and may stimulate some important antioxidant enzymes.
i.e. superoxide dismutase, glutathione peroxidase and glutathione reductase. This
study focused on the effect of melatonin in rat sepsis model by using the Chaudry
method, cecal ligation and puncture(CLP) that the cecum was ligated with 3-0 silk
and punctured with 21-gauge needle twice.
Rats
were divided into 3 groups: the control group(Sham operation group), the ethanol-admin-istered
group, and the melatonin-administered group. There were eight rats in each group.
Melatonin l0mg/kg was administered subcutaneously every one hour. Parameters to
be checked were tumor necrosis factor(TNF-α) and IL-1β in rat serum and malondialdehyde(MDA),
xanthine oxidase, and histopathologic findings in the lung and the liver. Each parameter
was obtained 2, 4, 6 and l0 hours after operation by sacrificing the rats at that
time. The concentration of TNF-α increased persistently in sepsis induced groups
and was significantly lower (p<0.05) 2 hours after operation in the melatonin-administered
group (39.5±12.1pg/ml) than in the ethanol-administered group (82.0±9.1pg/ml)
and was lower 4, 6, and l0 hours after operation in the melatonin-administered group,
but this last data was not statistically significant. The concentration of IL-1β
in the melatonin-administered group was lower than that of the ethanol-administered
group, but this was not statistically significant.
The
concentration of MDA in the lung in the ethanol-administered and the melatonin-administered
group at l0 hours after operation was 199.3±51.l and 56.5±23.3 pmol/mg protein,
respectively, which indicates a statistically significant difference (ANOVA test,
p<0.001). The concentration of MDA in the liver 6 and 10 hours after operation
in the ethanol-administered and melatonin-administered groups was 260.6±38.5, 291.2±65.l
and 172.6±25.3, 148±9.1 pmol/mg protein, respectively, showing a statistically
significant difference. There was more of an elevation in the concentration of xanthine
oxidase in the lung and the liver of the ethanol-administered group, but it was
statistically insignificant. Histopathologic findings of the lung in the melatonin-administered
group 6 hours after operation showed intact alveoli and minimal infiltration of
polymorphonuclear leukocytes in alveoli and interstitial thickening with many PMNs
infiltrations and those of the liver in the melatonin-administered group showed
less infiltration of PMNs in the portal space.
In
conclusion, melatonin was considered to have an anti-oxidant activity, a scavenging
effect on free oxygen radical, and an inhibitory activity for an infiltration to
the lung and the liver, especially in the early septic period. Further studies on
the effect of a late septic period and the therapeutic dose of melatonin are needed.
Key
Words : Sepsis, Melatonin, Tumor necrosis factor |
