Departments of 1 Emergency and Critical Care Medicine and 3 Anatomy, School of Medicine, Keio University, Tokyo 1608582; and 2 Central Pharmaceutical Research Institute, Japan Tobacco Incorporated, Osaka, Japan 5691125
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ABSTRACT |
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Many patients who
experience surgical stress, including burn injury, become susceptible
to severe sepsis and septic organ dysfunction, which remains the
primary contributor to morbidity and mortality in burn patients. In the
present study, we developed a murine model of burn-primed sublethal
endotoxemia by producing a 15% BSA full-thickness burn on the dorsum
of BALB/c mice under ether anesthesia and administering 10 mg/kg of LPS
intravenously on day 11 to model endotoxemia. The prior burn
injury in this model induced two-peaked production of cytokines,
TNF-, and macrophage inflammatory protein-2 at 2 and 12 h after
LPS administration, and it was associated with increased mortality. We
also assessed the effect of pharmacological modulation with cytokine
synthesis inhibitors prednisolone and JTE-607 and found that
pretreatment with them attenuated later cytokine production and
decreased mortality after LPS administration. We speculate that the
prior burn injury primed the mice for the secondary insult via cytokine
production. These results also suggested that an anticytokine strategy
might serve as a novel prophylactic therapy for septic organ
dysfunction in burn-primed patients.
two-hit phenomenon; priming; systemic inflammatory response syndrome; chemokine; JTE-607
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INTRODUCTION |
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THE SEVERE
COMPLICATIONS that occur after burn injury are divided into two
phases according to the time after the burn insult. Early complications
during the first week postburn are mainly characterized by hypovolemic
shock, shock-induced renal failure, and burn wound infection
(20). Great advances in fluid management based on
hemodynamic monitoring (2, 33), widespread use of early
excision, and the development of new wound care materials (30,
31) over the last three decades have reduced mortality, especially during the first week. The late complications are mainly sepsis and the secondary multiple organ dysfunction syndrome (MODS), which remain the primary contributors to morbidity and mortality in
burn patients (3). Similarly, it is well known that many patients who experience hemorrhagic shock, major trauma, or surgery become susceptible to severe sepsis and MODS. A "two-hit"
phenomenon has recently been proposed to account for the development of
MODS in critically ill surgical patients, in which burn insult, major trauma, or surgery is designated as the "first hit" and the inducer of amplified responses, such as local and systemic bacterial infection, is referred to as the "second hit" (9, 25). These
accelerated responses are assumed to be attributable to the endotoxemia
that results from "burn wound sepsis" or "bacterial
translocation" and to overproduction of proinflammatory cytokines.
Because a number of investigators have found that a variety of
biochemical mediators, including cytokines, are involved in these
pathophysiological mechanisms and the development of burn injury
(4), pharmacological modulation with anti-inflammatory
drugs, particularly cytokine synthesis inhibitors, may serve as an
effective strategy for prevention of tissue injury and organ
dysfunction as a result of the two-hit phenomenon. We used two
independent cytokine synthesis inhibitors, prednisolone (PSL) and an
N-benzoyl-L-phenylalanine derivative, JTE-607,
in the current study. Although PSL is an established anti-inflammatory
glucocorticoid that inhibits both pro- and anti-inflammatory cytokine
synthesis in monocytes (19), glucocorticoids also inhibit T lymphocyte production of cytokines, such as interleukin (IL)-2 and
interferon (IFN)- (32), phagocytosis, and the secretion of reactive oxygen species (ROS) by macrophages (6), which are pivotal to self- defense. Accordingly, treatment with
glucocorticoids may increase the risk of infection (1).
JTE-607 was discovered as a novel low molecular inhibitor of the
synthesis of multiple cytokines that potently inhibits the production
of tumor necrosis factor (TNF)-
, IL-1
, IL-6, IL-8, and IL-10 by
lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear
cells (PBMCs). JTE-607 is less immunosuppressive than
glucocorticoids insofar as it does not inhibit the production of IL-2
and IFN-
by T lymphocytes, phagocytosis, ROS production, or major
histocompatibility complex class II antigen expression by human PBMCs
(18).
In the present study, to elucidate the pathophysiological mechanisms of
the two-hit phenomenon, we developed a murine model of burn-primed
sublethal endotoxemia and analyzed plasma and lung cytokines in
addition to mortality. We determined two proinflammatory cytokines,
TNF- and macrophage inflammatory protein-2 (MIP-2), in this study,
because the former is the initial key mediator of sequential
inflammatory events, and the latter is a murine homolog of human IL-8,
a dominant neutrophil chemotactic mediator in various
neutrophil-mediated acute inflammations (11, 29). We also
assessed the effect of pharmacological modulation with the two cytokine
synthesis inhibitors.
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MATERIALS AND METHODS |
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Animal Preparations
Male BALB/c mice (Charles River, Yokohama, Japan) weighing 23-28 g (7 wk old) were caged in an environment in which the temperature and relative humidity were controlled, and a 12-h light/dark cycle was maintained. They were given free access to standard mouse feed and water throughout the course of the experiments. Animals were randomized to a sham-burn group and a burn group. On the day before the experiments, the dorsum of all animals was shaved under pentobarbital anesthesia (50 mg/kg in 0.25 ml 0.9% normal saline solution, intraperitoneally). Under effective ether anesthesia, the animals were placed in a template, and the shaved area was exposed to steam at 100°C for 5 s, producing a burn of ~15% of their total body surface area (TBSA) (27). This method produces a histologically proven full-thickness nonlethal burn injury (unpublished observation). Burn wounds became covered with eschar, and there was no evidence of infection macroscopically. Sham-burn animals were similarly anesthetized and shaved but not exposed to steam. Immediately after burn injury (or sham), all animals received fluid resuscitation with 4 ml of normal saline solution intraperitoneally and were returned to the same conditions after the procedures. No analgesics were used during the experiment, because full-thickness burns do not cause pain, and analgesics affect immunological responses. On day 11 after the sham-burn or burn injury, a 10 mg/kg dose of LPS (Escherichia coli 0111:B4 endotoxin; Sigma Chemical, St. Louis, MO) in 10 ml/kg of normal saline solution was administered intravenously into all animals to model endotoxemia after burn injury. All animal studies were approved by the Laboratory Animal Care and Use Committee of Keio University School of Medicine.Preparation of Compounds to Modulate Cytokine Synthesis
We used two independent anti-inflammatory drugs, PSL (Shionogi, Osaka, Japan) and JTE-607 (Japan Tobacco, Tokyo, Japan), to inhibit cytokine synthesis. PSL (3 mg · kgExperimental Protocols
Experiment 1.
The experimental protocol of the initial study is shown in Fig.
1. Mice were randomly divided into a
sham-LPS group and a burn-LPS group, and LPS was administered
intravenously on day 11 after the sham-burn or burn injury.
The first series of experiments was performed to determine survival at
72 h after LPS administration in both groups (n = 4, each group). The second series of experiments was designed to
determine the time course of the changes in cytokine levels up to
16 h after LPS administration to the sham-burned and burned mice.
The animals were killed at 0, 2, 8, 12, and 16 h after LPS
administration to obtain blood and lung samples (n = 4, each group).
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Experiment 2.
The protocol of experiment 2 was designed to determine
whether cytokines are involved in the mechanism of the combined effect of burn insult and endotoxin in this murine model by investigating the
effects of cytokine synthesis inhibitors PSL and JTE-607. The study
design and experimental protocol of the second study are shown in Fig.
2. Mice were randomly divided into four
groups: a sham-LPS (sham) group, burn-LPS group (positive control,
PCTL), a PSL group, and a JTE-607 (JTE) group. In the PCTL, PSL, and JTE groups, 15% of TBSA full-thickness burn was created on the dorsum.
After the burn injury, PSL in the PSL group and JTE-607 in the JTE
group were injected subcutaneously daily for 10 days before LPS
administration. A 10 ml/kg dose of 5% mannitol as the vehicle was
injected by similar methods in the sham group and the PCTL group. On
day 11, at 1 h after the final injection of PSL,
JTE-607, or vehicle, LPS was administered intravenously to model
endotoxemia. The first series of experiments was performed to determine
survival up to 72 h after LPS administration in each group
(n = 10, each group). The second series of experiments
was designed to determine the cytokine levels (n = 8, each group), gene expression (n = 4, each group),
myeloperoxidase (MPO) activity (n = 8, each group), and
histopathological findings at 12 h after LPS administration to
each group. Because the dose of LPS used in this experiment was
sublethal, we did not examine the effect of two anti-inflammatory
drugs, PSL and JTE-607, on endotoxemic mice without prior burn insult.
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Sample Collection and Histopathological Examination
Mice were killed under effective ether anesthesia. Blood samples were collected by heart puncture. After being centrifuged at 400 g for 10 min, the plasma samples were removed and stored atCytokine Determination by ELISA
The TNF-Quantitation of MIP-2 mRNA by Real-Time RT-PCR
mRNA expression in lung tissue was determined by a real- time RT-PCR. The MIP-2 mRNA level is expressed as a relative ratio to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA level, as described previously (26). Briefly, total RNA was extracted from each lung tissue with RNAeasy kits (Qiagen, Germany), and single-stranded cDNA was synthesized by Moloney murine leukemia virus reverse transcriptase (GIBCO BRL, Rockville, MD) with oligo(dT)20 primer. Gene expression was measured by a quantitative PCR method with a dual-labeled fluorogenic probe and 7700 Prism sequence detector (Perkin Elmer, Foster City, CA) as proposed by Gibson and coworkers (16). The probe was designed between the forward and reverse primer sites and labeled with a reporter fluorescent dye (6-carboxyfluorescein) at the 5' end and a quencher fluorescent dye (6-carboxy-tetramethyl rhodamine) at the 3' end. Accumulation of PCR products was detected directly by monitoring the increase in fluorescence of the reporter dye.Measurement of MPO Activity
MPO activity in the supernatants of the lung tissue was assayed by a standard spectrophotometric technique (7). A 20-µl volume of test samples or standard MPO (Sigma Chemical) was mixed with 430 µl of acetate buffer (pH = 5.4) containing 1.56 mM tetramethylbenzidine (Dojin, Kumamoto, Japan), 50 µl of 3 mM hydrogen peroxide (Wako), and 20 µl of 300 U/ml catalase (Wako). Then, 2 ml of 0.2 N acetate was added to the samples, and the absorbance change atStatistics
The differences between cytokine levels at various times were analyzed by the unpaired t-test. Survival within 72 h was analyzed by the Cox-Mantel test. The cytokine levels, gene expression, and MPO activity of the samples were analyzed by a one-way ANOVA followed by Fisher's protected least significant differences test. A P value of <0.05 was considered significant. All data are expressed as means ± SE of the mean values unless otherwise specified. ![]() |
RESULTS |
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Prior Burn Insult Decreases Survival and Induces a Two-Peaked Cytokine Increase After LPS administration
In the survival study, all four mice (100%) in the sham-LPS group had survived at 72 h after LPS administration, but none of the four mice (0%) in the burn-LPS group survived. LPS administration to burned mice resulted in poor survival. Figure 3, A and B, indicates the time course of the changes in plasma cytokine TNF-
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PSL and JTE-607 Improved Survival Within 72 h After LPS Administration
The Kaplan-Meier survival curves up to 72 h after LPS administration are shown in Fig. 4. All 10 mice (100%) in the sham group survived at 72 h after LPS administration, whereas none of the 10 (0%) survived in the PCTL group, the same as in the previous results. Five of the 10 mice (50%) in the PSL group and 7 of the 10 mice (70%) in the JTE group survived. Pretreatment with PSL and JTE-607 significantly improved survival within 72 h after LPS administration.
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PSL and JTE-607 Attenuated Acute Lung Injury and Decreased Lung MPO Activity
The histopathological findings in the lung in the animals with and without prior burn injury are shown in Fig. 5, A and B. LPS administration resulted in pulmonary edema associated with neutrophil emigration into the interstitium and alveolar space. The severity of pulmonary edema and the increase in neutrophil emigration into the lungs were more prominent in the PCTL group (Fig. 5B) than in the sham group (Fig. 5A) but were obviously attenuated in the PSL group (Fig. 5C) and the JTE group (Fig. 5D). Figure 7C shows the MPO activity in the lung tissue in each group. MPO activity in the PCTL group (0.574 ± 0.051 U/mg) was significantly higher than in the sham group (0.405 ± 0.022 U/mg, P < 0.005), also indicating neutrophil accumulation in the lungs. Lung MPO activity in the PSL group (0.244 ± 0.016 U/mg) and JTE group (0.257 ± 0.032 U/mg) was significantly lower (P < 0.005, respectively), corroborating the mitigation of neutrophil accumulation.
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Plasma TNF- and MIP-2 Levels Were Attenuated by PSL and JTE-607
at 12 h After LPS Administration
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Lung MIP-2 Levels and Gene Expression Were Attenuated by PSL and JTE-607 at 12 h After LPS Administration
Figure 7A shows the MIP-2 levels in the right lung tissue homogenate of each group. The MIP-2 levels in the PCTL group (142.5 ± 12.4 pg/mg) were higher than in the sham group (70.0 ± 7.5 pg/mg, P < 0.005), but the levels in the PSL group (11.6 ± 1.5 pg/mg) and JTE group (38.9 ± 7.3 pg/mg) were lower than in the PCTL group (P < 0.005, respectively). Figure 7B shows the expression of MIP-2 mRNA in the right lung in each group as a ratio to that of GAPDH (MIP-2/GAPDH mRNA ratio). The MIP-2/GAPDH mRNA ratio in the PCTL group (0.975 ± 0.048) was higher than in the sham group (0.345 ± 0.135, P < 0.05), but the ratios in the PSL group (0.052 ± 0.009) and JTE group (0.075 ± 0.033) were lower than in the PCTL group (P < 0.005, respectively).
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DISCUSSION |
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We developed a murine model of burn-primed sublethal endotoxemia
in this study and found that prior burn injury induced two-peaked production of cytokines after LPS administration 11 days after the burn
injury and that it was associated with increased mortality. We also
showed that pretreatment with two independent anti-inflammatory drugs,
PSL and JTE-607, attenuated the later cytokine production and decreased
mortality after LPS administration. We therefore speculate that prior
burn injury primed the mice for secondary insult through production of
inflammatory cytokines, such as TNF- and MIP-2. The results also
suggest that an anticytokine strategy might serve as a novel
prophylactic therapy for septic organ dysfunction in patients primed by
burns or other insults.
Burn-Primed Endotoxemia and the Two-Hit Phenomenon
This study demonstrates that secondary administration of a sublethal dose of LPS 11 days after the injury induced sustained production of TNF-With regard to initial burn insult, it is reasonable to hypothesize
that the injured skin or subcutaneous tissue plays a major role in
inducing the augmented inflammatory response, including dysregulated
cytokine production, which resulted in organ dysfunction, particularly
ALI. This hypothesis is supported by the finding that early excision
and grafting reduce TNF- production in animal models (10,
28) and improve the survival in clinical studies (30,
31). The mechanisms of augmented cytokine production may also be
related to the ischemia-reperfusion injury of the related area,
and it is quite unlikely that cytokine synthesis inhibitors were
directly associated with wound healing during the observation period in
this study, since we did not find any differences in the burned area
among treated and untreated groups.
In the present study, we administered LPS intravenously as the second
hit, and the increased mortality was associated with sustained
production of TNF- and MIP-2 in our model. Clinically, systemic
infection as a complication or detection of plasma LPS frequently occur
in burn patients, and they are thought to be attributable to the burn
wound or bacterial translocation (34). There is a study
showing that higher levels of plasma endotoxin are associated with
poorer outcome (36). Although it did not show a direct
association between the augmented cytokine production and poor outcome
of burn patients, it is possible to hypothesize that higher levels of
LPS induced higher production of proinflammatory cytokines.
ALI as the Outcome of Accelerated Inflammatory Response
An augmented inflammatory response has also been observed in animal models of ALI. Hemorrhagic shock and resuscitation 1 h before LPS administration has been reported to induce augmented production of lung cytokine-induced neutrophil chemoattractant (CINC), but not MIP-2, and to subsequently induce ALI (12). Acid aspiration 24 h before LPS administration has been shown to exaggerate ALI and induce a greater increase in plasma TNF-Sepsis and sepsis-related MODS, particularly ALI, have recently become major complications after burn injury, and they are considered to be the primary contributor to morbidity and mortality (3). Because the onset of ALI usually occurs more than a week later (8), we think our model is relevant to actual burn patients clinically.
Chemokines in ALI
The proinflammatory cytokine MIP-2, chosen as a major parameter in our investigation, is a member of the C-X-C chemokine family and a murine homolog of human IL-8 (11, 29). IL-8 is well recognized as a key mediator in various inflammatory lung diseases, including acute respiratory distress syndrome (ARDS) (24) and inhalation injury (14). High levels of proinflammatory cytokines, TNF-The IL-8 family, including MIP-2, exhibits potent neutrophil chemotactic activity, and its members are key mediators in recruiting neutrophils, which play a major role in tissue injury and host defense against various infections (13, 17). The accumulation of neutrophils in the lung tissue of PCTL mice was indicated from the increase in lung MPO activity, and ALI was confirmed histopathologically after LPS administration. On the basis of these findings that lung MIP-2 production was increased and its inhibition attenuated ALI, we speculate that MIP-2 induced neutrophil-mediated ALI in our model. By contrast, these findings were minimal in the sham group. We conclude that the prior burn insult triggered an exaggerated response to sublethal LPS through an as yet unidentified mechanism.
Pharmacological Modulation With Cytokine Synthesis Inhibitors
In the two-hit phenomenon, initially less severely injured patients eventually develop MODS as a result of an exaggeration of their inflammatory response caused by a second or subsequent insult, such as infection (9, 25). If our hypothesis explaining the two-hit phenomenon is valid, that is, if the burn-primed hosts produce greater amounts of cytokines than in ordinary sepsis, the modulation of the exaggerated response with anti-inflammatory drugs, particularly cytokine synthesis inhibitors, should improve organ dysfunction.Glucocorticoids, a class of multifunctional anti-inflammatory drugs,
are well known for their ability to potently inhibit the synthesis of
various proinflammatory cytokines (19). Administration of
dexamethasone inhibited TNF and IL-1 synthesis and improved survival in
a murine model of septic shock (5). In
corticosteroid-treated patients with ARDS, survivors were demonstrated
to show greater reductions in plasma and BAL TNF-, IL-1
, IL-6,
and IL-8 levels, especially in the later phase of ARDS, compared with
the nonsurvivors, indicating a dominant role of inflammatory
cytokines in worsening the outcome of ARDS (21). JTE-607
is a newly developed small molecule that targets proinflammatory
cytokine production by monocytes (18). Pretreatment with
two independent cytokine synthesis inhibitors, PSL and JTE-607,
decreased the plasma and lung cytokine levels as well as lung cytokine
production, and these changes were associated with attenuation of ALI
and decreased mortality.
Although the mechanism by which prior burn insult induces sustained cytokine production is unknown, we hypothesize that augmented production of these cytokines is the major mechanism responsible for the ALI and high mortality in this model. Furthermore, we predict that pharmacological modulation of cytokine synthesis immediately after the burn insult will serve as an effective means of preventing ALI and other types of organ dysfunction in primed patients. However, it is unknown whether pretreatment with cytokine synthesis inhibitors, particularly PSL, will increase the risk of infection in the long term.
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ACKNOWLEDGEMENTS |
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We thank Kazuko Nakane and Kenichi Inushima for technical help.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Fujishima, Dept. of Emergency and Critical Care Medicine, School of Medicine, Keio Univ., 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan (E-mail: fujishim{at}sc.itc.keio.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 27, 2002;10.1152/ajplung.00108.2002
Received 11 April 2002; accepted in final form 24 September 2002.
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