Anesth Analg 2007;104:646-654
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000255288.68199.eb
CRITICAL CARE AND TRAUMA
Acupuncture Stimulation of ST36 (Zusanli) Attenuates Acute Renal but Not Hepatic Injury in Lipopolysaccharide-Stimulated Rats
Chin-Liang Huang, MD, PhD*,
Pei-Shan Tsai, PhD
,
Tao-Yeuan Wang, MD
,
Li-Ping Yan, PhD
,
Heng-Ze Xu, MD*, and
Chun-Jen Huang, MD, PhD||¶#
From the *Acupuncture and Moxibustion Institute, Nanjing University of Traditional Chinese Medicine, Nanjing, China; Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan; Institute of Molecular Biology, Nanjing University of Traditional Chinese Medicine, Nanjing, China; ||Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan; ¶Mackay Medicine, Management, and Nursing College, Taipei, Taiwan; and #Graduate Institute of Pharmacology, Taipei Medical University, Taipei, Taiwan.
Address correspondence and reprint requests to Dr. Chun-Jen Huang, Department of Anesthesiology, Mackay Memorial Hospital, 92 Sec. 2 Chung San N. Rd., Taipei 10449, Taiwan. Address e-mail to sean{at}ms2.mmh.org.tw.
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Abstract
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BACKGROUND: We sought to determine the effects of ST36 acupuncture on sepsis-induced kidney and liver injuries.
METHODS: A total of 120 rats were randomized into 10 groups: 1) lipopolysaccharide (LPS), 2) normal saline (N/S), 3) LPS + ST36, 4) ST36, 5) LPS + P-ST36, 6) P-ST36, 7) LPS + Sham, 8) Sham, 9) LPS + P-Sham, and 10) P-Sham groups. Rats in the LPS + ST36, ST36, LPS +Sham, and Sham groups received ST36 (designated as "ST36") or a nonacupoint (designated as "Sham") acupuncture for 30 min followed by LPS or N/S injection. Rats in the LPS + P-ST36, P-ST36, LPS + P-Sham, and P-Sham groups received LPS or N/S injection for 3 h followed by a 30 min of ST36 or a "nonacupoint" acupuncture. Rats were killed at 6 h after LPS injection.
RESULTS: LPS caused prominent kidney and liver injuries. The renal and hepatic nitric oxide (NO) concentrations and inducible NO synthase (iNOS) expression were also increased by LPS. ST36 acupuncture pretreatment significantly attenuated the LPS-induced kidney injury and the increases in renal NO concentration and iNOS expression. However, ST36 acupuncture pretreatment did not affect the LPS-induced liver injury and increases in hepatic NO concentration or iNOS expression. Furthermore, ST36 acupuncture performed after LPS did not affect the LPS-induced organ injuries or increases in NO concentration and iNOS expression.
CONCLUSIONS: ST36 acupuncture pretreatment significantly attenuated sepsis-induced kidney, but not liver, injury in rats, whereas ST36 acupuncture performed after sepsis induction had no protective effects against sepsis-induced organ injuries.
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Introduction
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Sepsis readily causes upregulation of inducible nitric oxide synthase (iNOS) and resultant nitric oxide (NO) overproduction (1). This overproduced NO subsequently initiates a cascade of inflammatory responses that lead to tissue injury and, eventually, multiple organ dysfunctions (1). Previous data indicated that therapies aiming at decreasing NO exposure can help reduce the pathological sequelae of inflammation (2).
Though the underlying mechanisms remain to be studied, increasing data indicate that acupuncture stimulation of ST36 (Zusanli) exhibited significant antiinflammatory effects. For instance, ST36 acupuncture has been shown to inhibit tumor necrosis factor-
(TNF-) production (3), attenuate trauma-induced immunosuppression (4), and reverse sepsis-induced neutrophil migration impairment in septic rats (5). ST36 acupuncture has also been shown to activate the parasympathetic efferent pathway (6), a pathway thought to have significant antiinflammatory effects against sepsis (7). All these data suggest the therapeutic potential of acupuncture stimulation of ST36 against sepsis.
The lungs, liver, and kidneys are three of the organs most vulnerable to sepsis (8). We have recently shown (9) that rats pretreated with ST36 acupuncture had less lung injury and less pulmonary iNOS expression during sepsis. However, the question of whether ST36 acupuncture has similar protective effects against sepsis-induced liver and kidney injuries remains unanswered. We thus conducted this intact animal study with the hypothesis that acupuncture stimulation of ST36 attenuates sepsis-induced liver and kidney injuries in septic rats. In addition, we also evaluated the effects of ST36 acupuncture on hepatic and renal iNOS expression. To extend the clinical use of ST36 acupuncture in sepsis, we also investigated the effects of ST36 acupuncture administered after induction of sepsis.
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METHODS
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A total of 120 adult male Sprague-Dawley rats (National Science Council, Taiwan) (200–250 g) were used for the experiments. All animal studies were approved by the Institutional Animal Use and Care Committee of Mackay Memorial Hospital and the care and handling of the animals were in accordance with National Institutes of Health guidelines.
Acupuncture Protocols
The acupuncture protocols were developed according to previously published protocols (3,5,9,10). Rats were lightly immobilized using special cages and handling to minimize stress. Manual acupuncture stimulation of ST36 was performed by inserting a pair of stainless steel pins 0.3 mm diameter with a depth of 1.5 mm into the bilateral ST36 acupoint (acupuncture point) (3,5,9,10). The ST36 acupoint was identified at the belly of the tibialis cranialis muscle below the cranial crest of the tibia (3,5,9,10). The needle was firmly gripped to identify "De-Qi." To control the effects of needle insertion, sham acupuncture was performed by needle stimulation of a nonacupoint that located the nearby ST36 in hamstring muscles (3,5,9,10). Rats that received ST36 acupuncture were designated as "ST36." Rats that received stimulation of a nonacupoint were designated as "Sham." The needle was twirled and twisted (>360°) in the clockwise and counter-clockwise rotations alternatively at a frequency of 60 turns/min for 1 min followed by a 1 min break throughout the 30 min of acupuncture stimulation, as we previously reported (10). Rats were allowed to acclimate to the stress of needle insertion for 30 min before the start of experiments.
Experimental Protocols
An independent research assistant generated the random allocation sequence using computerized software. For Study 1 (pretreatment study), rats were randomized to three groups: the ST36 group, the Sham group, and the no treatment group. Each group was further randomly assigned into one lipopolysaccharide (LPS) group and one normal saline (N/S) group, resulting in a total of six groups (LPS + ST36, ST36, LPS + Sham, Sham, LPS, and N/S; n = 12 in each group). For Study 2 (posttreatment study), the rats were randomly assigned to two groups, LPS group and the N/S group. The LPS and N/S groups were further divided into one group receiving ST-36 acupuncture posttreatment (P-ST36) and one group receiving sham acupuncture posttreatment (P-Sham), resulting in four groups (LPS + P-ST36, P-ST36, LPS + P-Sham, and P-Sham; n = 12 in each group). The random assignment sequence was concealed until data collection was completed. Research assistants who collected the physiologic measurements and performed the assays were blinded to the group assignments.
Modified from a previously published paper (11), we used the LPS injection model to induce sepsis. In brief, rats were treated with intraperitoneal (i.p.) injection of Escherichia coli endotoxin (LPS, 20 mg/kg, Serotype 0127:B8; Sigma-Aldrich, St. Louis, MO) to induce sepsis. According to our previous experience, this protocol caused significant hemodynamic alterations, acute organ injuries, and iNOS expression at approximately 5–6 h after LPS injection with a low average mortality rate of <1% (9). To serve as controls, rats in the N/S, ST36, P-ST36, Sham, and P-Sham groups received i.p. injection of an equal amount of N/S. In the LPS + ST36, LPS + Sham, ST36, or Sham group, stimulation of ST36 or a nonacupoint was preformed 1 h before LPS or N/S injection. In the LPS + P-ST36, LPS + P-Sham, P-ST36, or P-Sham group, a 30-min stimulation of ST36 or a nonacupoint was preformed 3 h after LPS or N/S injection.
The body temperature of each animal was maintained with a heating lamp. Mean arterial blood pressure (MAP) and heart rate (HR) were monitored using a small animal tail-cuff blood pressure analyzer (MK2000; Muromachi Kikai Co., Tokyo, Japan) every 2 h throughout the experiment. As the expression of iNOS mRNA in rat glomeruli has been shown to plateau at 4–6 h after administration of LPS (12), we decided to kill the rats with an injection of high-dose pentobarbital at 6 h after LPS or N/S injection.
Tissue Sample Collection
After removal, the left kidney and half of the liver tissues were snap frozen in liquid nitrogen and stored at –80°C for subsequent analysis. The right kidney and the second half of liver tissue were put in 10% formaldehyde for histopathological analysis.
Biochemical Analysis
The plasma concentrations of blood urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin were used to assess kidney and liver injuries (13).
Histopathological Analysis
The tissues were embedded in paraffin wax, serial sectioned, and stained with hematoxylin and eosin. According to morphological characteristics (e.g., interstitial edema, congestion, hemorrhage, or focal necrosis) and the number of polymorphonuclear neutrophil (PMN) per high-power field (HPF, 400x) in 10 randomly selected areas, the kidney and liver changes were classified as normal, mild, moderate, or severe inflammation by a pathologist blinded to the experiment.
Myeloperoxidase Activity Assay
Myeloperoxidase (MPO) activity of the harvested tissue samples was quantified, as we previously reported (14), to determine tissue injuries. In brief, snap-frozen tissue samples were homogenized in PE buffer and then centrifuged. The pellet was then resuspended in C-TAB buffer and then sonicated and centrifuged. The resultant supernatant was collected and incubated in a water bath for 2 h at 60°C. Spectrophotometric absorbance at 650 nm was measured and compared with a linear standard curve to determine the MPO activity.
NO Measurement
The sums of stable NO metabolites, nitrite, and nitrate were measured using chemiluminescence. The collected tissue samples were processed according to our previous report (15). The sample content of NO was quantified using a Sievers 280 NO analyzer (Sievers Inc., Boulder, CO). Operation of this equipment was performed in accordance with the manufacturer's manual.
Quantitative Real-Time Polymerase Chain Reaction
The iNOS mRNA concentrations in the harvested samples were quantified using quantitative real-time polymerase chain reaction (PCR). The assay was performed using the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA), SYBR green core reagent, and Ampli-Taq gold polymerase. Primer sequences for iNOS were modified in the same manner as in a previously published article (16). PCR was performed twice using 25 µL reactions, and cDNA loading was normalized to rat 18s rRNA. The amount of gene transcript was then measured using the comparative (2–
CT) method described by Applied Biosystems.
Immunoblotting Assay
Protein extraction and concentration measurement were performed according to our previous experiment (14). Equal amounts of protein (65 µg) were then loaded to Tris-glycine polyacrylamide gels and separated by electrophoresis. The proteins were then transferred to nitrocellulose membranes (Bio-Rad Laboratories, Hercules, CA). The membranes were then incubated in primary antibody solution of iNOS (monoclonal iNOS antibody, Transduction Laboratories, Lexington, KY) or ß-actin (as an internal standard, monoclonal ß-actin antibody, Novus Biologicals, Littleton, CO). Bound antibody was detected by chemiluminescence (ECL plus kit; Amersham Pharmacia Biotec, Piscataway, NJ). Densitometric techniques were performed to quantify the protein band densities using NIH software (Scion Corp., Frederic, MD).
Statistical Analysis
One-way analysis of variance (ANOVA) was used to determine the between-group differences. The Student- Newman-Keuls test was used for post hoc analysis. All data were presented as mean ± sd. The significance level was set as 0.05. A commercial software package (SigmaStat for Windows Version 3.1, SPSS, Chicago, IL) was used for data analysis.
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RESULTS
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Hemodynamic data
All rats survived the experiment. The baseline HR and MAP in each group were similar. The HR and MAP in the N/S, ST36, P-ST36, Sham, and P-Sham groups remained stable throughout the experiment. In contrast, exposure to LPS (the LPS group) significantly increased the HR at 2 h after injection and decreased the MAP at 4 h after injection. HR at the end of the experiment in the LPS group was significantly higher than that in the N/S group (Table 1). In contrast, MAP at the end of the experiment in the LPS group was significantly lower than that in the N/S group (Table 1). Stimulation of ST36 or a nonacupoint 1 h before or 3 h after LPS injection did not affect the effects of LPS on HR and MAP as the HR and MAP in the LPS, LPS + ST36, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were comparable (Table 1).
Biochemical Analyses
The BUN, Cr, AST, ALT, and total bilirubin concentrations in the N/S, ST36, P-ST36, Sham, and P-Sham groups were low (Table 2). The BUN, Cr, AST, ALT, and total bilirubin concentrations in the LPS group were significantly higher than those in the N/S group (Table 2). Though higher than those in the N/S group, the BUN and Cr concentrations in the LPS + ST36 group were significantly lower than those in the LPS group (Table 2). In contrast, the AST, ALT, and total bilirubin concentrations in the LPS + ST36 group were similar to those in the LPS group (Table 2). The BUN, Cr, AST, ALT, and total bilirubin concentrations in the LPS, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were comparable (Table 2).
Histopathological Analysis
Histopathological analyses revealed normal-to-mild inflammatory changes in the kidneys and liver from the N/S, ST-36, P-ST36, Sham, and P-Sham groups (Figs. 1A and D). In contrast, 75% (9/12) of the kidneys in the LPS group had severe inflammatory changes (Fig. 1C) and 25% (3/12) had moderate inflammatory changes (Fig. 1B). Similar results were observed in the LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups. In contrast, 25% (3/12) of the kidneys in the LPS + ST36 group had severe inflammatory changes (Fig. 1C) and 75% (9/12) had moderate inflammatory changes (Fig. 1B). Analyses also revealed that 83% (10/12) of the livers in the LPS group were classified as having severe inflammation (Fig. 1F) and 17% (2/12) as having moderate inflammation (Fig. 1E). Similar results were observed in the LPS + ST36, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups.
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Figure 1. Microscopic findings illustrate kidney and liver inflammation in kidney and liver tissues stained with hematoxylin-eosin (400x). According to the morphological characteristics, changes in the kidneys and livers were classified as normal, mild, moderate, or severe inflammation. (A) Representative microscopic findings of normal to mild kidney inflammation. (B) Representative microscopic findings of moderate kidney inflammation. (C) Representative microscopic findings of severe kidney inflammation. (D) Representative microscopic findings of normal to mild liver inflammation. (E) Representative microscopic findings of moderate liver inflammation. (F) Representative microscopic findings of severe liver inflammation.
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PMN Infiltration and MPO Activity
The number of PMN and MPO activity in the kidneys and livers from the N/S, ST36, P-ST36, Sham, and P-Sham groups were low (Figs. 2 and 3). In contrast, renal PMN infiltration and MPO activity in the LPS group were significantly higher than those in the N/S group (approximately 11-fold and twofold higher; Figs. 2 and 3). Renal PMN infiltration and MPO activity in the LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were similar to those in the LPS group. Though significantly higher than those in the N/S group, renal PMN infiltration and MPO activity in the LPS + ST36 group were significantly lower than those in the LPS group (Figs. 2 and 3). Hepatic PMN infiltration and MPO activity in the LPS group were also significantly higher than those in the N/S group (approximately 18-fold and fourfold higher; Figs. 2 and 3). Furthermore, hepatic PMN infiltration and MPO activity in the LPS + ST36, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were similar to those in the LPS group (Figs. 2 and 3).
NO Measurement
The NO concentration in the kidneys and livers from the N/S, ST36, P-ST36, Sham, and P-Sham groups were low (Fig. 4). Renal and hepatic NO concentrations in the LPS group were significantly higher than those in the N/S group (approximately twofold and fourfold higher; Fig. 4). In addition, hepatic NO concentrations in the LPS, LPS + ST36, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were comparable (Fig. 4). Renal NO concentrations in the LPS, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were also comparable. However, renal NO concentrations in the LPS + ST36 group were significantly less than those in the LPS group (Fig. 4).
Expression of iNOS
The iNOS mRNA and protein concentrations in the kidneys and livers from the N/S, ST-36, P-ST36, Sham, and P-Sham groups were low (Figs. 5, 6A and B). Renal and hepatic iNOS mRNA concentrations in the LPS group were significantly higher than those in the N/S group (approximately threefold and 4.5-fold higher; Fig. 5). Similarly, renal and hepatic iNOS protein concentrations in the LPS groups were significantly higher than those in the N/S group (approximately 2.5-fold and fivefold higher; Figs. 6A and B). In addition, hepatic iNOS mRNA and protein concentrations in the LPS, LPS + ST36, LPS + P-ST36, LPS + Sham, and LPS + P-Sham groups were comparable (Figs. 5 and 6B). Renal iNOS mRNA and protein concentrations in the LPS, LPS + P-ST36, and LPS + P-Sham groups were also comparable (Figs. 5 and 6A). However, renal iNOS mRNA and protein concentrations in the LPS + ST36 group were significantly less than those in the LPS group (Figs. 5 and 6A). Though renal iNOS protein concentrations in the LPS + Sham group were similar to those in the LPS group (Fig. 6A), renal iNOS mRNA concentrations in the LPS + Sham group were significantly less than those in the LPS group (Fig. 5). Renal iNOS mRNA concentrations in the LPS + ST36 group were significantly less than those in the LPS + Sham group (Fig. 5).
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DISCUSSION
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Data from this study demonstrated that pretreatment of ST36 acupuncture significantly attenuated LPS-induced kidney injury. Pretreatment of ST36 acupuncture also significantly attenuated LPS-induced upregulation of renal iNOS and NO biosynthesis. These data suggest the antiinflammatory potential of the prophylactic use of ST36 acupuncture against sepsis.
Regulation of iNOS expression is complex (17,18). For instance, iNOS expression requires activation of nuclear factor (NF)-
B (17,18). In addition, TNF-, interleukin (IL)-1ß, and interferon-
synergistically activate iNOS expression (17,18). Although the question of whether the effect of ST36 acupuncture on iNOS expression involves NF-B remains to be answered, ST36 acupuncture has been reported to significantly increase the serum level of adrenocortical hormones (19)—the hormones that inhibit NF-B (20). Previous data also demonstrated that ST36 stimulation significantly attenuated the production of TNF- (3). Since NF-B is the crucial factor for maximal transcription of a wide array of proinflammatory molecules, including TNF- and iNOS (21), we speculate that ST36 acupuncture may act through inhibiting NF-B activation to attenuate iNOS expression and resultant NO biosynthesis. In addition, we (15) previously demonstrated that the surge of plasma and hepatic NO concentrations in LPS-treated rats occurred as early as 3 h after LPS exposure, suggesting an early activation of NF-B after exposure to LPS. This presumed early activation of NF-B may explain, at least in part, our observation that administration of ST36 acupuncture after sepsis exhibits no significantly protective effect against sepsis-induced kidney injury. In the present study we chose to administer ST36 posttreatment at 3 h after exposure to LPS and the rats were then killed 3 h after ST36 posttreatment. One may argue that posttreatment ST36 acupuncture might have exhibited protective effects if a longer duration (e.g., 6 h) had been allowed between the administration of ST36 acupuncture and termination of the experiment. However, we previously demonstrated that longer LPS exposure time tended to induce more NO production in stimulated rats (15) and thus it is unlikely that ST36 posttreatment will exhibit beneficial effects after a longer LPS exposure.
Stimulation of the parasympathetic efferent pathway has been shown to decrease TNF- production in septic rats (22). Agonists of cholinergic receptor, such as acetylcholine, nicotine, and muscarine, have also been reported to attenuate the production of TNF-, IL-1ß, IL-6, and IL-18 in activated macrophages (7,22). This has been termed the "cholinergic antiinflammatory pathway " by Pavlov and Tracey (7). They further identified the 7 subunit of the nicotinic receptor as essential in mediating the effects of the cholinergic antiinflammatory pathway (23). ST36 acupuncture has been shown to significantly activate the parasympathetic efferent pathway in freely moving conscious rats (6). Judging from these data, we speculate that ST36 acupuncture may also act through activating the cholinergic antiinflammatory pathway and, perhaps, the 7 subunit of nicotinic receptor to exert its antiinflammatory effects. In addition, manipulations that activate the cholinergic antiinflammatory pathway, such as vagal electrostimulation or a specific agonist of the 7 subunit of nicotinic receptor, may very likely offer alternative and clinically relevant solutions to acupuncture. As a part of the innate immune system, the cholinergic antiinflammatory pathway has also been reported to be activated by endotoxin (7). We, thus, further speculate that stimulation of the cholinergic antiinflammatory pathway after endotoxin installation may not increase the antiinflammatory capacity of the host. This concept may also explain our observation that administration of ST36 acupuncture before, but not after, sepsis exhibits a protective effect against sepsis-induced kidney injury.
The liver is the major response organ for intestinally derived infection (24). The liver is also the major response organ for i.p. inoculation of E. coli endotoxin (25). We observed higher PMN infiltration and higher MPO activity in the liver than in the kidneys in LPS-stimulated rats, suggesting that the former was affected by endotoxin to a greater extent than the latter. Our data also demonstrated that pretreatment with ST36 acupuncture had no effect on liver injury, hepatic iNOS expression, and hepatic NO production induced by LPS. The observed discrepancy in response to ST36 acupuncture pretreatment between the liver and kidneys suggests an organ-specific effect of ST36 acupuncture in attenuating LPS-induced iNOS expression and resultant NO over-production. Alternatively, as the magnitude of organ injuries induced by LPS tends to be related to the doses of LPS being administered (26), it is likely that ST36 acupuncture might have prevented liver injury had a smaller dose of LPS been used to induce sepsis.
Acupuncture stimulation itself causes significant stress in animals, including immobilization and needle insertion (19). In addition, the stress of immobilization and/or needle insertion causes significant, but transient, increases in the production of adrenocortical hormones (19,27). To avoid interference, we chose to lightly immobilize the rats using special cages and handling to minimize the stress of immobilization. The rats were also allowed to acclimate to the stress of needle insertion for 30 min before the experiments. We believe this should have significantly reduced the procedural stress and allowed ST36 acupuncture to demonstrate its effects. This idea was supported by our data that rats in the LPS + Sham and LPS groups had similar tissue injury, iNOS protein concentrations, and NO production. However, judging from the data that renal iNOS mRNA concentrations in the LPS + Sham group were significantly less than those in the LPS group, we speculate that stress effects, though minimal, were not completely abolished. Our data also revealed that real-time PCR, but not immunoblotting, identified renal iNOS concentration differences between the LPS + ST36 and LPS + Sham groups.
Several limitations of our study are likely to have affected outcomes and clinical applicability. First, we used a LPS injection model to induce sepsis. The pathophysiology of monomicrobial (e.g., LPS injection) and that of polymicrobial-induced sepsis (e.g., cecal ligation and puncture) are different (11). Therefore, the effects of ST36 acupuncture stimulation reported in this study may not necessarily apply to animals treated with the polymicrobial sepsis models. Second, this study did not use specific iNOS inhibitors or NO scavengers to further elucidate the role of the iNOS/NO pathway. Therefore, no definitive cause- effect relationship can be drawn from our data. Third, though our data clearly demonstrated the beneficial effects of ST36 acupuncture pretreatment against LPS-induced renal injury, the optimal time lapse required before acupuncture pretreatment can exert its antiinflammatory effects, and this remains to be determined. In addition, the question of whether pretreatment with ST36 acupuncture has prolonged antiinflammatory effects was not investigated in this study. Therefore, the clinical relevance of acupuncture is yet to be determined. Fourth, this study only investigated the effects of ST36 acupuncture. It is likely that incorporation of an additional acupoint may increase the protective effects of ST36 acupuncture against sepsis (4).
In summary, data from this study demonstrated that pretreatment with ST36 acupuncture significantly attenuates sepsis-induced kidney, but not liver, injury in LPS-stimulated rats. In addition, ST36 acupuncture administered after the induction of sepsis had no beneficial effects against sepsis-induced kidney injury.
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Footnotes
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Accepted for publication November 20, 2006.
Supported by Mackay Memorial Hospital grant MMH 95105.
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Abstract
Introduction
