Single-Stage Surgical Treatment of Acute Type A Aortic Dissection and Blunt Abdominal Trauma: A Case Report.

A 53-year-old man suddenly developed chest and back pain while driving, resulting in an accident. Computed tomography revealed acute type A aortic dissection with malperfusion of the left lower extremity, retroperitoneal extravasation, hematoma in the anterior mediastinum, and ascites in the rectovesical pouch. Exploratory laparotomy before aortic repair revealed intestinal perforation and retroperitoneal bleeding, which were repaired, and an ascending aortic replacement was performed. Visceral trauma with active bleeding should be treated with priority, even if the need for systemic heparinization accompanies acute type A aortic dissection during surgery for aortic dissection.

Successful Surgical Repair of Type A Acute Aortic Dissection in a Patient with Vascular Ehlers-Danlos Syndrome.

Surgery for vascular complications of a patient with vascular Ehlers-Danlos syndrome (vEDS) is challenging due to the fragility of the associated tissues. In this study, we present a type A acute aortic dissection case in a patient with vEDS successfully treated via total arch replacement. A 42-year-old woman was transferred to our hospital 10 days after the onset of symptoms and underwent emergency surgery. Intraoperative findings revealed severe inflammatory changes without tissue fragility that is distinctive of vEDS. The postoperative course was uneventful except for left recurrent laryngeal nerve palsy, and 24 months after the operation, the patient has remained free from any arterial event.

Influence of preoperative right ventricular function on left ventricular remodeling and survival after subvalvular repair for functional mitral regurgitation.

OBJECTIVES: The objective of this study was to analyze our surgical experiences with mitral valve plasty (MVP) combined with subvalvular procedures (SVPs) for functional mitral regurgitation (FMR) and to determine which preoperative factors affected clinical outcomes. METHODS: This study retrospectively analyzed 33 patients who underwent MVP combined with SVPs for FMR with a left ventricular ejection fraction lower than 40% and advanced remodeled left ventricles. The mean follow-up period was 49 ± 33 months. RESULTS: The preoperative mean right ventricular fractional area change (RVFAC) used to quantify right ventricular (RV) systolic function was 26 ± 11%. Sixteen patients (48%) had an RVFAC < 26%. One patient died during hospital stay, and nine more patients died of cardiac causes during follow-up. The 3- and 5-year rates of freedom from cardiac-related mortality were 78% and 68%, respectively. RVFAC was the significant predictor of cardiac-related mortality in a univariate analysis (risk ratio [RR] = 0.92, 95% confidence interval [CI] 0.85-0.99, p = 0.03) and demonstrated a non-significant tendency to predict cardiac-related mortality in the Cox multivariate analysis (RR = 0.94, 95% CI 0.86-1.003, p = 0.08). Continued reverse left ventricular remodeling was associated with an RVFAC ≥ 26%. At 3 years, there was also a significant difference in survival rates of cardiac-related mortality between patients with an RVFAC ≥ 26% and < 26% (94% vs. 61%; p = 0.03). CONCLUSIONS: Preoperative RV function affected left ventricular remodeling and cardiac-related mortality after MV surgery. MVP combined with SVPs for FMR provided promising results for patients without severe RV dysfunction.

Clinical Outcomes of a Customized Mitral Valve Plasty for Functional Mitral Regurgitation with a Low Ejection Fraction and Implications for Preoperative Right Ventricular Function.

PURPOSE: To evaluate clinical outcomes of customized mitral valve plasty (MVP) for the treatment of functional mitral regurgitation (FMR) with a low ejection fraction (EF) and to determine which preoperative factors affected the clinical outcome. METHODS AND RESULTS: MVP was adjusted according to the degree of left ventricle (LV) remodeling. We performed mitral annuloplasty (MAP) alone in 14 patients and added subvalvular procedures (SVPs) in 22 patients at a high risk of recurrent MR. During follow-up, reverse LV remodeling was obtained and the 3-year and 5-year non-recurrence rates of MR grade ≥2 were 94% and 89%, respectively. Two patients died during their hospital stay, and four more patients died of cardiac causes during follow-up. The 3-year and 5-year rates of freedom from cardiac-related mortality were 86% and 81%, respectively; no significant difference was observed between the two treatment groups. Right ventricular fractional area change (RVFAC) was a significant predictor of cardiac mortality. Patients with an RVFAC of <26% had significantly poorer cardiac-related mortality (71% at 3 years) than those with an RVFAC of ≥26% (95% at 3 years). CONCLUSION: Customized MVP provided durable mitral competence and reverse LV remodeling. Preoperative RV function was associated with cardiac-related mortality.

Successful treatment of left ventricular patch infection by latissimus dorsi muscle flap covering without patch removal.

Removal of the infected prosthesis is considered an essential procedure in the treatment of prosthetic graft infection following cardiovascular surgery. Here, we present a case of left ventricular patch infection following repair of left ventricular rupture that was successfully treated by coverage with a latissimus dorsi muscle flap without patch removal. A 61-year-old man underwent double-patch repair for left ventricular-free wall rupture following posterior myocardial infarction. He underwent drainage and omental transposition with re-sternotomy for postoperative mediastinitis by Candida albicans, followed by pericardial fenestration via left thoracotomy for infectious pericarditis; however, left ventricular patch infection was detected. Considering the high invasiveness of a reoperation for patch removal, we preserved and covered the patch using a left pedicled latissimus dorsi muscle flap via left thoracotomy. The postoperative course was uneventful, and the patient was asymptomatic with no signs of recurrence at 30 months.

Long-Term Growth of the Neoaortic Root After Arterial Switch Operation.

BACKGROUND: The growth of the neoaortic root after the arterial switch operation for the transposition of the great arteries remains unclear. This study aimed to investigate the growth of the neoaortic root and identify risk factors for neoaortic root dilatation. METHODS: Serial angiographic measurements of the neoaortic root for at least 10 years were evaluated in 145 patients. A total of 1,876 measurements of the sinuses of the Valsalva and the neoaortic annuli were obtained. A linear mixed effects model was used for z-score analysis, including evaluation of risk factors for neoaortic root dilatation. To assess changes in the time course of neoaortic root absolute diameters, a nonlinear mixed effects model with a growth curve model was used. RESULTS: The growth curve revealed progressive growth of the neoaortic root during somatic growth and stabilization in adulthood without normalization. The growth rates of the sinus and annulus were 0.0046 and 0.029 z-score per year, respectively. The sinus and annulus were estimated to grow up to 47 ± 1 mm and 31 ± 1 mm, respectively. Major risk factors for neoaortic root dilatation were double-outlet right ventricle (parameter estimate [PE] = 2.1, 95% confidence interval [CI] = 1.5 to 2.7, p < 0.0001 for sinus; PE = 1.2; 95% CI = 0.7 to 1.6, p < 0.0001 for annulus) and presence of neoaortic valve insufficiency (PE = 0.9; 95% CI = 0.4 to 1.5; p < 0.001 for sinus; PE = 1.6, 95% CI = 1.2 to 2.0, p < 0.0001 for annulus). CONCLUSIONS: The risk for neoaortic root dilatation was common. Long-term surveillance is mandatory, particularly in patients with double-outlet right ventricle and neoaortic valve insufficiency.

[Mitral Valve Replacement with a Low-Profile Bioprosthesis in Combination with Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy;Report of a Case].

An 83-year-old woman diagnosed with hypertrophic obstructive cardiomyopathy was referred to our hospital. Her echocardiogram revealed diffuse left ventricular hypertrophy, severe mitral valve regurgitation with systolic anterior motion of the mitral valve, and left ventricular obstruction with a peak outflow gradient of 142 mmHg. Cardiac catheterization revealed a peak pressure gradient of 60 mmHg across the left ventricular outflow tract. Because of the patient's advanced age, as well as uncertainty regarding our ability to resolve her mitral regurgitation, we performed mitral valve replacement with a St. Jude Medical Epic porcine low-profile bioprosthesis in combination with septal myectomy. The patient's postoperative course was uneventful. At 1 year after the operation, her functional status was New York Heart Association class I. The echocardiogram showed the peak outflow gradient markedly decreased to 9 mmHg.

[Aortic Root Reimplantation for Extra-cardiac Unruptured Sinus of Valsalva Aneurysm].

Aneurysms of the sinus of Valsalva are rare. We report a case of extra-cardiac unruptured aneurysm of the sinus of Valsalva with moderate aortic regurgitation (AR). A 57-year-old woman was referred to our institution because of AR. Echocardiography showed moderate AR and computed tomographic scanning demonstrated an extra-cardiac aneurysm of the unruptured sinus of Valsalva, which extended from the right sinus of Valsalva to the non-coronary sinus of Valsalva. She underwent aortic root reimplantation procedure with a Valsalva graft. Although mild AR was observed postoperatively, her postoperative course was uneventful.

[Valve plasty for mitral regurgitation caused by partial papillary muscle rupture after acute myocardial infarction;report of a case].

A 58-year-old woman was referred to our hospital because of acute myocardial infarction. Percutaneous coronary intervention for total occlusion of the circumflex coronary artery was performed successfully. However, she had heart failure that was gradually getting worse because of mitral valve regurgitation. Therefore, we performed valve plasty using the resection and suture method for mitral regurgitation caused by partial papillary muscle rupture. Her postoperative course was uneventful, and she was discharged on postoperative day 26. At 6 months after the operation, her functional status was New York Heart Association(NYHA) class I and transthoracic echocardiogram showed no mitral regurgitation( MR).

Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor.

Aryl hydrocarbon receptor (AhR) activators have been shown to induce members of the cytochrome P450 (P450) 1 family. Here we demonstrate that the AhR activators induce CYP3A4 through human pregnane X receptor (PXR). AhR activators, polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased CYP3A4 reporter activity and CYP3A4 mRNA expression in HepG2 cells. The CYP3A4 reporter activity was also increased by treatment with cigarette tar. The increased CYP3A4 reporter activity was clearly knocked down by the introduction of human PXR-small interfering RNA, but not by that of human AhR-small interfering RNA. The CYP3A4 reporter activity enhanced by overexpression of human PXR was further increased by treatment with PAHs and TCDD as well as by treatment with rifampicin. These results suggest that PAHs contained in cigarette smoke induce CYP3A4 in human liver.

Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress.

Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.

Construction of a system that simultaneously evaluates CYP1A1 and CYP1A2 induction in a stable human-derived cell line using a dual reporter plasmid.

Human CYP1A1 and CYP1A2 genes are in a head-to-head orientation on chromosome 15 and are separated by a 23-kb intergenic space. To our knowledge, this is the first report on a stable cell line that contains the 23-kb full-length regulatory region and is able to simultaneously assess the transcriptional activation of CYP1A1 and CYP1A2 genes. The stable cell line that constitutively expresses the reporter activities was constructed by inserting the dual reporter plasmid containing the 23-kb region between the CYP1A1 and CYP1A2 genes into the chromosome. Transcriptional activation of the CYP1A1 and CYP1A2 genes was measured simultaneously using luciferase (Luc) and secreted alkaline phosphatase (SEAP) activities, respectively. To demonstrate the utility of the stable cell line, CYP1A1/1A2 induction by the majority of compounds previously identified as CYP1A1/1A2 inducers was measured. The results clearly show that all compounds caused induction of reporter activities. In addition to assessing transcriptional activation of the CYP1A1 and CYP1A2 genes by measuring reporter activities, we determined the intrinsic CYP1A1 and CYP1A2 mRNA levels by treating them with the same compounds. The results suggest that this stable cell line may be used to rapidly and accurately predict CYP1A1/1A2 induction.

Malondialdehyde-modified low density lipoprotein (MDA-LDL)-induced cell growth was suppressed by polycyclic aromatic hydrocarbons (PAHs).

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) and oxidized LDL (Ox-LDL), which accelerate the pathogenesis of arteriosclerosis, are thought to be involved in parthenogenesis caused by smooth muscle cell proliferation. In this study, we investigated the suppression mechanism of polycyclic aromatic hydrocarbons (PAHs) on the growth of an MDA-LDL-induced human acute monocyte leukemia suspension cell line (THP-1 cells). We found that PAHs suppressed MDA-LDL-induced THP-1 cell growth. Cotreatment with benzo[a]pyrene (BaP) or 3-methylchoranthrene (3-MC) decreased MDA-LDL-induced THP-1 cell growth, whereas treatment with benzo[e]pyrene (BeP) or pyrene, which is not a ligand for the arylhydrocarbon receptor (AhR), did not decrease THP-1 cell growth. Our findings clearly demonstrated that THP-1 cell growth, which was suppressed by PAHs, was restored by the addition of alpha-naphtoflavone, which is a partial antagonist to AhR. Moreover, it was shown that cotreatment with MDA-LDL and BaP markedly induced the expression of human cytochrome P4501A1 (hCYP1A1) messenger ribonucleic acid (mRNA) and significantly induced the expressions of p53 and p21 mRNAs. In support of these findings, AhR small interfering RNA suppressed the induced level of p21 mRNA and by BaP and the overexpression of hCYP1A1 significantly induced levels of p21 mRNA. On the other hand, the uptake rate of [(14)C]BaP into cells was increased more significantly by cotreatment with MDA-LDL than by treatment with [(14)C]BaP alone. These results strongly suggest that the suppression of MDA-LDL-induced THP-1 cell growth is caused by the increased uptake of PAHs, which strongly activate the AhR signal pathway accompanying DNA damage.

Preventive effects of a biscoclaurine alkaloid, cepharanthine, on endotoxin or tumor necrosis factor-alpha-induced septic shock symptoms: involvement of from cell death in L929 cells and nitric oxide production in raw 264.7 cells.

The preventive effects of cepharanthine, a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, on the lethality and cell death caused by endotoxin or tumor necrosis factor (TNF)-alpha-induced syndrome in septic shock were investigated. In these experiments, we estimated the survival of mice treated with a lethal dose of endotoxin (50 mg/kg, i.p.) or recombinant human (rh) TNF-alpha (10,000 units/mouse, i.v.) together with a sublethal dose (1 mg/kg, i.p.) of endotoxin. Cepharanthine clearly protected mice from endotoxin-induced and endotoxin/rhTNF-alpha-induced lethal shock. In in vitro experiments, cepharanthine (3 micro g/ml) definitely inhibited cell death in mouse L929 fibroblast cells incubated with rhTNF-alpha (100 units/ml) at 37 degrees C for 24 h. On the other hand, non-apoptotic programmed death of cells was observed by fluorescence microscopy in rhTNF-alpha (100 units/ml)-treated L929 cells. In the 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay after 48-h drug exposure, the cell proliferation of L929 cells was significantly increased by the addition of cepharanthine (1 and 3 micro g/ml). It seems that the preventive effect of cepharanthine on rhTNF-alpha-induced cytotoxicity in fibroblast cells occurs through an increase of cell proliferation by the drug. In addition, cepharanthine suppressed nitric oxide (NO) production by endotoxin-stimulated Raw 264.7 mouse macrophage cells. These findings suggest that cepharanthine prevents lethality or cytotoxicity through suppression of endotoxin-induced NO in macrophages and that its effects are possibly mediated by the enhancement of the proliferation of fibroblast cells. Cepharanthine may therefore protect against some of the various disturbances caused by endotoxin through its ability to inhibit NO production in septic shock.

Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis.

This review showed the common pathogenic mechanism in the development of non-alcoholic or alcoholic steatohepatitis. In particular, we describe the role of innate immune system and oxidative stress caused by gut-derived endotoxin. Gut-derived endotoxin plays an important role in alcoholic liver injury. It was reported that acute ethanol administration reduced activation of Kupffer cells. It is therefore possible that alcohol-induced hepatocellular damage occurs as a result of bacterial or endotoxin translocation under a reduction of the reticuloendothelial system (RES) function in alcoholic liver disease (ALD). On the other hand, recently, attention has been directed toward the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxin via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol-induced liver injury. It is generally accepted that activation of the innate immune system and increased release of proinflammatory cytokines and other mediators plays an important role in the development of ALD. It was shown that Kupffer cells activation by endotoxin via Toll-like receptor (TLR-4) is involved in alcohol-induced liver injury and that ethanol-induced oxidative stress is important in the regulation of transcription factor NF-kappaB activation and that cytokine production by Kupffer cells. TNF-alpha and free radicals are produced in early alcohol-induced liver injury. In support of this finding, the pathology caused by alcohol was blocked nearly completely in TNF-alpha receptor 1. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divides disease mechanisms into "first and second" hit. The best candidates for these second hits were considered to be oxidative stress (CYP2E1 induction) and associated lipid peroxidation and cyokines, principally, TNF-alpha. Some of the most definitive data on the importance of the innate immune system or oxidative stress in the pathogenesis of liver disease come from studies of alcoholic and non-alcoholic steatohepatitis in animals.

Oxidative stress and septic shock: metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia.

This review describes the role of oxidative stress caused by endotoxin challenge in sepsis or septic shock symptoms. We observed that endotoxin injection resulted in lipid peroxide formation and membrane damage (near 60-150 kDa) in the livers of experimental animals, causing decreased levels of scavengers or quenchers of free radicals. The administration of alpha-tocopherol completely prevented injury to the liver plasma membrane caused by endotoxin, and suggested that lipid peroxidation by free radicals might occur in a tissue ischemic state, probably by disseminated intravascular coagulation (DIC), in endotoxemia. In mice, depression of Ca(2+)-ATPase activity in the liver plasma membrane may contribute to the membrane damage caused by endotoxin, and the increase of [Ca(2+)](i) in the liver cytoplasm may partially explain the oxidative stress that occurs in endotoxemia. It seems that endotoxin-induced free radical formation is regulated by Ca(2+) mobilization. Moreover, we have suggested that the oxidative stress caused by endotoxin may be due, at least in part, to the changes in endogenous zinc or selenium regulation during endotoxemia. Interestingly, the extent of TNF-alpha-induced oxidative stress may be the result of a synergism between TNF-alpha and gut-derived endotoxin. It is likely that bacterial or endotoxin translocation plays a significant role in TNF-alpha-induced septic shock. On the other hand, although nitric oxide (NO) has been implicated in the pathogenesis of vascular hyporesponsiveness and hypotension in septic shock in our experimental model, it is unlikely that NO plays a significant role in liver injury caused by free radical generation in endotoxemia.

Preventive effects of a traditional Chinese medicine (Sho-saiko-to) on septic shock symptoms; approached from heme metabolic disorders in endotoxemia.

Sho-saiko-to, one of the the most frequently prescribed Kampo medicines, is used to treat chronic hepatitis and has shown confirmed clinical efficacy. The present study was performed with respect to heme metabolism to study the preventive effects of Sho-saiko-to against endotoxemia. Endotoxin was injected intraperitoneally at a dose of 6 mg/kg into Sho-saiko-to (500 mg/kg/d, p.o.)-pretreated rats, and its administration clearly prevented the endotoxin-induced hypoferremia. In rats pretreated with Sho-saiko-to, the activity of hepatic delta-aminolevulinate synthetase and cytochrome P-450 level 18 h after endotoxin injection were significantly increased as compared to rats treated with endotoxin alone. Similarly, Sho-saiko-to significantly depressed the endotoxin-induced increase in heme oxygenase activity in liver microsomes. These findings suggested that the extent of shock syndrome caused by endotoxin may be due, at least in part, to changes in heme metabolic disturbance during endotoxemia. Sho-saiko-to may therefore protect rats against lethality caused by endotoxin through its ability to regulate the heme metabolism in septic shock.

Preventive effects of a traditional Chinese medicine (Sho-saiko-to) on endotoxin-induced cytotoxicity and tumor necrosis factor-alpha production in J774A.1 Cells.

Sho-saiko-to, one of the most frequently prescribed Kampo medicines, is used clinically to treat chronic hepatitis and has shown confirmed clinical efficacy. The present study investigated whether Sho-saiko-to can suppress cytotoxicity and tumor necrosis factor (TNF)-alpha production in endotoxin-treated J774A.1 cells. Sho-saiko-to (10-20 microg/ml) did not affect the proliferation of J774A.1 cells, while a high concentration (50 microg/ml) of Sho-saiko-to induced a slight reduction in cell viability. Treatment with Sho-saiko-to (10-50 microg/ml) significantly inhibited endotoxin (10 microg/ml)-induced cytotoxicity in J774A.1 cells. In addition, Sho-saiko-to (20 microg/ml) suppressed TNF-alpha production by endotoxin (1 microg/ml)-activated J774A.1 cells. These findings suggest that the Kampo prescription Sho-saiko-to suppresses cytotoxicity or TNF-alpha production in macrophages treated with endotoxin and that it may be useful in improving septic shock symptoms. Sho-saiko-to may therefore protect against some of the various disturbances caused by endotoxins through its ability to inhibit TNF-alpha production in septic shock.

[Metabolic aspects of endotoxin as a model of septic shock--approached from oxidative stress].

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca2+, Zn2+, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca2+ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms.

Role of Zn(2+) in oxidative stress caused by endotoxin challenge.

The role of Zn(2+) in oxidative stress during endotoxemia was investigated. In rats fed a Zn(2+)-deficient diet (Zn(2+) concentration of less than 1.5 mg/kg) for 8 weeks, the Zn(2+) level in the serum was about 62% lower than that in rats fed a Zn(2+)-adequate diet (Zn(2+) concentration, 50 mg/kg). The Zn(2+) level in serum 18 h after administration of endotoxin (6 mg/kg, i.p.) to Zn(2+)-deficient diet rats was markedly lower than that of the endotoxin/Zn(2+)-adequate diet group. Lipid peroxide formation in the liver of Zn(2+)-deficient diet rats was markedly increased 18 h after endotoxin injection compared with that in the endotoxin/Zn(2+)-adequate diet group. Metallothionein in the liver of endotoxin/Zn(2+)-adequate diet rats was increased more than 17-fold by endotoxin administration, while a markedly lower level of metallothionein was observed in the endotoxin/Zn(2+)-deficient diet group. On the other hand, treatment with ZnSO(4) (100 microM) significantly increased endotoxin (1 microg/ml)-induced tumor necrosis factor-alpha (TNF-alpha) production in J774A.1 cells. Our results clearly demonstrated that treatment with ZnSO(4) significantly inhibited the endotoxin-induced increase in intracellular Ca(2+) level in J774A.1 cells. However, a cell membrane-permeable Zn(2+) chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 1 microM), did not affect the endotoxin-induced TNF-alpha production or Ca(2+) level in J774A.1 cells. In addition, we investigated whether Zn(2+) can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated cells. Treatment with ZnSO(4) (50 microM) significantly inhibited endotoxin-induced NO production in J774A.1 cells, but did not affect endotoxin-induced cytotoxicity. These findings suggest that zinc may play an important role, at least in part, in the oxidative stress during endotoxemia.