Mantle Cell Lymphoma Causing Recurrent Pleural Effusions: A Case Report.

Mantle cell lymphoma (MCL) is a rare type of B cell non-Hodgkin's lymphoma. MCL is most commonly identified in the gastrointestinal tract. Yet, many other extranodal sites have been described in the literature, including the rare instances of the primary site being the pleura of the lung. We present a case with a 73-year-old female who presented with a three-month history of unintentional weight loss, nocturnal fever, and night sweats. She had recurrent left pleural effusions; however, thoracentesis and pleural fluid cytology were negative for malignancy. A definitive diagnosis was achieved after the patient underwent video-assisted thoracic surgery. MCL presenting as a pleural effusion is rarely reported in the literature.

Rare Primary Pulmonary Marginal Zone Lymphoma Presenting with Incidental Pulmonary Nodules.

Pulmonary malignancies carry a significant morbidity and mortality and are one of the leading causes of cancer-related deaths worldwide. Primary pulmonary lymphoma is a rare malignancy which should be considered in the differential of solitary pulmonary nodule or lung mass especially in a low-risk patient presenting with constitutional symptoms. Here, we describe a case of an elderly male who presented to our clinic with incidental pulmonary nodules and subsequent workup revealed low grade B cell non-Hodgkin's lymphoma consistent with diagnosis of primary pulmonary marginal zone lymphoma.

Acute hypoxic respiratory failure secondary to antisynthetase syndrome: A case report and review of literature.

OBJECTIVE: Antisynthetase syndrome is a condition that includes interstitial lung disease and inflammatory myositis in its definition. The interstitial lung disease of this syndrome can vary in severity and if not identified soon enough, can lead to severe respiratory failure. Here we present a patient who had a working diagnosis of acute eosinophilic pneumonia. He initially improved after prolonged hospitalization and course of high dose steroids. CT chest revealed interval improvement in his bilateral ground glass and reticular opacities but residual fibrotic interstitial lung disease. However, he decompensated subsequently with relapsed hypoxia during activity. We hope that this review will bring awareness to antisynthetase syndrome and provide tools for earlier diagnosis and treatment. The primary objective of this study was to review presenting symptoms, diagnosis, treatment and outcomes. This review is unique because we focused on antisynthetase syndrome that initially manifested with lung symptoms rather than myositis or skin changes. METHODS: We have performed a comprehensive review of 30 cases of antisynthetase syndrome in the literature (including our case). RESULTS: Total 30 cases reported, 17 male patients and 13 female patients. Only 43% of the cases presented with lung symptoms alone, while 57% of the cases presented with lung and muscle symptoms simultaneously. CONCLUSION: This supports the fact that antisynthetase syndrome most commonly presents with lung and muscle manifestations simultaneously. The fact that our case presented with lung findings alone led to the delay in his diagnosis.

A Case of Chronic Cough in a Winemaker.

BACKGROUND: Fungi have been known to cause a variety of respiratory conditions, ranging from mold- associated asthma to allergic bronchopulmonary mycosis and invasive disease. More recently some fungal species have been implicated in a non-asthmatic chronic cough syndrome. CASE PRESENTATION: A 59-year-old male presented to the pulmonary clinic with chronic nonproductive cough. Workup included pulmonary function tests with methacholine challenge, sputum cultures, CT scans of the chest and therapeutic trial with proton pump inhibitors. Sputum cultures repeatedly showed Saccharomyces cerevisiae and patient had elevated specific IgA and IgG. Bronchoscopy was unremarkable, except for tracheal mucosa biopsies revealing acute and chronic inflammation. A one-month course of steroids provided temporary relief of chronic cough, but symptoms returned once steroids were discontinued. He also experienced temporary relief away from home. Upon further evaluation, the patient described his hobby of wine making which was believed to be the source of Saccharomyces cerevisiae. Once he stopped wine making at home and cleared his cellar, his symptoms stopped and have not returned since. CONCLUSION: We describe a rare presentation of non-asthmatic chronic cough associated with exposure to Saccharomyces cerevisiae. This is the first report of fungi associated chronic cough without asthmatic features outside of Japan and the first one associated with Saccharomyces cerevisiae. This report provides further evidence linking fungi with chronic cough syndrome without the features of asthma or allergic bronchopulmonary mycosis.

Nephrotic syndrome-induced thromboembolism in adults.

Nephrotic syndrome (NS) is a well-defined syndrome characterized by the presence of nephrotic range of proteinuria, hypoalbuminemia, and hyperlipidemia. Although venous thromboembolism (VTE) is a well-reported complication associated with NS, the incidence, prevalence, risk factors, treatment options, and preventative strategies are not well-established. Thromboembolic phenomena in nephrotic patients are postulated to be a result of the urinary loss of antithrombotic factors by affected kidneys and increased production of prothrombotic factors by the liver. Most cases of VTE associated with NS reported in the literature have a known diagnosis of NS. We report a case of a young female presenting with dyspnea and a pulmonary embolism. She was found to have NS and right renal vein thrombosis. We review the available literature to highlight the best approach for clinicians treating VTE in patients with NS.

Spontaneous, Life-Threatening Hemorrhagic Cardiac Tamponade Secondary to Rivaroxaban.

Bleeding is the most feared complication of anticoagulants. Rivaroxaban is a newer oral anticoagulant with a favorable regimen due to lack of frequent blood monitoring and fewer drug interactions. We report a case of spontaneous pericardial hemorrhage associated with rivaroxaban. Within 10 days of starting rivaroxaban for atrial fibrillation, the patient developed a life-threatening cardiac tamponade leading to shock and multiorgan failure. After urgent pericardiocentesis/drainage, the patient recovered. This case highlights the necessity of larger clinical trials and consensus guideline on monitoring the effects of novel oral anticoagulants and development of an antidote for reversal in cases of major bleeding events.

Intravenous colistin-induced acute respiratory failure: A case report and a review of literature.

The emergence of multi-drug-resistant gram negative bacillary infections has regained popularity of ancient drugs such as polymyxins. We report a case of acute respiratory failure induced by use of intravenous colistimethate, which is one of the forms of polymyxin. The patient is a 31 year old female with paraplegia due to spina bifida who underwent excisional debridement of large lumbosacral decubitus ulcer with osteomyelitis infected with pan-resistant Pseudomonas aeruginosa and MRSA. Six days after initiation of intravenous colistimethate and vancomycin, she developed acute respiratory failure requiring mechanical ventilation. Pan-culture was negative including a chest radiograph. V/Q scan showed low probability for pulmonary embolism. Echocardiogram showed normal right ventricle with no strain or pulmonary hypertension. Colistimethate was discontinued. Within 24 hours, she was extubated. In the early years after introduction of polymyxin, there were several reports of acute respiratory paralysis. The mechanism is thought to be noncompetitive myoneuronal presynaptic blockade of acetylcholine release. Though a direct causal relationship for respiratory failure is often difficult to establish in current era with multiple co morbidities, the timeframe of apnea, acuity of onset as well as rapid recovery in our case clearly point out the causal relationship. In addition, our patient also developed acute renal failure, presumably due to colistimethate induced nephrotoxicity, a possible contributing factor for her acute respiratory failure. In summary, colistimethate can induce acute neurotoxicity including respiratory muscular weakness and acute respiratory failure. Clinicians should consider its toxicity in the differential diagnosis of acute respiratory failure especially in critically ill patients.

Spontaneous Tumor Lysis Syndrome in Metastatic Melanoma.

Tumor lysis syndrome (TLS) complicating non-hematologic malignancy is infrequent and spontaneous TLS is a very rare occurrence in patients with solid tumors. We report a case of spontaneous TLS in a patient with metastatic melanoma. Clinicians should have awareness of the possibility of spontaneous TLS in patients with solid tumors and should recognize the clinical presentation and laboratory tests for its diagnosis.

Heat shock factor 1 inhibits nuclear factor-kappaB nuclear binding activity during endotoxin tolerance and heat shock.

RATIONALE: Sepsis, endotoxin tolerance, and heat shock (HS) all display down-regulation of innate immunity. We hypothesize that HS factor 1 (HSF-1) induces competitive inhibition of nuclear factor-kappaB (NF-kappaB)-induced signal transduction in both endotoxin tolerance and HS. OBJECTIVES: We compared endotoxin tolerance and HS in RAW 264.7 cells. We transfected cells with an HS protein 70 (HSP70) plasmid to test whether HSP70 is the mediator of HS-induced NF-kappaB inhibition. We studied the effects of endotoxin stimulation and HS, both separately and together, on "wild-type" cells, cells transfected with the HSP70 plasmid, and cells transfected with vehicle. FINDINGS: Heat shock protein 70 plasmid-transfected cells had increased HSP70 expression and demonstrated decreased nitric oxide (NO) release and inducible NO synthase messenger RNA expression in response to endotoxin compared with wild-type and empty plasmid-transfected cells. Heat shock completely abolished subsequent NO and inducible NO synthase messenger RNA expression in wild-type cells. Heat shock factor 1 reached maximum expression 60 to 90 minutes after HS. Heat shock protein 70-transfected cells still displayed endotoxin-induced NF-kappaB nuclear binding, whereas endotoxin tolerance, HS, and exposure to HSF-1, but not exposure to an unrelated promoter, inhibited NF-kappaB nuclear binding. CONCLUSIONS: Endotoxin tolerance and HS appear to share a common immune suppressive effect, possibly through HSF-1-mediated competitive inhibition of NF-kappaB nuclear binding.

Effects of hypercapnia on BP in hypoalbuminemic and Nagase analbuminemic rats.

STUDY OBJECTIVE: To determine if animals with abnormally low albumin levels are more susceptible to the effects of hypercapnia on BP compared to normal animals. DESIGN: Prospective, controlled laboratory experiment. SETTING: University research laboratory. ANIMALS: Eighteen male Sprague-Dawley rats: 6 rats 10 to 12 weeks old (young Sprague-Dawley [YSD]), 6 rats 6 to 9 months old (old Sprague-Dawley [OSD]), and 6 rats 10 to 12 weeks old (Nagase analbuminemic mutant Sprague-Dawley [NAR]). METHODS: Under general anesthesia and paralysis, we varied the Paco(2) by changing the respiratory rate on mechanical ventilation. Mean arterial pressure (MAP) was monitored in a continuous fashion. We obtained arterial blood for blood gas and electrolyte analysis, and nitric oxide (NO) production. RESULTS: OSD rats had reduced serum albumin, while NAR rats were analbuminemic. Although NAR animals had a decreased buffer capacity compared to age-matched control animals (0.010 vs 0.013, p < 0.05), the MAP decreased in an identical fashion in all three groups. NO production increased with hypercapnia but was similar in all three groups. However, NAR rats had consistently higher plasma strong ion gap (2.8 to 4.1 mEq/L greater) compared to either YSD or OSD rats (p < 0.01), and baseline strong ion difference (mean +/- SD) was significantly lower in NAR rats (28.7 +/- 2.1 mEq/L) compared to either YSD rats (33.0 +/- 5.1 mEq/L) or OSD rats (31.2 +/- 5.1 mEq/L) [p < 0.05]. CONCLUSIONS: These findings suggest that analbuminemic or hypoalbuminemic rats are not more susceptible to hypercapnia-induced hemodynamic instability. Baseline values for apparent strong ion difference are lower in NA rats consistent with a reduced buffer base resulting from analbuminemia.

Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis.

RATIONALE: Hyperchloremic acidosis is common in the critically ill and is often iatrogenic. We have previously shown that hyperchloremic acidosis increases nuclear factor-kappaB DNA binding in lipopolysaccharide-stimulated RAW 264.7 cells. However, evidence that hyperchloremic acidosis leads to increased inflammation in vivo has been limited to nitric oxide. OBJECTIVES: To determine if acidosis, induced by dilute hydrochloric acid (HCl) infusion, will increase circulating inflammatory mediator levels in an experimental model of severe sepsis in rats. METHODS: Eighteen hours after inducing lethal sepsis by cecal ligation and puncture in 20 adult, male, Sprague-Dawley rats, we randomized animals into three groups. In groups 2 and 3, we began an IV infusion of 0.1 N HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L, respectively. In group 1, we infused a similar volume of lactated Ringer solution. In all groups infusion continued 8 h or until the animal died. MEASUREMENTS AND MAIN RESULTS: We measured arterial blood gases, whole-blood lactate, and chloride, tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 levels at 0 h, 4 h, and 8 h. All measured cytokines increased over time. Compared to group 1, animals in groups 2 and 3 exhibited greater increase in all three cytokines, with the greatest increases seen with severe acidosis. CONCLUSION: Moderate (SBE, - 5 to - 10) and severe (SBE, - 10 to - 15) acidosis, induced by HCl infusion, increases circulating levels of IL-6, IL-10, and TNF in normotensive septic rats.

The phase 2 enzyme inducers ethacrynic acid, DL-sulforaphane, and oltipraz inhibit lipopolysaccharide-induced high-mobility group box 1 secretion by RAW 264.7 cells.

The diuretic ethacrynic acid (EA) has been shown to inhibit signaling by the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB). Accordingly, we sought to determine whether this compound is capable of inhibiting the release of cytokines [interleukin (IL)-6 and IL-10] and NO from RAW 264.7 murine macrophage-like cells stimulated with lipopolysaccharide (LPS). Additionally, we sought to determine whether EA can inhibit secretion of high-mobility group box 1 (HMGB1), a nuclear protein that is secreted by immunostimulated macrophages and functions in the extracellular milieu as a proinflammatory mediator. In a concentration-dependent manner, EA inhibited secretion of IL-6, IL-10, nitric oxide, and HMGB1. As expected, EA inhibited NF-kappaB DNA binding in LPS-stimulated RAW 264.7 cells. Treating these cells with pyrrolidine dithiocarbamate, SN50 (amino acid sequence AAVALLPAVLLALLAPVQRKRQKLMP) or 5-(thien-3-yl)-3-aminothiophene-2-carboxamide (SC-514) also inhibited LPS-induced NF-kappaB DNA binding, but these compounds failed to inhibit LPS-induced HMGB1 secretion. These findings suggested that inhibition of HMGB1 secretion by EA might occur via a mechanism unrelated to the NF-kappaB signaling pathway. Because EA is an electrophilic compound that is known to be capable of inducing expression of so-called phase 2 proteins, we sought to determine whether two other phase 2 enzyme inducers, oltipraz and DL-sulforaphane, also are capable of inhibiting HMGB1 release from immunostimulated macrophages. Incubating RAW 264.7 cells with either oltipraz or DL-sulforaphane inhibited LPS-induced HMGB1 secretion. Moreover, both EA and DL-sulforaphane inhibited relocalization of nuclear HMGB1 into the cytoplasm of LPS-stimulated RAW 264.7 cells. These data suggest that phase 2 inducers may exert anti-inflammatory effects by inhibiting secretion of the cytokine-like nuclear protein HMGB1.

Science review: extracellular acidosis and the immune response: clinical and physiologic implications.

Metabolic acidosis is among the most common abnormalities seen in patients suffering from critical illness. Its etiologies are multiple and treatment of the underlying condition is the mainstay of therapy. However, growing evidence suggests that acidosis itself has profound effects on the host, particularly in the area of immune function. Given the central importance of immune function to the outcome of critical illness, there is renewed interest in elucidating the effects of this all too common condition on the immune response. In this review we concentrate on the effects of extracellular acids on production and release of inflammatory mediators, and we demonstrate that different acids produce different effects despite similar extracellular pH. Finally, we discuss potential clinical implications.

Cytokine removal with a novel adsorbent polymer.

BACKGROUND/AIMS: We sought to characterize a novel adsorbent polymer in terms of cytokine removal. METHODS: We challenged 50 rats with lipopolysaccharide to obtain cytokine-rich blood and circulated this through cartridges containing polymer. In separate experiments, cell-free supernatants were passed through cartridges containing polymer. We measured tumor necrosis factor alpha, interleukin 10 and interleukin 6 concentrations under a variety of conditions to evaluate adsorption kinetics. RESULTS: All three cytokines were rapidly removed from the blood with less than 50% of the initial concentrations present after 1 h of circulation through the cartridge. There was no significant difference in the effect across a range of blood flows and Ca2+ concentrations. Adsorption was decreased somewhat by extremely low temperature (4 degrees C). CONCLUSION: The adsorbent polymer removes cytokines with high efficiency, and binding is relatively unaffected by a variety of physical conditions.

Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.

OBJECTIVES: Previous studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. DESIGN: Randomized controlled laboratory experiment. SETTING: University laboratory. SUBJECTS: Sixty-six adult Sprague-Dawley rats. INTERVENTIONS: We conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-kappaB DNA binding. MEASUREMENTS AND MAIN RESULTS: Mean survival time among hemoadsorption-treated animals was 629+/-114 vs. 518+/-120 mins for sham-treated animals (p <.01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p <.05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-kappaB DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. CONCLUSIONS: Hemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.

Hemoadsorption to improve organ recovery from brain-dead organ donors: a novel therapy for a novel indication?

While brain-dead organ donors represent the majority of the organ donor pool, it appears that graft survival is adversely affected by brain death itself. Brain death has been shown to cause severe disturbances in the hormonal, hemodynamic and immunological homeostasis, which could in part be responsible for the inferior outcome of organs originating from brain-dead donors compared to living donors. Hemodynamic effects of brain death lead to a wide fluctuation in mean perfusion pressures, blood flow to the organs and systemic oxygen consumption, altering regional perfusion. In addition, a wide array of immunological changes has been shown to occur after brain death contributing to organ injury and hemodynamic instability. Recent studies have shown that brain death upregulates multiple lymphocyte- and macrophage-derived cytokines and the injured brain itself may be the source of proinflammatory factors such as S100B. This increased inflammatory response seen during and immediately after brain death has also been associated with poor allograft function. Furthermore, there is evidence to suggest that the massive inflammatory response seen in brain-dead donors could also lead to increased immunogenicity and accelerated allograft rejection after transplantation. Hence, we hypothesize that nonspecific downregulation of this inflammatory response by hemoadsorption could potentially lead to improved donor organ and allograft function. As a 'proof of concept' we tested the ability of a novel hemoadsorbent to remove S100B in vitro using two human glioblastoma cell lines. Our results indicate a >80% reduction in S100B after 2 h of circulation with the sorbent.

Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis.

STUDY OBJECTIVE: To determine the effects of hyperchloremic acidosis, induced by dilute HCl infusion, on BP and circulating inflammatory mediators in an experimental model of severe sepsis in the rat. DESIGN: Randomized, open-label, controlled experiment. SETTING: University research laboratory. PARTICIPANTS: Twenty-four adult, male, Sprague-Dawley rats. INTERVENTION: Eighteen hours after inducing lethal sepsis by cecal ligation and puncture, animals were randomized and classified into three groups. In groups 2 and 3, we began an IV infusion of 0.1 N HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L, respectively. In group 1, we infused a similar volume of lactated Ringer solution. In all groups, infusions were continued for 8 h or until the animals died. MEASUREMENTS: We measured mean arterial pressure (MAP), arterial blood gases, electrolytes, plasma nitrate/nitrite, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 levels at 0 h, 3 h, 6 h, and 8 h. RESULTS: MAP remained stable in group 1 but decreased in groups 2 and 3 (p < 0.001), such that at 8 h MAP was much higher in group 1 (94 +/- 9.2 mm Hg) [+/- SD] compared to either group 2 (71.6 +/- 20.1 mm Hg) or group 3 (49.4 +/- 33.2 mm Hg) [p = 0.01]. This change in MAP correlated with the increase in plasma Cl(-) (R(2) = 0.50, p < 0.0001) and less well with the decrease in pH (R(2) = 0.24, p < 0.001). After 6 h of acidosis, plasma nitrite levels were significantly higher in group 2 animals compared to either group 1 or group 3 animals (p < 0.05). Plasma TNF-alpha, IL-6, or IL-10 levels were not significantly different from control animals. CONCLUSION: Moderate acidosis (SBE of 5 to 10 mEq/L), induced by HCl infusion, worsened BP and increased plasma nitrate/nitrite levels but had no effect on circulating cytokines in septic rats. However, severe acidosis (SBE of 10 to 15 mEq/L), while still causing hypotension, did not affect plasma nitrate/nitrite levels.

Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells.

Metabolic acidosis frequently complicates sepsis and septic shock and may be deleterious to cellular function. Different types of metabolic acidosis (e.g., hyperchloremic and lactic acidosis) have been associated with different effects on the immune response, but direct comparative studies are lacking. Murine macrophage-like RAW 264.7 cells were cultured in complete medium with lactic acid or HCl to adjust the pH between 6.5 and 7.4 and then stimulated with LPS (Escherichia coli 0111:B4; 10 ng/ml). Nitric oxide (NO), IL-6, and IL-10 levels were measured in the supernatants. RNA was extracted from the cell pellets, and RT-PCR was performed to amplify corresponding mediators. Gel shift assay was also performed to assess NF-kappa B DNA binding. Inc easing concentrations of acid caused increasing acidification of the media. Trypan blue exclusion and lactate dehydrogenase release demonstrated that acidification did not reduce cell viability. HCl significantly increased LPS-induced NO release and NF-kappa B DNA binding at pH 7.0 but not at pH 6.5. IL-6 and IL-10 expression (RNA and protein) were reduced with HCl-induced acidification, but IL-10 was reduced much more than IL-6 at low pH. By contrast, lactic acid significantly decreased LPS-induced NO, IL-6, and IL-10 expression in a dose-dependent manner. Lactic acid also inhibited LPS-induced NF-kappa B DNA binding. Two common forms of metabolic acidosis (hyperchloremic and lactic acidosis) are associated with dramatically different patterns of immune response in LPS-stimulated RAW 264.7 cells. HCl is essentially proinflammatory as assessed by NO release, IL-6-to-IL-10 ratios, and NF-kappa B DNA binding. By contrast, lactic acidosis is anti-inflammatory.

Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells.

Ethyl pyruvate (EP), an effective scavenger of reactive oxygen species, is also an anti-inflammatory agent in a variety of in vivo and in vitro model systems. To gain a better understanding of the molecular basis for the anti-inflammatory effects of EP, we compared the pharmacological properties of EP andN-acetyl-l-cysteine (NAC), a well studied scavenger of reactive oxygen species and a precursor for the endogenous antioxidant glutathione (GSH). The studies were performed using RAW 264.7 murine macrophage-like cells that were stimulated with lipopolysaccharide (LPS). Although EP and NAC both inhibited LPS-induced nitric oxide and interleukin (IL)-6 secretion, the former compound was considerably more potent than the latter. EP markedly inhibited inducible nitric-oxide synthase, IL-6, and IL-10 mRNA induction, whereas the effects of NAC were minimal. EP inhibited LPS-induced nuclear factor-kappaB DNA binding to a much greater extent than did NAC. Both compounds inhibited LPS-induced lipid peroxidation, but the two compounds had qualitatively different effects on cellular levels of GSH. Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cell-permeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.