Heat stress prevents the decrease in succinate dehydrogenase activity in the extensor digitorum longus of streptozotocin-induced diabetic rats.

This study aimed to investigate whether heat stress (HS) prevents a decrease in succinate dehydrogenase (SDH) activity and heat shock protein 60 (HSP60) and superoxide dismutase 2 (SOD2) contents in the extensor digitorum longus of streptozotocin (STZ)-induced diabetic rats. Twelve-week-old male Wistar rats were assigned to one of the four groups (n=6/group): control (Con), HS, diabetes mellitus (DM), and diabetes mellitus and heat stress (DM+HS). Diabetes was induced by the administration of STZ (50 mg/kg). HS was initiated 7 days after STZ treatment and performed at 42 °C for 30 min 5 times a week for 3 weeks. SDH activity was decreased in the DM and DM+HS groups. However, SDH activity was greater in the DM+HS group than in the DM group. Although HSP60 content was lower in the DM group than in the Con group, it was maintained in the DM+HS groups and was higher than that in the DM group. SOD2 content was decreased only in the DM group. These findings suggest that HS prevents the decrease in SDH activity in the skeletal muscle induced by DM. According to this mechanism, the maintenance of SOD2 and HSP60 by HS may suppress the increase in oxidative stress.

Heat stress attenuates skeletal muscle atrophy of extensor digitorum longus in streptozotocin-induced diabetic rats.

To investigate whether heat stress attenuates skeletal muscle atrophy of the extensor digitorum longus (EDL) muscle in streptozotocin-induced diabetic rats, 12-week-old male Wistar rats were randomly assigned to four groups (n = 6 per group): control (Con), heat stress (HS), diabetes mellitus (DM), and diabetes mellitus/heat stress (DM + HS). Diabetes was induced by intraperitoneal injection of streptozotocin (50 mg/kg). Heat stress was induced in the HS and DM + HS groups by immersion of the lower half of the body in hot water at 42 °C for 30 min; it was initiated 7 days after injection of streptozotocin, and was performed once a day, five times a week for 3 weeks. The muscle fiber cross-sectional area of EDL muscles from diabetic and non-diabetic rats was determined; heat stress protein (HSP) 72 and HSP25 expression levels were also analyzed by western blotting. Diabetes-induced muscle fiber atrophy was attenuated upon heat stress treatment in diabetic rats. HSP72 and HSP25 expression was upregulated in the DM + HS group compared with the DM group. Our findings suggest that heat stress attenuates atrophy of the EDL muscle by upregulating HSP72 and HSP25 expression.

Diffuse Liver Metastasis of Small-Cell Lung Cancer Presenting as Acute Liver Failure and Diagnosed by Transjugular Liver Biopsy: A Rare Case in Whom Nodular Lesions Were Detected by Enhanced CT Examination.

Small-cell lung cancer (SCLC) is a subgroup of lung cancer with a high frequency of liver metastasis, which is a predictor of poor prognosis. Diffuse liver metastases of SCLC with no visible nodular lesions in the liver when examined using computed tomography (CT) are relatively rare; however, a few cases with rapid progression to acute liver failure that were diagnosed after death have been reported. In this paper, we report a 63-year-old man with diffuse liver metastases of SCLC that were histologically diagnosed using a transjugular liver biopsy while the patient was alive, even though no lesions were visible during a contrast-enhanced CT examination.

Natural history of bleeding risk in colonic diverticulosis patients: a long-term colonoscopy-based cohort study.

BACKGROUND: The natural history of bleeding risk from colonic diverticulosis remains unclear. AIM: To identify the incidence of bleeding in colonic diverticulosis patients and associated risk factors. METHODS: A cohort of 1514 patients with colonoscopy-confirmed asymptomatic diverticulosis was selected between 2001 and 2013. Age, sex and location of colonic diverticulosis (right or left side, or bilateral) were assessed. The endpoint was a bleeding event, and data were censored at the time of last colonoscopy. The cumulative and overall incidences of bleeding were estimated using the Kaplan-Meier and person-years methods. The Cox proportional hazards model was used to estimate age- and sex-adjusted hazard ratios (aHRs). RESULTS: The median follow-up period was 46 months. Bleeding events occurred in 35 patients, and the median time-to-event interval was 50 months. Kaplan-Meier analysis showed that the cumulative incidence of diverticular bleeding was 0.21% at 12 months, 2.2% at 60 months and 9.5% at 120 months. By the person-years method, the overall incidence rate of bleeding was 0.46 per 1000 patient-years. On multivariate analysis, age ≥70 (aHR. 3.7) and bilateral diverticulosis (aHR, 2.4) were significant risk factors for bleeding. CONCLUSIONS: This long-term follow-up study demonstrated that the cumulative incidence of bleeding from diverticulosis was approximately 2% at 5 years and 10% at 10 years, and the overall incidence was 0.46 per 1000 patient-years. Bilateral diverticulosis increased the risk of bleeding.

Changes in antioxidant enzymes and lipid peroxidation in extensor digitorum longus muscles of streptozotocin-diabetic rats may contribute to muscle atrophy.

We investigated muscle atrophy, major antioxidant enzymes and lipid peroxidation in the extensor digitorum longus (EDL, predominantly fast fibers) and soleus (predominantly slow fibers) muscle of streptozotocin-diabetic rats. Female Wistar rats were divided into a control (n = 5) and streptozotocin-induced diabetic group (n = 5). Eight weeks after diabetes induction the EDL and soleus muscles were removed and catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase activity (SOD), and thiobarbituric acid reactive substances (TBARS) levels measured. The CAT activity increased in both the EDL and soleus muscles of the diabetic rats (p < 0.01), whereas the GPX and SOD activities were increased only in the EDL muscle (p < 0.01 and p < 0.05). The TBARS levels were only increased in the EDL muscle of the diabetic rats (p < 0.01). Both muscles showed significant atrophy but the EDL muscle elicited the greatest atrophy. In conclusion, it appears that adaptive responses to oxidative stress were adequate in the soleus muscle, but not in the EDL muscle, of diabetic rats. Thus fast twitch muscle fibers may be more susceptible to oxidative stress than slow twitch muscle fibers and this may contribute to muscle atrophy under diabetic conditions.

Relationship between clinical factors and severity of esophageal candidiasis according to Kodsi's classification.

Severe Candida esophagitis (CE) may lead to development of strictures, hemorrhage, esophagotracheal fistula, and a consequent decrease in quality of life. Although the severity of CE has been classified based on macroscopic findings on endoscopy, the clinical significance remains unknown. The aim of the study was to elucidate the predictive clinical factors for endoscopic severity of CE. Patients who underwent upper endoscopy and answered questionnaires were prospectively enrolled. Smoking, alcohol, human immunodeficiency virus (HIV) infection, diabetes mellitus, chronic renal failure, liver cirrhosis, systemic steroids use, proton pump inhibitor use, H2 blocker use, and gastrointestinal (GI) symptoms were assessed on the same day of endoscopy. GI symptoms including epigastric pain, heartburn, reflux, hunger cramps, nausea, dysphagia, and odynophagia were assessed on a 7-point Likert scale. Endoscopic severity was classified as mild (Kodsi's grade I/II) or severe (grade III/IV). Of 1855 patients, 71 (3.8%) were diagnosed with CE (mild, n = 48; severe, n = 23). In the CE patients, 50.0% (24/48) in the mild group and 23.1% (6/23) in the severe group did not have any GI symptoms. In HIV-infected patients (n = 17), a significant correlation was found between endoscopic severity and declining CD4 cell count (Spearman's rho = -0.90; P < 0.01). Multivariate analysis revealed that GI symptoms (odds ratio [OR], 3.32) and HIV infection (OR, 3.81) were independently associated with severe CE. Patients in the severe group experienced more epigastric pain (P = 0.02), reflux symptoms (P = 0.04), dysphagia (P = 0.05), and odynophagia (P < 0.01) than those in the mild group. Of the GI symptoms, odynophagia was independently associated with severe CE (OR 9.62, P = 0.02). In conclusion, the prevalence of CE in adults who underwent endoscopy was 3.8%. Silent CE was found in both mild and severe cases. Endoscopic severity was associated with characteristic GI symptoms and comorbidity of HIV infection. A decline in immune function correlated with CE disease progression.

Predictive value of endoscopic findings in the diagnosis of active intestinal amebiasis.

Endoscopic diagnosis of amebic colitis can be difficult because its appearance may mimic other forms of colonic disease. The aim of this study was to identify predictive endoscopic findings for amebic colitis. Patients with suspected amebic colitis based on distinctive endoscopic findings such as aphthae or erosions, ulcers, exudates, or a bump, were included in the study. A total of 157 patients were selected, 50 of whom had amebic colitis. The sensitivity and specificity of endoscopic findings that were significantly associated with amebic colitis were: cecal lesions (80% and 54%), multiple number of lesions (96% and 29%), presence of aphthae or erosions (84% and 37%), and presence of exudate (88% and 74%). Multivariate analysis revealed that the best combination of findings to predict amebic colitis was the presence of cecal lesions, multiple lesions, and exudates, which corresponded to an area under the receiver operating characteristic curve of 0.89 (95% confidence interval 0.82-0.95).

Recurrence of colonic diverticular bleeding and associated risk factors.

AIM: Colonic diverticular bleeding often recurs, but the risk factors remain unclear. Our aim was to identify risk factors for recurrence in patients with diverticular bleeding. METHOD: Seventy-two hospitalized patients who were diagnosed with diverticular bleeding between 2004 and 2008 were analyzed. Rebleeding was considered as the main outcome measure, with the duration until recurrence identified from medical records. Potential risk factors for rebleeding, such as underlying pathologies, medication and smoking and drinking habits, were investigated from the medical records on initial admission. RESULTS: Of the 72 patients, 19 had a diverticular disease on the right, 16 on the left side and 37 on both sides of the colon. Recurrence was identified in 27 (38%) patients at a median interval of 1535 days. The cumulative incidence of rebleeding at 6, 12 and 24 months was 15%, 20% and 33%. Multivariate analysis revealed nonsteroid anti-inflammatory drugs (NSAIDs) (hazard ratio (HR), 2.57; 95% confidence interval (CI), 0.89-7.46; P=0.08), antiplatelet drugs (HR, 2.39; 95% CI, 1.01-5.67; P=0.05) and hypertension (HR, 4.16; 95% CI, 1.22-14.2; P=0.02) to be risk factors for rebleeding. CONCLUSION: Patients with colonic diverticular bleeding show high recurrence rates within a short period. Risk factors for recurrence have been identified as the use of NSAIDs or antiplatelet drugs and hypertension.

Endoscopic ablation therapy of Barrett's esophagus.

Barrett's esophagus (BE) is an important risk factor for esophageal carcinoma and its incidence is rising. Amongst the various available endoscopic ablative therapies, radiofrequency ablation (RFA) is currently regarded as the most promising one, since RFA achieves high eradication rates of dysplasia and intestinal metaplasia with minimal complications. Patients with BE are advised to undergo regular endoscopic surveillance for dysplasia or cancer and endoscopy with four quadrant biopsy sampling at intervals of 1-2 cm of the entire length of BE remains the current standard for the detection of dysplasia or cancer. The management of BE depends on the histology of the biopsy specimens obtained during endoscopy, which includes non-dysplastic BE (ND-BE), low grade dysplasia, high grade dysplasia and adenocarcinoma. However, histological evaluation of dysplasia is fraught with error because of inter-observer variability even among expert gastrointestinal pathologists, and as a result, it often leads to false-negative or false-positive diagnoses. Non-dysplastic mucosa in BE shows clonal molecular aberrations, loss of cell cycle control, and other features of "neoplasia". These changes occur prior to morphologic expression of neoplasia (dysplasia). Given the difficulties of dysplasia assessment in mucosal biopsies, the molecular characteristics of ND-BE and LGD, and safe and effective profiles of RFA, this technique should be considered as a treatment option for the whole spectrum of BE patients.

Current understandings of Helicobacter pylori, peptic ulcer and gastroesophageal reflux disease.

H. pylori infection is a major pathogen inducing gastric mucosal inflammation and causing dysregulation of normal acid inhibitory regulatory mechanisms. The overall effect on gastric acid secretion is dependent on the location and severity of inflammation. Eradication results in healing of gastric mucosal inflammation, healing of peptic ulcers, prevention of new peptic ulcers, prevention or reduction in gastric cancer risk and in transmission of the infection. Neither H. pylori infection nor H. pylori eradication causes gastroesophageal reflux disease (GERD). H. pylori eradication also does not impede anti-secretory drug therapy of GERD. Misunderstandings of the negative association between H. pylori infection and GERD and/or Barrett's esophagus and misuse of the epidemiologic concept of ''protection'' led to considerable confusion and likely resulted in some patients receiving poor care. Current evidence is consistent with the notion that H. pylori should be eliminated whenever the organism is found. However, H. pylori infection has become increasing difficult to cure in part due to the emergence of antimicrobial resistance. In Western countries, triple therapy consisting of a proton pump inhibitor, amoxicillin and clarithromycin no longer achieves adequate eradication rates and will soon need to be abandoned. When used, legacy triple therapy should be given for 14 days. Fluorquinolones may temporarily be useful: 10-14 day duration is superior to 7 days. However, worldwide resistance is rapidly increasing. Other potential replacement therapies and strategies are discussed including sequential therapies, high-dose proton pump inhibitor plus amoxicillin, and new quadruple therapies.

Rapid identification of female Culexmosquito species using Expert System in the South East Asian region.

UNLABELLED: Rapid identification of mosquito (vector) species is critical for vector control and disease management. Pictorial keys of mosquito species are currently used for the identification of new mosquito species. However, this approach is not very effective. Here, we describe the use of an ID3 algorithm (part of artificial intelligence) for the rapid identification of the South East Asian female Culex mosquito species. AVAILABILITY: http://www.envisiict.org/

Mechanism of apoptosis in HL-60 cells induced by n-3 and n-6 polyunsaturated fatty acids.

The biochemical properties and specificity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) are not well known. Because PUFAs induce apoptosis of different cells, we studied the effect of various PUFAs, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA), on the fate of cultured human promyelocytic leukemia cells (HL-60) to elucidate the mechanism of apoptosis and the difference in action between n-3 and n-6 PUFAs. Fairly low concentrations of PUFAs inhibited the growth of HL-60 cells and induced their apoptosis by a mechanism that is sensitive to DMSO, an antioxidant, and z-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk), a pan-caspase inhibitor. PUFAs stimulated the generation of reactive oxygen species (ROS) and activated various types of caspase-like proteases, such as caspase-3, -6, -8, and -9, but not caspase-1. In addition, PUFAs triggered the reaction leading to the cleavage of Bid, a death agonist member of the Bcl-2 family, and also released cytochrome c from mitochondria into the cytosol. PUFAs also decreased the mitochondrial membrane potential of intact HL-60 cells. All of these actions of n-3 PUFAs were stronger than those of AA, an n-6 PUFA, although the mechanism is not known. PUFAs stimulate swelling and membrane depolarization of isolated mitochondria in a cyclosporin A-sensitive manner. The results indicated that PUFA-induced apoptosis of HL-60 cells may be caused, in part, by direct action on the cells and by activation of the caspase cascade through cytochrome c release coupled with mitochondrial membrane depolarization.

GM-CSF mediates alveolar macrophage proliferation and type II cell hypertrophy in SP-D gene-targeted mice.

Mice deficient in surfactant protein (SP) D develop increased surfactant pool sizes and dramatic changes in alveolar macrophages and type II cells. To test the hypothesis that granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates alveolar macrophage proliferation and activation and the type II cell hypertrophy seen in SP-D null mice, we bred SP-D and GM-CSF gene-targeted mice to obtain littermate double null, single null, and wild-type mice. Bronchoalveolar lavage levels of phospholipid, protein, SP-D, SP-A, and GM-CSF were measured from 1 to 4 mo. There was an approximately additive accumulation of phospholipid, total protein, and SP-A at each time point. Microscopy showed normal macrophage number and morphology in GM-CSF null mice, numerous giant foamy macrophages and hypertrophic type II cells in SP-D null mice, and large but not foamy macrophages and mostly normal type II cells in double null mice. These results suggest that the mechanisms underlying the alveolar surfactant accumulation in the SP-D-deficient and GM-CSF-deficient mice are different and that GM-CSF mediates some of the macrophage and type II cell changes seen in SP-D null mice.

Activation of caspase-3 by lysosomal cysteine proteases and its role in 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH)-induced apoptosis in HL-60 cells.

We previously reported that in addition to mitochondrial cytochrome c dependent activation, lysosomal cysteine proteases were also involved in the activation of caspase-3. In this study, we have separately obtained the lysosomal and mitochondrial caspase-3 activating factors in a crude mitochondrial fraction and characterized their ability to activate pro-caspase-3 in the in vitro assay system. When a rat liver crude mitochondrial fraction containing lysosomes (ML) was treated with a low concentration of digitonin, lysosomal factors were selectively released without the release of a mitochondrial factor (cytochrome c, Cyt.c). Treatment of ML with Ca(2+) in the presence of inorganic phosphate (P(i)), in contrast, released mitochondrial Cyt.c without the release of lysosomal factors. The obtained lysosomal and mitochondrial factors activated caspase-3 in different manners; caspase-3 activation by lysosomal and mitochondrial factors was specifically suppressed by E-64, a cysteine protease inhibitor, and caspase-9 inhibitor, respectively. Thus, the activation of caspase-3 by lysosomal factors was found to be distinct from the activation by mitochondrial Cyt.c dependent formation of the Apaf-1/caspase-9 complex. To further determine whether or not the activation of caspase-3 by lysosomal cysteine proteases is involved in cellular apoptosis, the effect of E-64-d, a cell-permeable inhibitor of cysteine protease, on 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH)-induced apoptosis in HL-60 cells was investigated. As a result, DNA fragmentation induced by AAPH was found to be remarkably (up to 50%) reduced by pretreatment with E-64-d, indicating the participation of lysosomal cysteine proteases in AAPH-induced apoptosis in HL-60 cells.

Effect of n-3 and n-6 polyunsaturated fatty acids and their ethylesters on stimuli-dependent superoxide generation in neutrophils.

Polymorphonuclear leukocytes from healthy volunteers (HPMN) generated superoxide (O2*-) following treatment with various stimuli, such as phorbol myristate acetate (PMA), opsonized zymozan (OZ) and arachidonic acid (AA). Other types of n-3 polyunsaturated fatty acids (PUFAS), such as docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), also stimulated O2*- generation. The free form of DHA enhanced the generation of O2*- induced by PMA but inhibited that induced by OZ. In contrast, the ethylester of DHA (DHA-E) inhibited O2*- generation induced by PMA but stimulated that induced by OZ. Similar effects were also observed with ethylesters of EPA (EPA-E), DPA (DPA-E) and AA (AA-E). High concentrations of DHA-E reduced the PMA-induced formation of superoxide without affecting the cellular activity of protein kinase C (PKC). Similar phenomena were also observed with oral neutrophils from healthy volunteers (OPMN). These results indicate that PUFAS and their esters affect 02*- generation in human PMN via different pathways, thereby modulating inflammatory reactions.

RIKEN integrated sequence analysis (RISA) system--384-format sequencing pipeline with 384 multicapillary sequencer.

The RIKEN high-throughput 384-format sequencing pipeline (RISA system) including a 384-multicapillary sequencer (the so-called RISA sequencer) was developed for the RIKEN mouse encyclopedia project. The RISA system consists of colony picking, template preparation, sequencing reaction, and the sequencing process. A novel high-throughput 384-format capillary sequencer system (RISA sequencer system) was developed for the sequencing process. This system consists of a 384-multicapillary auto sequencer (RISA sequencer), a 384-multicapillary array assembler (CAS), and a 384-multicapillary casting device. The RISA sequencer can simultaneously analyze 384 independent sequencing products. The optical system is a scanning system chosen after careful comparison with an image detection system for the simultaneous detection of the 384-capillary array. This scanning system can be used with any fluorescent-labeled sequencing reaction (chain termination reaction), including transcriptional sequencing based on RNA polymerase, which was originally developed by us, and cycle sequencing based on thermostable DNA polymerase. For long-read sequencing, 380 out of 384 sequences (99.2%) were successfully analyzed and the average read length, with more than 99% accuracy, was 654.4 bp. A single RISA sequencer can analyze 216 kb with >99% accuracy in 2.7 h (90 kb/h). For short-read sequencing to cluster the 3' end and 5' end sequencing by reading 350 bp, 384 samples can be analyzed in 1.5 h. We have also developed a RISA inoculator, RISA filtrator and densitometer, RISA plasmid preparator which can handle throughput of 40,000 samples in 17.5 h, and a high-throughput RISA thermal cycler which has four 384-well sites. The combination of these technologies allowed us to construct the RISA system consisting of 16 RISA sequencers, which can process 50,000 DNA samples per day. One haploid genome shotgun sequence of a higher organism, such as human, mouse, rat, domestic animals, and plants, can be revealed by seven RISA systems within one month.

Mechanism of dibucaine-induced apoptosis in promyelocytic leukemia cells (HL-60).

Dibucaine, a local anesthetic, inhibited the growth of promyelocytic leukemia cells (HL-60) without inducing arrest of the cell cycle and differentiation to granulocytes. Typical DNA fragmentation and DNA ladder formation were induced in a concentration- and time-dependent manner. The half-maximal concentration of dibucaine required to induce apoptosis was 100 microM. These effects were prevented completely by the pan-caspase inhibitor z-Val-Ala-Asp-(OMe)-fluoromethylketone (z-VAD-fmk), thereby implicating the cysteine aspartase (caspase) cascade in the process. Dibucaine activated various caspases, such as caspase-3, -6, -8, and -9 (-like) activities, but not caspase-1 (-like) activity, and induced mitochondrial membrane depolarization and the release of cytochrome c (Cyt.c) from mitochondria into the cytosol. Processing of pro-caspase-3, -8, and -9 by dibucaine was confirmed by western blot analysis. Bid, a death agonist member of the Bcl-2 family, was processed by caspases following exposure of cells to dibucaine. However, 100 microM dibucaine scarcely inhibited oxidative phosphorylation, but it induced membrane permeability transition in isolated rat liver mitochondria. Taken together, these data suggest that dibucaine induced apoptosis of HL-60 cells through activation of the caspase cascade in conjunction with Cyt.c release induced by a processed product of Bid and depolarization of the mitochondrial membrane potential.

Effects of a magnetic fields on the various functions of subcellular organelles and cells.

Magnetic fields (MF) are widely distributed in environment and their effects are increasing by the development of electrical machines. Several investigators reported that the MF might affect various functions of cells. However, an acceptable hypothesis has not yet been proposed. Thus, we studied the effects of weak MFs on various biological functions of cells, such as mitochondrial functions, stimulation dependent signal transduction of neutrophils, cell growth and transformation of HL-60 cells, H(2)O(2)-induced apoptosis and the expression of apoptotic genes in HL-60 cells. As a result of the study, a weak MF has scarcely any effects on various biological functions of cells. We also studied the direct effect of a static strong MF (SSMF, 600-2000 G) on the functions of cells or on Fe(2+)-induced lipid peroxidation and on reactive oxygen species (ROS) generation in oral polymorphonuclear leukocytes (OPMN) without stimulation using Ferrite magnets. The generation of ROS from OPMN was slightly inhibited but Fe(2+)-induced lipid peroxidation of biological membrane was slightly stimulated by exposure to the SSMF. At present, however, conclusive results have been neither obtained experimentally nor any acceptable idea proposed.

Selective inhibition of formyl-methionyl-leucyl-phenylalanine (fMLF)-dependent superoxide generation in neutrophils by pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

It has been shown previously that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, such as compactin, lovastatin, and pravastatin, block cholesterol synthesis, suppress lymphocyte functions, and beneficially affect atherogenesis. Recently, it was reported that compactin and lovastatin inhibit the respiratory burst of DMSO-differentiated HL-60 cells, an effect reversed by mevalonic acid. The mode of action of these inhibitors in this role is not understood fully. Thus, we studied the mechanism of inhibition of neutrophil superoxide (O2*-) generation by pravastatin and found that pravastatin at 0.5 mM inhibited the receptor-mediated tyrosine kinase (TK)-dependent pathway of O2*- generation and also luminol chemiluminescence but not the protein kinase C (PKC)-dependent or the TK- and PKC-independent pathways of O2*- generation in neutrophils. Pravastatin also inhibited the tumor necrosis factor-alpha- and formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of a tyrosine of a 115-kDa protein. These effects were not reversed by mevalonate. From these results it is concluded that pravastatin inhibited receptor-mediated O2*-generation by decreasing tyrosine phosphorylation but not by inhibiting the formation of an intermediate in the biosynthesis of cholesterol.