Biomedical subjects

K Takeuchi

Publications and source records attributed to K Takeuchi.

At least 109 records · Page 6Linked to original sources

PubMed1999

Significant differences in the frequency of transcriptional units, types and numbers of repetitive elements, GC content, and the number of CpG islands between a 1010-kb G-band genomic segment on chromosome 9q31.3 and a 1200-kb R-band genomic segment on chromosome 3p21.3.

We determined the nucleotide sequence of the entire 1,010,525-bp insert contained in CEPH YAC clone 867e8. This human genomic segment was derived from chromosome 9q31.3 and corresponds to a G-band region. We compared this segment, in terms of structure, with a previously characterized 1,201,033-bp sequence in CEPH YAC936c1 that had come from a portion of human chromosome 3p21.3 corresponding to an R-band region. The two segments were significantly different with respect to the frequency of transcriptional units, the types and numbers of repetitive elements present, their GC content, and the number of CpG islands. Alu elements, GC content, and CpG islands all showed positive correlations with the abundance of exons, but the distribution of LINE1s did not. These observations might reflect an influence of the first three of these features on the functions or expression of genes in the respective regions. In addition to a novel gene (F36) lying at the centromeric end of the 9q segment, we found a cluster of placenta-specific genes within a small section (about 400 kb) on the telomeric side of YAC867e8. This cluster consisted of four apparently unrelated ESTs and two genes, pregnancy-associated plasma protein-A (PAPP-A) and a novel gene (tentatively named EST-YD1). Our characterization of the two chromosomal regions provided evidence that genes are not evenly distributed throughout the human genome, and that gene richness is correlated with the GC content and with the frequency of either Alu elements or CpG islands.

Alu Elements↗

PubMed1999

Transcriptional suppression of rat angiotensin AT1a receptor gene expression by interferon-gamma in vascular smooth muscle cells.

Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cells (VSMC) via its specific receptor AT1 subtype, possibly leading to atherosclerosis in hypertension. On the other hand, a cytokine interferon (IFN)-gamma has been shown to have an anti-atherosclerotic effect. In the present study, we examined a possible role of IFN-gamma in AT1 receptor gene regulation in VSMC. A firefly luciferase expression vector driven by the rat AT1a receptor gene promoter ( approximately 3.2 kb) was transfected into the cultured rat VSMC, and luciferase expression was determined to estimate the transcription function of the AT1a receptor gene promoter. RT-PCR was also carried out to determine mRNA expression of AT1a receptor in VSMC. IFN-gamma treatment decreased AT1a receptor mRNA expression as well as luciferase expression in a dose-dependent manner. The analysis with deletion DNA fragments showed that the IFN-responsive element was located between -987 and -331 positions, where multiple GAS (gamma interferon activated site)-like elements were identified. The expression suppression was reversed by either a MAPKK inhibitor PD98059 or a Jak-2 inhibitor AG-490. These results suggest that IFN-gamma can inhibit AT1 receptor expression at gene transcription level, and that the transcription suppression is dependent on MAP kinase and Jak-2. Inhibition of AT1a receptor expression may possibly be implicated in the anti-atherosclerotic action of IFN-gamma in VSMC.

Animals↗

PubMed1999

Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases.

A duplication in the fibrillin-1 gene has been implicated as the cause of the tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemic sclerosis (SSc). In addition to the production of abnormal fibrillin-1 protein, the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of Choctaw Native Americans with the highest prevalence of SSc yet described, a chromosome 15q haplotype containing the fibrillin-1 gene has been strongly associated with SSc. With a recombinant human fibrillin-1 protein, autoantibodies to fibrillin-1 were detected in the sera of Native American SSc patients that correlated significantly with disease. Abs to fibrillin-1 also were detected in sera from Japanese, Caucasian, and African-American SSc patients. Compared with other ethnic groups, Japanese and Native American SSc patients had significantly higher frequencies of anti-fibrillin-1 Abs. Sera from patients with diffuse SSc, calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasias syndrome and mixed connective tissue disease also had significantly higher frequencies of anti-fibrillin-1 Abs than sera from controls or patients with other non-SSc connective tissue diseases (lupus, rheumatoid arthritis, and Sjögren's syndrome). Ab specificity for fibrillin-1 was demonstrated by the lack of binding to a panel of other purified autoantigens. The results presented demonstrate for the first time the presence of high levels of anti-fibrillin-1 Abs in a significant portion of patients with SSc.

Adult↗

PubMed1999

Thrombopoietin augments stem cell factor-dependent growth of human mast cells from bone marrow multipotential hematopoietic progenitors.

The effects of thrombopoietin (TPO) and/or stem cell factor (SCF) on the development of human mast cells from CD34(+) bone marrow (BM) cells were investigated using a serum-deprived liquid culture system. Mast cells were identified by measurement of intracellular histamine content, immunocytochemical staining, and flow cytometric analysis. Whereas SCF alone generated only a small number of tryptase+ cells, the addition of TPO to the culture containing SCF resulted in an apparent production of mast cells from 3 weeks until at least 15 weeks. Some of the cells reacted with an antichymase monoclonal antibody as well. Based on the effects of growth factor(s) on a later phase of the mast cell growth, TPO may stimulate an early stage of mast cell development in combination with SCF, whereas subsequent growth seems to be supported by SCF alone. Single-cell culture studies indicated that the CD34(+)CD38(-)c-kit+ cells and CD34(+)CD38(+)c-kit+ cells were responsible for the SCF + TPO-dependent mast cell production. Two-step culture assays clearly showed that mast cells originated from multilineage colony-forming cells that had potential to differentiate into neutrophil/mast cell lineages, neutrophil/macrophage/mast cell lineages, or neutrophil/macrophage/mast cell/erythroid lineages. These results suggest that TPO plays an important role in the development of human mast cells from CD34(+) BM cells in concert with SCF, and provide direct evidence of the differentiation into the mast cell lineage of human multipotential BM-derived progenitors.

Cell Differentiation↗

PubMed1999

Pax-6 is required for thalamocortical pathway formation in fetal rats.

Pax-6, a transcription regulatory factor, has been demonstrated to play important roles in eye, nose, and brain development by analyzing mice, rats, and humans with a Pax-6 gene mutation. We examined the role of Pax-6 with special attention to the formation of efferent and afferent pathways of the cerebral cortex by using the rat Small eye (rSey2), which has a mutation in the Pax-6 gene. In rSey2/rSey2 fetuses, cortical efferent axons develop with normal trajectory, at least within the cortical anlage, when examined with immunohistochemistry of the neuronal cell adhesion molecule TAG-1 and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) labeling from the cortical surface. A remarkable disorder was found in the trajectory of dorsal thalamic axons by immunostaining of the neurofilament and the neural cell adhesion molecule L1 and DiI labeling from the dorsal thalamus. In normal rat fetuses, dorsal thalamic axons curved laterally in the ventral thalamus without invading a Pax-6-immunoreactive cell cluster in the ventral part of the ventral thalamus. These axons then coursed up to the cortical anlage, passing just dorsal to another Pax-6-immunoreactive cell cluster in the amygdaloid region. In contrast, in rSey2/rSey2 fetuses, dorsal thalamic axons extended downward to converge in the ventrolateral corner of the ventral thalamus and fanned out in the amygdaloid region without reaching the cortical anlage. These results suggest that Pax-6-expressing cell clusters along the thalamocortical pathway (ventral part of the ventral thalamus and amygdala) are responsible for the determination of the axonal pathfinding of the thalamocortical pathway.

Afferent Pathways↗

PubMed1999

A neurally enriched coronin-like protein, ClipinC, is a novel candidate for an actin cytoskeleton-cortical membrane-linking protein.

Brain-enriched human FC96 protein shows a close sequence similarity to the Dictyostelium actin-binding protein coronin, which has been implicated in cell motility, cytokinesis, and phagocytosis. A phylogenetic tree analysis revealed that FC96 and two other mammalian molecules (p57 and IR10) form a new protein family, the coronin-like protein (Clipin) family; thus hereafter we refer to FC96 as ClipinC. A WD domain and a succeeding alpha-helical region are conserved among coronin and Clipin family members. ClipinC is predominantly expressed in the brain, and discrete areas in the mouse brain were intensely labeled with anti-ClipinC antibodies. ClipinC was also shown to bind directly to F-actin in vitro. Immunocytochemical analysis revealed that ClipinC accumulated at focal adhesions as well as at neurite tips and stress fibers. Furthermore, ClipinC was associated with vinculin, which is a major component of focal contacts. These results indicate that ClipinC is also a component part of the cross-bridge between the actin cytoskeleton and the plasma membrane. These findings and the previously reported function of coronin suggest that ClipinC may play specific roles in the reorganization of neuronal actin structure, a change that has been implicated in both cell motility and growth cone advance.

Actins↗

PubMed1999

Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.

Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.

Animals↗

PubMed1999

Dibasic benzo[B]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[B]thiophenes.

A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.

Structure-Activity Relationship↗

PubMed1999

Usefulness of measurement of plasma atrial natriuretic peptide levels in exercise testing of patients with coronary heart disease.

Atrial natriuretic peptide secretion on exercise testing may be exaggerated by left ventricular dysfunction due to multivessel coronary disease rather than by scintigraphically detectable myocardial ischemia. The measurement of plasma atrial natriuretic peptide levels during exercise test may provide additional information regarding the severity of coronary heart disease.

Aged↗

PubMed1999

Characterization of a 1200-kb genomic segment of chromosome 3p22-p21.3.

We previously determined the nucleotide sequence and characterized the 685-kb proximal half of CEPH YAC936c1, which corresponds to a portion of human chromosome 3p21.3. In the study reported here, we characterized the remaining 515-kb of this YAC clone corresponding to the telomeric half of its human insert. The newly sequenced region contained a total of ten genes including six reported previously: phospholipase C delta 1 (PLCD1), human activin receptor type IIB (hActR-IIB), organic cation transporter-like 1 (OCTL1), organic cation transporter-like 2 (OCTL2), oxidative stress response 1 (OSR1), and human xylulokinase-like protein (XYLB). The remaining four genes present in the telomeric region included two known genes, MyD88 and ACAA, and two novel genes. One (designated ENGL) of the novel sequences was found to encode an amino-acid sequence homologous to the family of DNA/RNA endonucleases, especially endonuclease G. The other gene F56 revealed no significant homology to any known genes. These results disclosed complete physical and transcriptional maps of the 1200-kb region of 3p present in YAC 936c1.

Amino Acid Sequence↗

PubMed1999

Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus.

PIP3BP is a phosphatidylinositol 3,4,5-trisphosphate-binding protein (PIP3BP) abundant in brain, containing a zinc finger motif and two pleckstrin homology (PH) domains. Staining of rat brain cells with anti-PIP3BP antibody and determination of localization of PIP3BP fused to the green fluorescent protein (GFP-PIP3BP) revealed that PIP3BP was targeted to the nucleus. Targeting was dependent on a putative nuclear localization signal in PIP3BP. Generation of PIP3 in the nucleus was detected in H2O2-treated 293T cells, nerve growth factor (NGF)-treated PC12 cells, and platelet-derived growth factor (PDGF)-treated NIH 3T3 cells. Translocation of phosphatidylinositol 3-kinase (PI 3-kinase) to the nucleus and enhanced activity of PI 3-kinase in the nucleus fraction were observed after H2O2 treatment of 293T cells, suggesting that PI 3-kinase can be activated in the nucleus as well as in the membrane after appropriate stimulation of the cells. Co-expression of the constitutively active PI 3-kinase with PIP3BP resulted in exportation of the protein from the nucleus to the cytoplasm, suggesting that PIP3BP can function as a PIP3-binding protein in the intact cells. These results imply that there may be an unknown function of PI 3-kinase in the nucleus.

3T3 Cells↗

PubMed1999

Neutrophilic cell production by combination of stem cell factor and thrombopoietin from CD34(+) cord blood cells in long-term serum-deprived liquid culture.

In the present study, we investigated the effects of stem cell factor (SCF) and/or thrombopoietin (TPO) on the cell production by cord blood CD34(+) cells using a serum-deprived liquid culture system. Although SCF alone supported a modest production of neutrophilic cells and a remarkable generation of mast cells, the addition of TPO to the culture containing SCF caused an apparent generation of neutrophilic cells, identified by immunocytochemical staining and flow cytometric analysis. The significant production of neutrophilic cells by SCF and TPO was persistently observed from 2 weeks to 2 to 3 months of culture. The interaction between SCF and TPO on the neutrophilic cell generation was greater than the combined effects of SCF with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The addition of neutralizing antibody against G-CSF or GM-CSF did not influence the SCF + TPO-dependent neutrophilic cell production. A single-cell culture study showed that not only CD34(+)CD38(+) c-kit+ cells but also CD34(+)CD38(-)c-kit+ cells were responsible for the neutrophilic cell generation. In clonal cell cultures, GM progenitors as well as erythroid progenitors and multipotential progenitors expanded in the cultures supplemented with SCF and TPO. The neutrophilic cells grown by SCF + TPO were at myeloblast to band cell stages, and scarcely matured to segmented neutrophils. In addition, the cells generated by SCF + TPO were stained with monoclonal antibodies against myeloperoxidase, elastase, lactoferrin, and CD11b, but they had negligible levels of alkaline phosphatase (ALP) and CD35. The replating of the CD34(-)c-kit-/low CD15(+) cells grown by SCF + TPO into a culture containing SCF + G-CSF permitted both the terminal maturation into segmented cells and the appearance of ALP and CD35. These results indicate the existence of a G-CSF/GM-CSF-independent system of neutrophilic cell production.

ADP-ribosyl Cyclase↗

PubMed1999

Usefulness of newly designed pigtail catheter with multiple side holes by reducing incidence of ventricular ectopy.

This study was designed to determine whether a newly designed 5 Fr pigtail catheter of Jet Balance with multiple side holes reduces the incidence of ventricular ectopy during left ventriculography. To examine the catheter movement in vitro, we injected a colored glycerin solution by an injector through 5 Fr Jet Balance catheter and 6 Fr conventional pigtail catheter suspended in a water filled, glass container. A recoil of the catheter caused by injection was observed for a 6 Fr conventional catheter; however, no catheter movement was observed when a 5 Fr Jet Balance was used. To evaluate clinical usefulness of the 5 Fr Jet Balance, we compared the number of incidence of ventricular ectopy during left ventriculography between 5 Fr Jet Balance and 6 Fr conventional pigtail catheters. In 104 consecutive patients who underwent left ventriculography, a 5 Fr Jet Balance was used in 55 patients (5 Fr Jet Balance group), and a 6 Fr conventional pigtail in 49 patients (6 Fr conventional pigtail group). The 5 Fr Jet Balance group had a significantly lower incidence of VPB (21.8% vs. 42.9%, P = 0.02), ventricular tachycardia (1.9% vs. 14.3%, P = 0.02), and multiple VPB (9.0% vs. 34.7%, P = 0.001), respectively, than the 6 Fr conventional pigtail group. In conclusion, a 5 Fr Jet Balance pigtail catheter is useful and safe as regard to the incidence of ventricular ectopy during left ventriculography. Cathet. Cardiovasc. Intervent. 48:220-225, 1999.

Aged↗

PubMed1999

Apoptosis of erythroid precursors under stimulation with thrombopoietin: contribution to megakaryocytic lineage choice.

Although the effect of thrombopoietin (TPO) on megakaryocyte production is well established, its role in the commitment of multipotential hematopoietic progenitors to the megakaryocytic lineage remains to be determined. In the present study, we attempted to clarify the determination process of megakaryocytic lineage as a terminal differentiation pathway under stimulation with TPO. Day 7 cultured cells grown by TPO derived from cord blood CD34+ cells were divided into four subpopulations on the basis of CD34 and CD41 expression. The CD34-/CD41- cells showed the labeling pattern of anti-CD42b and anti-CD9 antibodies closer to that of the CD34+/CD41- cells than the CD34+/CD41+ cells. Replating experiments revealed that approximately 40% of the CD34-/CD41- cells proliferated in response to a combination of growth factors, and more than 80% of them were pure erythroid precursors. However, this subpopulation failed to grow/survive and fell into apoptosis in the presence of TPO alone. In contrast, the CD34+/CD41+ cells, which predominantly contained megakaryocytic precursors, exerted a low but significant proliferative potential in the presence of TPO. The insufficient response to TPO of the CD34-/CD41- cells may result from the apparently low expression of c-MpI, as determined by flow cytometric analysis and reverse transcription-polymerase chain reaction analysis. Therefore, these results suggest that the apoptosis of hematopoietic precursors other than megakaryocytic precursors is related to the determination of the terminal differentiation under the influence of TPO.

Antigens, CD↗

PubMed1999

Chemokine production by human megakaryocytes derived from CD34-positive cord blood cells.

To clarify the roles of megakaryocytes and platelets in the responses associated with infection and inflammation, we examined the effects of interleukin (IL) 1, the common mediator of the inflammatory process, on the development and secretory functions of megakaryocytes generated from CD34(+)cord blood cells under stimulation with thrombopoietin (TPO). The addition of IL-1alpha did not influence the generation, endomitosis or expression of surface makers of megakaryocytes, compared with TPO alone. However, IL-1alphaenhanced the ability of megakaryocytes to produce IL-8 and growth-regulating oncogene-alpha(GRO-alpha) in the presence of TPO. In contrast, the production of regulated on activation with normal T cell expressed and secreted (RANTES), platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) were not potentiated. A flow cytometric analysis and a reverse transcription-polymerase chain reaction analysis revealed IL-1 receptor type I (IL-1RI) expression of megakaryocytes generated by TPO. Moreover, the addition of an anti-IL-1RI monoclonal antibody significantly decreased the TPO plus IL-1alpha-induced secretion of IL-8 by the cultured megakaryocytes to the level attained by TPO alone. These results suggest that the production of IL-8 and GRO-alpha (but not RANTES), PF4 and beta-TG, by megakaryocytes is potentiated by signalling through IL-1RI with the aid of TPO. Thus, megakaryocytes and platelets may play an important role in the development of inflammation via chemokine release.

Antigens, CD34↗

PubMed1999

Activation of mitogen-activated protein kinases in in vivo ischemia/reperfused myocardium in rats.

In this study, we investigate the in vivo activation of mitogen-activated protein kinases (MAPK) as important signal transduction cascades observed after myocardial ischemia/reperfusion. Myocardial continuous ischemia and ischemia/reperfusion was produced in Wistar rats. The activities of MAPKs in the ischemic and ischemia/reperfused regions were measured using an in-gel kinase assay, an in vitro kinase assay and Western blot analysis. Activator protein-1 (AP-1) DNA binding activity was determined using an electrophoretic mobility shift assay. DNA fragmentation was detected as DNA ladders by agarose gel electrophoresis. The p46JNK and p55JNK activities of continuous ischemia were significantly increased at 30 min (5.9 and 4.2 fold, respectively P<0.05). Coronary reperfusion increased both p42ERK and p44ERK activities at 30 min (3.0 and 2.3 fold P<0.01), and both p46JNK and p55JNK activities at 30 min (1.4 and 1.7 fold P<0.05). The AP-1 DNA binding activities of continuous ischemia were significantly increased at 1, 3 and 7 days (28, 21 and 17 fold, respectively P<0.01). Coronary reperfusion markedly decreased AP-1 DNA binding activities at 1 (41%P<0.01) and 3 days (48%P<0.05). Myocardial DNA fragmentation was considerably more enhanced by reperfusion than continuous ischemia. In conclusion, our present work provides the first in vivo evidence that ERK and JNK are activated by reperfusion from the activities of continuous ischemia. These signal transduction mechanisms may be partially responsible for the myocardial injury.

Animals↗

PubMed1999

Increased JNK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling.

The in vivo signal transduction pathway, responsible for isoproterenol-induced cardiac hypertrophy or remodeling, remains to be clarified. The purpose of this study was to examine c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), activator protein-1 (AP-1) and nuclear factor-kappa B (NK-kappa B) DNA binding activity, which seem to be important in a signal transduction cascade upstream of the increased level of mRNA expression observed in isoproterenol-induced cardiac remodeling. Rats were continuously infused with saline and isoproterenol by intravenous injection (a short period; 0.5 microgram/kg/min) and an osmotic minipump (a long period; 0.5 or 3 mg/kg/day). Cardiac morphology was measured by echocardiography. JNK and ERK were measured by in gel kinase assay. AP-1 and NF-kappa B DNA binding activity was determined using an electrophoretic mobility shift assay. Echocardiogram showed that the thickness of the left ventricular anterior wall (AW) and left ventricular posterior wall (PW) increased at day 1 in low doses, and at day 1 in high doses. Isoproterenol significantly increased ERK and JNK activity at 15 min after intravenous infusion of 0.5 microgram/kg/min isoproterenol. At late phase about JNK and ERK activity, only a high dose of isoproterenol increased JNK. AP-1 DNA binding activities spurred by low or high doses of isoproterenol administration increased at 12 h, reached their peak of 24.1- and 37.1-fold (P < 0.01), respectively, at 24 h, and thereafter decreased. Although low doses of isoproterenol did not change the level of NF-kappa B DNA binding activities, high doses increased it to 10.9-fold (P < 0.01) at day 2. This study showed increased JNK, ERK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling. AP-1 may contribute to the isoproterenol-induced cardiac remodeling, and JNK or NF-kappa B may also play some roles in it.

Animals↗

PubMed1999

Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats.

Roles of enterobacteria, nitric oxide (NO) and neutrophil in indomethacin-induced small intestinal lesions were examined in rats. Indomethacin (10 mg kg-1), administered s.c. as a single injection, caused haemorrhagic lesions in the small intestine, mostly in the jejunum and ileum. The lesions were first observed 6 h after administration of indomethacin, the severity increasing progressively with time up to 24 h later. Following indomethacin, the enterobacterial numbers, inducible NO synthase (iNOS) activity and NO production in the intestinal mucosa were also increased with time, and changes in the former preceded those in the latter two as well as the occurrence of intestinal damage. Treatment of the animals with both NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine prevented intestinal lesions induced by indomethacin, with suppression of NO production. Both dexamethasone and FR167653 (an inhibitor of interleukin-1 beta/tumour necrosis factor-alpha production) also reduced the severity of intestinal lesions as well as the increase in iNOS activity following administration of indomethacin. Likewise, the occurrence of intestinal lesions was attenuated by pretreatment of the animals with anti-neutrophil serum (ANS). None of these treatments, however, affect the translocation of enterobacteria in the mucosa. By contrast, ampicillin (an anti-bacterial agent) suppressed the increase in mucosal iNOS activity as well as the enterobacterial numbers invaded in the mucosa and inhibited the occurrence of intestinal lesions after administration of indomethacin. These results strongly suggest that enterobacterial translocation in the mucosa is the first step required for activation of various factors such as iNOS/NO and neutrophils, all involved in the pathogenesis of indomethacin-induced intestinal lesions.

Animals↗