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Biomedical subjects

T Sawa

Publications and source records attributed to T Sawa.

At least 55 records · Page 3Linked to original sources
PubMed1999

The effects of two antiinflammatory pretreatments on bacterial-induced lung injury.

BACKGROUND: Two antiinflammatory therapies that have been effective in preventing acid-induced lung injury were evaluated. Specifically, their effects on a subsequent bacterial-airspace challenge were compared. Bacteria were instilled 24 h after acid-induced lung injury. Pseudomonas aeruginosa PAO-1 was used as the bacteria, because its effects in healthy lungs was documented previously. METHODS: New Zealand white rabbits were anesthetized and three pretreatments were administered: (1) pentoxifylline pretreatment (a 20-mg/kg bolus dose and then 6 mg x kg(-1) x h(-1) given intravenously), (2) 1 ml anti-tumor necrosis factor alpha antiserum given intravenously, or (3) normal saline given intravenously. The pretreatment doses were shown previously to prevent acid-induced lung injury. Then 1.2 ml/kg hydrochloric acid (HCl), pH 1.25, was instilled into the rabbits' right lungs. All the animals underwent mechanical ventilation for 8 h. Twenty-four hours after the acid instillation, the rabbits were anesthetized again and 2 ml/kg (10(9) colony forming units/ml) PAO-1 was instilled into their left lungs. The rabbits' breathing was aided by mechanical ventilation for another 8 h, and then they were killed and exsanguinated. RESULTS: Both pretreatments attenuated the acid-induced lung injury of the noninstilled left lungs. Arterial oxygen tension and the lung edema of pretreated, acid-exposed animals were significantly and almost equally improved (compared with no pretreatments) by either of the pretreatments. However, when the bacteria were instilled into the left lungs 24 h after the acid injury, the pentoxifylline pretreatment but not the anti-tumor necrosis factor alpha pretreatment prevented much of the bacteria-induced lung injury. Pentoxifylline pretreatment significantly improved the measurements of left lung edema and epithelial and endothelial permeability. There was also a trend for improved oxygenation in the pentoxifylline-pretreated and infected animals. In contrast, the anti-tumor necrosis factor alpha pretreatment did not prevent the bacteria-induced lung injury and increased some of the measurements of lung injury. CONCLUSIONS: Two antiinflammatory therapies that prevented acid-induced lung injury to the noninstilled left lungs had significantly different effects on a subsequent bacteria-induced lung injury to the left lungs. The therapies differed in their mechanism of tumor necrosis factor alpha blockade, and this may have affected the bacteria-induced injury to the lungs.

Animals↗
PubMed1999

Effects of antibiotic therapy on Pseudomonas aeruginosa-induced lung injury in a rat model.

The effect of antibiotics on the acute lung injury induced by virulent Pseudomonas aeruginosa PA103 was quantitatively analyzed in a rat model. Lung injury was induced by the instillation of PA103 directly into the right lower lobes of the lungs of anesthetized rats. The alveolar epithelial injury, extravascular lung water, and total plasma equivalents were measured as separate, independent parameters of acute lung injury. Four hours after the instillation of PA103, all the parameters were increased linearly depending on the dose of P. aeruginosa. Next, we examined the effects of intravenously administered antibiotics on the parameters of acute lung injury in D-galactosamine-sensitized rats. One hour after the rats received 10(7) CFU of PA103, an intravenous bolus injection of aztreonam (60 mg/kg) or imipenem-cilastatin (30 mg/kg) was administered. Despite an MIC indicating resistance, imipenem-cilastatin improved all the measurements of lung injury; in contrast, aztreonam, which had an MIC indicating sensitivity, did not improve any of the lung injury parameters. The antibiotics did not generate different quantities of plasma endotoxin; therefore, endotoxin did not appear to explain the differences in lung injury. This in vivo model is useful to quantitatively compare the efficacies of parenteral antibiotic administration on Pseudomonas airspace infections.

Animals↗
PubMed1999

In vitro induction of activation-induced cell death in lymphocytes from chronic periodontal lesions by exogenous Fas ligand.

Periodontitis is a chronic inflammatory disease which gradually destroys the supporting tissues of the teeth, leading to tooth loss in adults. The lesions are characterized by a persistence of inflammatory cells in gingival and periodontal connective tissues. To understand what mechanisms are involved in the establishment of chronic lesions, we hypothesized that infiltrating lymphocytes might be resistant to apoptosis. However, both Bcl-2 and Bcl-xL were weakly detected in lymphocytes from the lesions, compared with those from peripheral blood, suggesting that these cells are susceptible to apoptosis. Nevertheless, very few apoptotic cells were observed in tissue sections from the lesions. Lymphocytes from the lesions expressed mRNA encoding Fas, whereas Fas-ligand mRNA was very weakly expressed in lymphocytes from the lesions and in periodontal tissues. Since the results indicated that lymphocytes in the lesions might be susceptible to Fas-mediated apoptosis but lack the death signal, we next investigated if these lymphocytes actually undergo apoptosis by the addition of anti-Fas antibodies in vitro. Fas-positive lymphocytes from the lesions underwent apoptosis by these antibodies, but Fas-negative lymphocytes and Fas-positive peripheral lymphocytes did not undergo apoptosis by these antibodies. These results indicate that lymphocytes in the lesions are susceptible to activation-induced cell death and are induced to die by apoptosis after the addition of exogenous Fas ligand.

Adult↗
PubMed1999

Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia.

The pathogenesis of septic shock occurring after Pseudomonas aeruginosa pneumonia was studied in a rabbit model. The airspace instillation of the cytotoxic P. aeruginosa strain PA103 into the rabbit caused a consistent alveolar epithelial injury, progressive bacteremia, and septic shock. The lung instillation of a noncytotoxic, isogenic mutant strain (PA103DeltaUT), which is defective for production of type III secreted toxins, did not cause either systemic inflammatory response or septic shock, despite a potent inflammatory response in the lung. The intravenous injection of PA103 did not cause shock or an increase in TNF-alpha, despite the fact that the animals were bacteremic. The systemic administration of either anti-TNF-alpha serum or recombinant human IL-10 improved both septic shock and bacteremia in the animals that were instilled with PA103. Radiolabeled TNF-alpha instilled in the lung significantly leaked into the circulation only in the presence of alveolar epithelial injury. We conclude that injury to the alveolar epithelium allows the release of proinflammatory mediators into the circulation that are primarily responsible for septic shock. Our results demonstrate the importance of compartmentalization of inflammatory mediators in the lung, and the crucial role of bacterial cytotoxins in causing alveolar epithelial damage in the pathogenesis of acute septic shock in P. aeruginosa pneumonia.

Animals↗
PubMed1999

Migration inhibitory factor related protein-8 (MRP-8) is an autocrine chemotactic factor for periodontal ligament cells.

Previous studies have suggested that human periodontal ligament (PDL) cells secrete a chemotactic factor which stimulates motility in an autocrine manner. Here we report the partial amino acid sequence of a purified factor which shows 100% homology with human migration inhibitory factor related protein-8 (MRP-8). In addition, reverse-transcription polymerase chain-reaction (RT-PCR) analysis revealed that mRNA encoding MRP-8 was expressed in cultured human PDL cells. To confirm that MRP-8 is chemotactic for PDL cells, we synthesized 25 mer peptides overlapped by 5 amino acids covering the entire MRP-8 protein and tested them for their chemotactic activities. The data indicated that amino acid residues 21-45 showed chemotactic activity for cultured human PDL cells. The maximum chemotactic response was observed at the concentration of 10(-15) mol/mL for human PDL cells. The chemotactic activity was estimated to be approximately 1000-fold higher than that of platelet-derived growth factor (PDGF), insulin-like growth factors-I and -II (IGF-I, -II), and epidermal growth factor (EGF) when compared on a molar basis. Since MRP-8 is reported to be produced mainly by neutrophils and monocytes, the result of the current study may suggest another important role of MRP-8 in human PDL cells.

Amino Acid Sequence↗
PubMed1999

Lactonamycin, a new antimicrobial antibiotic produced by Streptomyces rishiriensis MJ773-88K4. II. Structure determination.

The absolute structure of a new antibiotic lactonamycin is described. The NMR studies deduced one of four possible structures for the aglycon attached by a rhodinose through glycosidic bond. The stereochemistry of the sugar obtained by an acid hydrolysis was determined to be L-form by measuring optical rotation. The stereochemistry of the aglycon was determined by X-ray crystallographic analysis.

Anti-Bacterial Agents↗
PubMed1999

[Current topics in the regulation of prostanoids--3. Prostanoid synthases and prostanoid receptors].

Formation of biologically active prostanoids from PGH2 occurs through a set of synthases for PGD, PGE, PGF, PGI and TXA2, following the cyclooxygenase reaction. Over the past few years, the genes of several prostanoid synthases have been cloned and the characteristics of the enzymes are now determined. In addition, receptors for prostanoids were also cloned and their structures were determined as G-protein coupled seven-transmembrane domain types belonging to the rhodopsin-type receptor superfamily. Based on these molecular biological findings, the mechanism of the diverse effects of prostanoids are being clarified. Selective inhibitors against the synthases and the selective agonists and antagonists for the prostanoid receptors are now being investigated rapidly for clinical application.

Animals↗
PubMed1999

[Current topics in the regulation of prostanoids--4. The feedback regulation by PPAR-gamma].

Recently, it has become known that lipophilic hormones such as steroids and thyroid hormones, or fat-soluble vitamins (vitamins A and D) pass through the cellular membrane and bind to the nuclear receptor superfamily to act as transcription factors. The metabolite of prostaglandin (PG) D2, 15-deoxy-D12,14PGJ2, has been identified as the ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear receptor superfamily. It forms a transcription factor and is responsible not only for the differentiation of fibroblasts to adipocytes, but also for the regulation of activated macrophages. It is now known that thiazolidinediones and non-steroidal anti-inflammatory drugs classified as cyclooxygenase blockers such as indomethacine and ibuprofen also act as PPAR-gamma agonists and inhibit cytokine production from activated macrophages. PPAR-gamma has become recognized as a new therapeutic target for inflammation control.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

[Intratumoral ethanol injection therapy using endoscopic video information system].

Bronchoscopic ethanol injection (BEI) therapy for endobronchial malignant tumor is thought to be an effective modality for airway dilatation and hemostasis without expensive special equipment. But if ethanol leaks into the airway, it causes severe coughing and erosion of bronchial wall. Using endoscopic video information system (EVIS), an assistant operator can observe an ethanol leak and inject an adequate volume. To evaluate the efficacy and adverse effect of BEI therapy, we treated 8 patients with endobronchial malignant tumor using EVIS. Under local anesthesia, a video-bronchoscope (Olympus BF200 or BF 1T200) was inserted orally, a transbronchial aspiration cytology (TBAC) needle was inserted via the biopsy channel, and injections of 0.2 ml of 99% ethanol into the tumor were repeated. After the tumor degenerated to necrotic tissue, it was removed with a biopsy forceps, and this maneuver was repeated for the existing fresh lesion. The total volume of injected ethanol was 4.5 + 1.6 ml (mean + SD). Airway obstruction and atelectasis were relieved in 4 cases, and hemostasis was obtained in 2 cases. In 2 cases, airway dilatation and hemostasis were not obtained. BEI was more effective in the patients with polypoid or nodular tumor protruding into the airway lumen. As for adverse effects, ethanol leaks caused a severe cough in 2 cases, although they were tolerable and treatment could be continued. BEI therapy using EVIS was thought to be useful to control airway obstruction by endobronchial polypoid tumor with good cost-effectiveness and fewer adverse effects.

Bronchial Neoplasms↗
PubMed1999

[Antimicrobial peptides/proteins--application to the therapy of sepsis].

Many antimicrobial peptides and proteins were discovered recently in various animals. Cecropins are insect-derived antimicrobial peptides which contain 35-39 amino acid residues. Magainins are amphibian-derived antimicrobial peptides with 21-27 amino acid residues. In mammals, defensins, 29-35 amino acid peptides, were identified in the granules of neutrophils and various epithelial cells. In addition, the granules of neutrophils in the mammal have been shown to have several antimicrobial proteins. Among them, bactericidal/permeability increasing protein (BPI) and cationic antimicrobial peptide-18 (CAP 18) have been found to have potent bactericidal activity against gram-negative bacteria and strong lipopolysaccharide-neutralizing function. The recombinant BPIs (recombinant BPI, 23-kDa N-terminal fragment of BPI, and lipopolysaccharide-binding protein-BPI fusion protein) and synthetic peptides derived from C-terminal of CAP 18 are now under investigation for the application to the therapy of sepsis or septic shock.

Animals↗
PubMed1998

Synthesis of anti-rheumatic agent epoxyquinomicin B.

Anti-rheumatic agent (+/-)-epoxyquinomicin B was synthesized for a 22% overall yield in eight steps from commercially available 3-hydroxy-4-nitrobenzaldehyde via the intermediate quinone 6 prepared by selective phenol oxidation of 5 by use of Fremy's salt as the key step.

Antirheumatic Agents↗
PubMed1998

Base-specific separation of oligodeoxynucleotides by capillary affinity gel electrophoresis.

Capillary affinity gel electrophoresis was applied to sequence-specific and base composition-specific recognition of oligodeoxynucleotides, utilizing the formation of heteroduplexes between a nucleic acid analogue immobilized into the capillary gel and soluble oligodeoxynucleotides with different sequences. Capillary affinity gel electrophoresis using capillaries filled with a conjugated gel of polyacrylamide and a synthetic nucleic acid analogue [poly(9-vinyladenine)] was effective for the selective separation of hexathymidylic acid from a mixture of four homopolymers of A6, C6, G6, and T6 and for the complete resolution of five heteropolymers of hexadeoxynucleotides (TAAAAA, TTAAAA, TTTAAA, TTTTAA, TTTTTA). We also demonstrated that capillary affinity gel electrophoresis was useful for the selective and the sensitive sequence-specific recognition of sequence isomers of DNA (TTTTAA, TTTTAAT, TTTATA, and TTTTAA).

Affinity Labels↗
PubMed1998

An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD.

In chronic obstructive pulmonary disease (COPD) which consists of emphysema and chronic bronchitis, alveolar tissue and/or bronchiolar walls are progressively destroyed. This suggests cell death by necrosis and/or apoptosis although no direct evidence of apoptosis has been reported. It was speculated that the apoptosis-related factors are associated with the progression of COPD. Fas/Apo-1 receptor (Fas), Fas ligand (Fas-L) and soluble Fas ligand (sFas-L) are inducers, while soluble Fas (sFas) is an inhibitor of apoptosis. In this study, plasma sFas and sFas-L were measured in 19 COPD patients receiving supplemental O2 (severe COPD) and 20 COPD patients not receiving supplemental O2 (mild/moderate COPD). Twenty-two age- and sex-matched healthy volunteers (healthy controls) and 20 patients receiving supplemental O2 and with level of hypoxaemia similar to severe COPD due to other pulmonary diseases (disease controls) were also examined. Plasma sFas-L was within normal limits in all groups. Plasma sFas levels were similar among healthy controls, disease controls, and mild/moderate COPD patients, but significantly increased in severe COPD (2.6 +/- 1.1, 2.6 +/- 0.2, 2.8 +/- 0.2 and 4.8 +/- 1.0 ng ml-1, respectively). Although PaO2 was lower in severe COPD than in mild/moderate COPD, and PaCO2 was higher in severe COPD than in mild/moderate COPD, they were close between severe COPD and disease controls. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in patients with COPD, but were similar in both severe and mild/moderate COPD patients. We conclude that increased plasma sFas, which is independent of hypoxaemia, and increases in PaCO2, TNF-alpha, IL-6 and inflammation, may be associated with progression of COPD.

Aged↗
PubMed1998

Induction of cyclooxygenase-2 in alveolar macrophages after acid aspiration: selective cyclooxygenase-2 blockade reduces interleukin-6 production.

BACKGROUND: Gastric acid aspiration can result in acute lung injury. In this study, the authors determined whether alveolar macrophages express cyclooxygenase-2 as a source of inflammatory mediators after acid aspiration. METHODS: Seventy-five microliters of hydrochloric acid solution, pH 1.15, was instilled into one lung in mice. After exposure, alveolar macrophages were harvested, and competitive polymerase chain reaction and enzyme-linked immunosorbent assay were performed to measure expression of cyclooxygenase-1 and -2, interleukin-1beta and -6, tumor necrosis factor-alpha, and inducible nitric oxide synthase (iNOS). The authors used immunocytochemistry to demonstrate expression of cyclooxygenase-2 in alveolar macrophages. Selective cyclooxygenase-2 blockade using N-2(-cyclohexyloxy-4-nitrophenyl) methane-sulphonamide was done to characterize prostaglandin-cytokine interaction. RESULTS: Acid aspiration induced upregulation of cyclooxygenase-2 and interleukin-6. Tumor necrosis factor-alpha and iNOS were not upregulated. Interleukin-1beta was upregulated even with saline instillation but could not be detected in the supernatant of the cell culture. Alveolar macrophages harvested from mice instilled with acid showed a trend toward more production of prostaglandin E2 and produced higher concentrations of interleukin-6 compared with alveolar macrophages from mice instilled with saline. Selective cyclooxygenase-2 blockade significantly decreased release of interleukin-6 from alveolar macrophages harvested from mice instilled with acid. CONCLUSIONS: Acid aspiration induces strong expression of cyclooxygenase-2 and production of interleukin-6 in alveolar macrophages. Selective cyclooxygenase-2 blockade reduced production of interleukin-6 by acid-stimulated alveolar macrophages. These studies suggest that the induction of cyclooxygenase-2 plays an important role in the systemic inflammatory response induced by acid aspiration.

Animals↗
PubMed1998

Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model.

CAP18 (cationic antimicrobial protein; 18 kDa) is a neutrophil-derived protein that can bind to and inhibit various activities of lipopolysaccharide (LPS). The 37 C-terminal amino acids of CAP18 make up the LPS-binding domain. A truncated 32-amino-acid C-terminal fragment of CAP18 had potent activity against Pseudomonas aeruginosa in vitro. We studied the antimicrobial and LPS-neutralizing effects of this synthetic truncated CAP18 peptide (CAP18106-137) on lung injury in mice infected with cytotoxic P. aeruginosa. To determine its maximal effect, the CAP18106-137 peptide was mixed with bacteria just prior to tracheal instillation, and lung injury was evaluated by determining the amount of leakage of an alveolar protein tracer (125I-albumin) into the circulation and by the quantification of lung edema. The lung injury caused by the instillation of 5 x 10(5) CFU of P. aeruginosa was significantly reduced by the concomitant instillation of CAP18106-137. However, the administration of CAP18106-137 alone, without bacteria, induced lung edema, suggesting that it has some toxicity. Also, the peptide did not significantly reduce the number of bacteria that had been simultaneously instilled, nor did it significantly improve the survival of the infected mice. The addition of CAP18106-137 to aztreonam along with the bacteria did decrease the level of antibiotic-induced release of inflammatory mediators including tumor necrosis factor alpha, interleukin-6, and nitric oxide and also improved the survival of the mice. Therefore, more investigations are needed to confirm the toxicities and the therapeutic benefits of CAP18106-137 as an adjunctive therapy to antibiotics in the treatment of infections caused by gram-negative bacteria.

Animals↗
PubMed1998

Role of alveolar macrophages in initiation and regulation of inflammation in Pseudomonas aeruginosa pneumonia.

To evaluate the role of alveolar macrophages (AMs) in acute Pseudomonas aeruginosa pneumonia in mice, AMs were depleted by aerosol inhalation of liposomes containing clodronate disodium. AM-depleted mice were then intratracheally infected with 5 x 10(5) CFU of P. aeruginosa. In addition to monitoring neutrophil recruitment and chemokine releases, lung injury was evaluated soon after infection (8 h) and at a later time (48 h). At 8 h, depletion of AMs reduced neutrophil recruitment, chemokine release, and lung injury. At 48 h, however, depletion of AMs decreased bacterial clearance and resulted in delayed movement of neutrophils from the site of inflammation with aggravated lung injury. With instillation of 5 x 10(7) CFU of bacteria, AM-depleted mice showed low mortality within 24 h of infection but high mortality at a later time, in contrast to non-AM-depleted mice. These results demonstrate that depletion of AMs has beneficial early effects but deleterious late effects on lung injury and survival in cases of P. aeruginosa pneumonia.

Acute Disease↗