Immunologic regulatory effects of human umbilical cord blood-derived mesenchymal stem cells in a murine ovalbumin asthma model.

BACKGROUND: Mesenchymal stem cells (MSCs) have multiple immunomodulatory properties and hold therapeutic potential for inflammatory diseases. However, the therapeutic and immunologic effects of human umbilical cord blood-derived MSCs (huMSCs) remain largely unexamined for asthma. OBJECTIVE: This study was to investigate the immunomodulatory properties of huMSCs in an ovalbumin (OVA)-induced murine asthma model. METHODS: Mice were injected intraperitoneally with OVA and an aluminium hydroxide adjuvant. huMSCs were administered via the tail vein (5×105 cells/100 uL) to female BALB/c mice prior to the initial OVA challenge. The effects of huMSCs were assessed by investigating airway hyperresponsiveness, histological changes, inflammatory cell numbers, serum allergen-specific antibodies, cytokine production in spleen, lung tissue, and bronchoalveolar lavage (BAL) fluid as well as expansion of regulatory T cells. RESULTS: Administration of huMSCs significantly reduced methacholine bronchial hyperresponsiveness and eosinophil counts in BAL cells. Similarly, there was a significant decrease in serum OVA-specific IgE and IgG1 levels along with Th2 cytokine production (IL-4, IL-5, and IL-13) in the lung and spleen tissues, whereas increased percentage of regulatory T cells was observed after treatment with huMSCs. CONCLUSIONS: Our results suggest that huMSC treatment reduces OVA-induced allergic inflammation, which could be mediated by regulatory T cells.

Staphylococcal enterotoxin IgE sensitization in late-onset severe eosinophilic asthma in the elderly.

BACKGROUND: Asthma in the elderly (aged ≥ 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late-onset asthma. Recent studies suggest staphylococcal enterotoxin IgE (SE-IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late-onset elderly asthma. OBJECTIVE: We aimed to examine the associations of SE-IgE sensitization with late-onset asthma in the elderly, using a database of elderly asthma cohort study. METHODS: A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE-IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12-month follow-up period. RESULTS: At baseline, serum SE-IgE concentrations were significantly higher in patients with asthma than in controls [median 0.16 (interquartile range 0.04-0.53) vs. 0.10 (0.01-0.19), P < 0.001]. Elderly asthma patients with high SE-IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE-IgE levels. In multivariate logistic regression analyses, the associations between serum SE-IgE concentrations and severe asthma were significant, independently of covariables [SE-IgE-high (≥ 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86-30.03, P = 0.005]. Multiple correspondence analyses also showed that high serum SE-IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first report on the significant associations of SE-IgE sensitization with late-onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late-onset eosinophilic asthma in the elderly.

Suppression of tumor cell growth both in nude mice and in culture by n-3 polyunsaturated fatty acids: mediation through cyclooxygenase-independent pathways.

Dietary n-3 polyunsaturated fatty acids (PUFAs), as compared with n-6 PUFAs, suppress cellular production of prostaglandins and tumor cell growth both in vitro and in vivo. However, the mechanism by which n-3 PUFAs suppress tumor growth is not understood. We investigated whether the suppression of tumor cell growth by dietary n-3 PUFAs is mediated through inhibition of cyclooxygenase (COX). A colon tumor cell line, HCT-116, that does not express COX was stably transfected with the constitutively expressed COX-1 or the inducible COX-2 cDNA using a retroviral transfection and infection system. Athymic nude mice transplanted with the cells expressing enzymatically active COX were fed isocaloric diets containing either safflower oil or fish oil for 2 weeks before the start of the experiment and for an additional 21 days after transplantation. Both tumor volume and tumor burden (tumor volume/body weight) were significantly reduced in mice fed the fish oil diet as compared with safflower oil-fed mice. This reduction occurred even in control mice that received injections with cells infected with the retroviral vector without COX-1 or COX-2 cDNA. The growth of tumor cells expressing COX was not different from the growth of those transfected with the vector alone in the nude mice and in soft agar. N-3 PUFAs, as compared with linoleic acid, also inhibited the growth of these cells in culture. This growth inhibition by n-3 PUFAs was not affected by COX-1 or COX-2 overexpression. Contrary to general belief, these results indicate that the suppression of tumor growth by dietary n-3 PUFAs is mediated through COX-independent pathways.

Activation and inactivation of cyclo-oxygenase in rat alveolar macrophages by aqueous cigarette tar extracts.

Cyclo-oxygenase (COX) activity and its level of expression, the release of arachidonic acid (AA), and the accumulation of prostaglandins (PGs) were determined in isolated rat pulmonary alveolar macrophages (PAM) exposed to aqueous cigarette tar (ACT) extracts. COX activity increased 3-fold above the initial activity within 2 h of incubation with ACT extracts and gradually decreased below the initial activity after 8 h of incubation. The increased COX activity after 2 h of incubation did not lead to increased accumulation of PGE2. Accumulated levels of PGE2 increased dramatically after 12 h of incubation despite decreased COX activity in cells incubated with ACT extracts. This increased accumulation of PGE2 was greater in cells derived from vitamin E deficient rats compared with control rats. Release of AA from cells was dramatically increased in cells incubated with ACT extracts in parallel to PG accumulation. Thus increased accumulation of PGE2 despite decreased COX activity after 12 h of incubation is likely the result of increased substrate availability. These results suggest that, contrary to earlier reports, cigarette smoke stimulates the formation of PGs in alveolar macrophages. Increased PG production may lead to suppressed immune response and enhanced risk of tumorigenesis in smokers' lungs.

Anti-angiogenic activity of triterpene acids.

Ursolic acid (UA) and oleanolic acid (OA) were examined for anti-angiogenic activities by using the chick embryo chorioallantoic membrane (CAM) assay. The presence of UA or OA inhibited angiogenesis in a dose-dependent manner; the doses required for half-maximal inhibition (ID50) were 5 micrograms and 40 micrograms per CAM, respectively. UA was a more potent angiogenic inhibitor than OA. We also tested for inhibitory effect on the proliferation of bovine aortic endothelial cell. They effectively inhibited the proliferation of bovine aortic endothelial cell in a concentration-dependent manner. The IC50 values of anti-proliferative effects were determined to be 5 microM for UA and 20 microM for OA. Based on these results, we speculated that the inhibitory effects on bovine aortic endothelial cell proliferation of UA and OA might be important for anti-angiogenesis.

Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.

Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor kappaB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor kappaB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.

The first imported case of pulmonary coccidioidomycosis in Korea.

Coccidioidomycosis is an endemic disease found in the southwestern part of North America. Travellers who visit the endemic area may carry the infection. We report a case of pulmonary coccidioidomycosis in a 74-year-old woman. She was healthy before visiting Arizona, U.S.A twice. After returning home, she began to complain of intermittent dry coughing. The symptom was mild, however, and she was treated symptomatically. Later a chest radiograph, which was taken 4 years after the onset of the symptom, showed a solitary pulmonary nodule in the right upper lobe. By percutaneous needle aspiration, a few clusters of atypical cells were noted in the necrotic background. A right upper and middle lobectomy was done. A 1.5 x 1.5 x 1.2 cm sized tan nodule was present in otherwise normal lung parenchyma. Microscopically, the nodule consisted of aggregates of multiple solid granulomas inside of which was mostly necrotic. Neutrophils and nuclear debris were scattered along the periphery of the necrotic foci. Numerous multinucleated giant cells were associated with the granulomas. In the necrotic area, mature spherules of Coccidioides immitis, which were 30-100 microm in diameter, were present. They contained numerous endospores which ranged from 5 to 15 microm and were also noted in multinucleated giant cells. The diagnosis of coccidioidomycosis was made. She is doing well after the resection.

Radiologic assessment in pulmonary lobar transplantation.

UNLABELLED: Pulmonary lobar transplantation provides a clue to the acute donor shortage. To examine the experimental and clinical applicability of lobar transplantation, the authors observed the extent of lung expansion and infiltrate in the allografted lobe through the sequential analysis of the early chest roentgenograms. MATERIALS AND METHODS: Twenty two mongrel dogs weighting 17 kg on average were used. Donor lung bloc was taken and flushed with Euro-Collins solution. The left lower lobar bloc was procured and implanted in the pneumonectomized recipient dog. The anastomosis was performed in the order of the pulmonary vein, artery, and bronchus. To assess the radiological pattern in the lobar allograft, a grading system was designed according to the extent of lung expansion and infiltrate. RESULTS: A) Expansion pattern: Good to excellent lung expansion was seen on postoperative day 0 in 6 out of 10 dogs; on day 1, 4/7; day 2, 3/12; day 3, 1/1; and day 4, 1/3, respectively. Radiographs on day 6, 7, and 12 also showed good expansion in one dog. B) Lung opacity pattern: Clear to minimal infiltrates were seen on day 0 in 8 out of 10 dogs; day 1, 7/17; day 2, 2/12; and day 4, 1/3. The same appearances were detected in a single dog on day 6, 7, and 12. C) Expansion-opacity correlation pattern: Radiographs on postoperative day 0 showed good expansion with mild infiltrates, and excellent expansion with minimal infiltrates were observed on day 1 in 3 out of 17 dogs, day 2, 1/12; and day 4, 1/3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Early allograft function in canine single lung transplant.

An assessment of early graft function in canine single lung transplant recipients was made by analysing early postoperative radiographic progression, lung perfusion, bronchial patency and bronchial anastomotic wound healing and histopathology of the allografted lung. Eighteen mongrel dogs weighing 15kg on average were used. Donor lung bloc with a generous atrial cuff, the pulmonary artery and left bronchus were taken and flushed with Euro-Collins solution which implanted in the pneumonectomized recipient dog. Anastomosis was done with the atrium, pulmonary artery and bronchus in that order. To assess an early graft function, a protocol for a grading system was designed into the chest roentgenogram, lung perfusion scan, bronchial patency and histopathologic progression of the bronchial anastomosis and allografted lung (Table 1). The results were obtained as follows: Radiographically, clear to infiltrate was seen in 67% (8/12), 33% (5/15), 30% (3/10) and 33% (2/6) on postoperative day 0, 1, 2 and 3 respectively. Lobar to total opacification was 33% (4/12), 67% (10/15), 70% (7/10) and 67% (4/6) on days 0 to 3 (Table 2). Perfusion scan showed normal to mild defect in 43% (3/7) and moderate to severe defect in 57% (4/7) on day 0 and 100% (5/5) on day 2 (Table 3). The bronchial anastomotic site showed patent to mild stenosis in 100% (8/8) on day 0 and mild stenosis in 2/2 on day 9 bronchofiberscopically, and showed normal wound healing in 38% (3/8), cellular infiltration in 38% (3/8) and infarction in 25% (2/8) up to day 9 postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis of all possible regioisomers of scyllo-inositol phosphate.

scyllo-Inositol is the all equatorial stereoisomer of myo-inositol. All possible 12 regioisomers of scyllo-inositol phosphate were synthesized for the first time via a scyllo-inositol benzoate intermediate, which was derived from a myo-inositol derivative. The stereoinversion of myo-inositol into scyllo-inositol was accomplished by Mitsunobu reaction of the vicinal cis-diol. The requisite intermediates, scyllo-inositol benzoates were obtained by benzoyl migration or random benzoylation, and phosphorylated to give scyllo-IPn.

Expandable metallic stent placement in patients with benign esophageal strictures: results of long-term follow-up.

PURPOSE: To evaluate the long-term effectiveness of expandable esophageal metallic stents in benign esophageal strictures. MATERIALS AND METHODS: The authors performed long-term follow-up of 14 expandable metallic stents in 12 patients (aged 16-72 years) with benign esophageal strictures. All 12 patients had initially undergone placement of one stent; two patients received an additional stent because of recurrent dysphagia. RESULTS: No procedural complications occurred. Delayed complications occurred in all patients. New strictures formed in six stents (five patients), migration occurred in seven stents (six patients), and both migration and formation of new strictures occurred in one stent (one patient). New stricture formation caused recurrence of dysphagia and necessitated further treatment. Three of four stents that migrated within 2 months after placement but none of the four stents that migrated more than 2 months after placement caused recurrence of dysphagia. Six patients died of unrelated causes 6-20 months after stent placement. The remaining six patients are still alive 24-48 (mean, 35) months after stent placement. CONCLUSION: The long-term effectiveness of expandable metallic stents in benign esophageal strictures is not encouraging because of the high delayed-complication rate. That the patients with migration showed improvement of dysphagia, however, may warrant further investigation of temporary placement of a retrievable covered stent.

Covered, expandable esophageal metallic stent tubes: experiences in 119 patients.

PURPOSE: To study fluoroscopic placement of covered expandable stent tubes in patients with esophagogastric strictures. MATERIALS AND METHODS: Under fluoroscopic guidance, 132 stent tubes were placed in 116 patients with malignant neoplasm; four, in three patients with benign lesions. All patients had aphagia or dysphagia to soft food or liquid. RESULTS: After placement (successful in 100% of cases), 93 (78%) of the patients could ingest solid food; 24 (20%), soft food. Complications in the 119 patients included blockage in 13, stent tube migration in 12, gastroesophageal reflux in nine, severe pain in nine, and delayed massive bleeding in four. Most major complications were managed by means of a balloon catheter, a second stent tube, or analgesics. One hundred four patients died 2-80 weeks after stent placement. CONCLUSION: Treatment with placement of a covered expandable stent tube is effective in most patients with dysphagia due to malignant esophogastric strictures and is less effective in patients with benign strictures.

A survival study of surgically treated lung cancer in Korea. Lung Cancer Surgical Study Group.

Survival rate over a 5-year period were studied in a series of 658 proven primary lung cancer patients treated by thoracic surgeons at 8 institutes during the period from 1976 to 1987 in Korea. The study was designed as a multi-center cooperative work for the statistical analysis of the followup result. Clinical data of age, sex, morbidity, and staging of the tumor were assessed in 540 patients to evaluate their 5-year survival rates. Eventually, 405 resectable patients were analyzed by stage, cell type, surgical procedure, and TNM status. The 5-year actuarial survival rates by stage in the resectable group were: stage I 39.7%, II 30.6% III A 16.3%, III B 6.7%, and IV 0%. The 5-year survival rates by cell type were: squamous cell 31.9%, adenocarcinoma 21.2%, large cell 11%, and small cell 6%. The survival rates by surgical procedures were: lobectomy 30.7% and pneumonectomy 25.7%. The survival rates by TNM status in the operable group were: T1 34.7%, T2 26.8%, T3 7.5%, T4 5%; N1 23%, N2 10%, N3 3%; MO 21%, and M1 0%, respectively. The overall actuarial 5-year survival rate in the group of 405 resectable patients was 25.9%.