Unusual enantiomeric separation due to residual amines in chiral crown ether stationary phase linked by long alkyl chain.

A new chiral stationary phase (CSP) in which (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was linked to a silica gel surface through a long alkyl chain and which did not contain additional aminoundecyl groups was prepared. Generally, when enantiomers containing a primary amine group are optically resolved using a crown-ether-type CSP, a higher resolution is achieved if the surface of the CSP does not contain any residual amine. In this study, the chiral separation factor and resolution factor of a CSP with a long alkyl chain such as the aminoundecyl group were unusually low in the absence of the residual aminoundecyl groups. In this study, a chiral column was prepared by introducing a chiral selector having a long alkyl chain on the surface of silica gel to separate enantiomers of α-amino acids. Furthermore, it was confirmed that the residual-amine-containing CSP, which was easier to synthesize, facilitated more effective enantiomeric separation than the CSP without residual amines.

Proline Hinged Amphipathic α-Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics.

Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). Thus, KL-L9P operates as a sensitizer to extend the antibacterial activity of most antibiotics to Gram-negative bacteria.

Oligomer Formation Propensities of Dimeric Bundle Peptides Correlate with Cell Penetration Abilities.

LK-3, an amphipathic dimeric peptide linked by two disulfide bonds, and related isomeric bundles were synthesized, and their cell penetrating abilities were investigated. The measurements using size exclusion chromatography and dynamic light scattering show that LK-3 and its isomers form cell penetrating oligomers. Calculations, performed for various types of peptide isomers, elucidate a strong correlation between the amphipathic character of dimers and cell penetration ability. The results suggest that the amphipathicities of LK-3 and related bundle dimers are responsible for their oligomerization propensities which in turn determine their cell penetrating abilities. The observations made in this study provide detailed information about the mechanism of cell uptake of LK-3 and suggest a plausible insight of the early stage of nanoparticle formation of the cell penetrating amphipathic peptides.

Optimal Methods for the Management of Iatrogenic Colonoscopic Perforation.

BACKGROUND/AIMS: Colonoscopic perforations have been managed with exploratory laparotomy, and have resulted in some morbidity and mortality. Recently, laparoscopic surgery is commonly performed for this purpose. The aim of this study was to compare the outcomes of several management strategies for iatrogenic colonoscopic perforations. METHODS: We retrospectively reviewed the medical records of patients who had been treated for colonoscopic perforation between January 2004 and April 2013 at CHA Bundang Medical Center in Korea. RESULTS: A total of 41 patients with colonoscopic perforation were enrolled. Twenty patients underwent conservative management with a success rate of 90%. Surgical management was performed in 23 patients including two patients who were converted to surgical management after the failure of the initial conservative management. Among 14 patients who underwent surgery at 8 hours after the perforation, there was no considerable difference in adverse outcomes between the laparotomy group and the laparoscopic surgery group. The medical costs and claim rate were 1.45 and 1.87 times greater in the exploratory laparotomy group, respectively. CONCLUSIONS: Conservative management of colonoscopic perforation could be an option for patients without overt symptoms of peritonitis or with a small defect size. If surgical management is required, laparoscopic surgery may be considered as the initial procedure even with a delayed diagnosis.

A case of nodular regenerative hyperplasia of the liver combined with toxic hepatitis.

Nodular regenerative hyperplasia (NRH) is an uncommon liver condition characterized by diffuse transformation of the hepatic parenchyma into regenerative nodules without fibrosis. Portal vasculopathy caused by abnormal hepatic venous flow may induce hepatocyte hyperplasia, which forms regenerative nodules. Underlying diseases or certain drugs may also be the cause of NRH. This condition is often underdiagnosed as the patients remain asymptomatic until development of portal hypertension, and histopathologic confirmation by liver biopsy is the only way of making a definite diagnosis. The management mainly involves prevention and treatment of the complications of portal hypertension. The frequency of diagnosis of NRH has increased rapidly in recent years, however, only a few cases have been reported in Korea. Here, we report on a case of NRH of the liver combined with toxic hepatitis.

Clinical characteristics of acute cholecystitis with elevated liver enzymes not associated with choledocholithiasis.

AIM/BACKGROUND: Elevated liver enzymes are observed occasionally in patients with acute cholecystitis who do not have choledocholithiasis. The etiology and mechanism of this phenomenon are not well known. We aimed to compare the clinical characteristics between acute cholecystitis with and without choledocholithiasis in patients with elevated liver enzymes. PATIENTS AND METHODS: The medical records of acute cholecystitis patients who underwent cholecystectomy between January 2001 and October 2011 were retrospectively reviewed. We retrieved data of patients who showed abnormal liver enzymes and underwent endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, or intraoperative cholangiography. RESULTS: We analyzed clinical characteristics and comorbidities in 424 patients. Among 424 cholecystectomy patients with abnormal liver enzymes, 178 (42%) patients did not have choledocholithiasis and 246 (58%) patients had choledocholithiasis. The median AST, ALT, and total bilirubin were 47, 82.5 IU/dl, and 1.21 mg/dl, respectively, in patients without choledocholithiasis and 58, 96 IU/dl, and 1.53 mg/dl, respectively, in patients with choledocholithiasis. In a multivariate logistic regression analysis, fatty liver [odds ratio (OR): 0.218; P<0.001], radiologic findings (OR: 0.414; P=0.001), and the level of total bilirubin (OR: 1.410; P=0.001) were independent predictors of choledocholithiasis. CONCLUSION: Elevated liver enzymes in patients with cholecystitis who do not have choledocholithiasis are correlated with the presence of fatty liver and the severity of radiologic finding.

Endoscopic resection of giant colonic lipoma: case series with partial resection.

Colonic lipoma, a very rare form of benign tumor, is typically detected incidentally in asymptomatic patients. The size of lipoma is reported variously from 2 mm to 30 cm, with higher likelihood of symptoms as the size is bigger. Cases with symptom or bigger lesion are surgically resected in principle; endoscopic resection, which has developed recently with groundbreaking advance of endoscopic excision technology, is being used more often but with rare report of success due to high chance of complications such as bowel perforation or bleeding. The authors report here, together with a literature review, our experiences of three cases of giant colonic lipomas showing complete remission after aggressive unroofing technique, at certain intervals, using snare catheter at the origin of the lipoma so that the remaining lipoma could be drained out of the exposed surface spontaneously, in order to reduce complications.

Myocardial ischemia caused by paroxysmal supraventricular tachycardia in a patient with anomalous origin of right coronary artery arising from left sinus of valsalva.

Anomalous origin of a coronary artery is rare and does not generally lead to myocardial infarction and paroxysmal supraventricular tachycardia (PSVT). We report an uncommon case of anomalous origin of the right coronary artery (RCA) originating from the left sinus of Valsalva with PSVT and myocardial ischemia. A 58-year-old man presented with PSVT. After arrhythmia subsided, electrocardiogram showed ST and T wave abnormalities, and transient cardiac enzymes were found to be elevated. Coronary CT angiography confirmed that there was anomalous origin of the RCA originating from the left sinus of Valsalva and no intracoronary stenotic lesion. He was managed with conservative treatment, having no symptoms on clinical follow-up for 4 years.

A case of transfusion-related acute lung injury induced by anti-human leukocyte antigen antibodies in acute leukemia.

Transfusion-related acute lung injury (TRALI) is a noncardiogenic pulmonary edema that occurs during or within 6 hours after transfusion. Risk factors for TRALI, which is relatively common in critically ill patients, include recent surgery, hematologic malignancy, and sepsis. Here, we report a case of TRALI induced by anti-human leukocyte antigen (anti-HLA) class II antibodies (HLA-DR) occurring after transfusion of platelet concentrates in a patient with acute leukemia. Although most patients with TRALI show improvement within 48-96 hours, our patient's condition rapidly worsened, and he did not respond to supportive treatment. TRALI is a relatively common and serious adverse transfusion reaction that requires prompt diagnosis and management.

Cysteinyl leukotriene upregulates IL-11 expression in allergic airway disease of mice.

BACKGROUND: Chronic airway inflammation and airway remodeling are important features of bronchial asthma. IL-11 is one of the important mediators involved in the process of airway inflammation and remodeling. Cysteinyl leukotrienes (cysLTs) play roles in recruitment of inflammatory cells, airway smooth muscle contraction, vascular leakage, increased mucus secretion, decreased mucociliary clearance, and airway fibrosis. OBJECTIVE: An aim of the present study was to determine the effect of the cysLTs on the regulation of IL-11 expression. METHODS: We used a C57BL/6 mouse model of allergic airway disease and murine tracheal epithelial cells to examine the effects of cysLTs on the regulation of IL-11 expression. RESULTS: Our present study with an ovalbumin-induced murine model of allergic airway disease revealed that levels of leukotriene C(4) (LTC(4)) in bronchoalveolar lavage fluids were increased and that administration of montelukast or pranlukast reduced the increased levels of LTC(4); the increased expression of IL-11 protein and mRNA in lung tissues; airway inflammation, bronchial hyperresponsiveness; the increased levels of TGF-beta(1), IL-4, and IL-13 in bronchoalveolar lavage fluids and lung tissues; and airway fibrosis. In addition, LTC(4) stimulates epithelial cells to produce IL-11. Our results also showed that cysLT type 1 receptor antagonists downregulated the activity of a transcription factor, nuclear factor kappaB, and BAY 11-7085 substantially reduced the increased levels of IL-11 after ovalbumin inhalation. CONCLUSION: These results suggest that cysLTs regulate the IL-11 expression in allergic airway disease. CLINICAL IMPLICATIONS: These findings provide one of the molecular mechanisms for the effects of cysLTs on airway inflammation and fibrosis in allergic airway diseases.

Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.

Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARgamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARgamma agonist, rosiglitazone, or pioglitazone, and PPARgamma on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-beta1, and NF-kappaB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARgamma agonists or adenovirus carrying PPARgamma2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta1, and NF-kappaB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappaB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta1 after TDI inhalation. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the TDI-induced asthma phenotype.

Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma.

BACKGROUND: Bronchial asthma is characterized by inflammation of the airways, which is usually accompanied by increased vascular permeability, resulting in plasma exudation. Vascular endothelial growth factor (VEGF) has been implicated in contributing to asthmatic tissue edema through its effect on vascular permeability. Many cellular responses of VEGF are regulated by the lipid products of phosphoinositide 3-kinase (PI3K). However, the effect of PI3K catalytic subunit p110delta on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110delta catalytic activity, has been identified. OBJECTIVE: We have sought to investigate the role of PI3K-delta, more specifically in the increase of vascular permeability. METHODS: Female BALB/c mice were sensitized and challenged with ovalbumin. We have investigated the effect of IC87114 on airway inflammation, T(H)2 cytokines expression, airway hyperresponsiveness, plasma extravasation, hypoxia-inducible factor 1alpha expression, and VEGF expression in a murine model of asthma. RESULTS: Our current study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of T(H)2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110delta reduces ovalbumin-induced upregulation of VEGF level. CONCLUSION: These results suggest that PI3K-delta inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice. CLINICAL IMPLICATIONS: These findings provide a crucial molecular mechanism for the potential role of PI3K-delta in asthma and other airway inflammatory disorders.

Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice.

BACKGROUND: Reactive oxygen species (ROSs) play a crucial role in the pathogenesis of airway inflammation. Peroxisome proliferator activated receptor (PPAR)-gamma is also involved in airway inflammation. We have demonstrated that the administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. However, the effects of PPARgamma on ROS generation in conditions associated with airway inflammation have not been clarified. OBJECTIVE: This study aimed to investigate the effects of the PPARgamma on ROS generation in allergic airway disease of mice. METHODS: We have used a female C57BL/6 mouse model for allergic airway disease to determine the role of PPARgamma. RESULTS: In this study with an ovalbumin-induced murine model of allergic airway disease, the increased ROS generation and the increased expression of T(H)2 cell cytokines, adhesion molecules, chemokines, and vascular endothelial growth factor in lungs after ovalbumin inhalation were significantly reduced by the administration of PPARgamma agonists or AdPPARgamma. We also showed that the increased nuclear factor-kappaB and hypoxia-inducible factor 1alpha levels in nuclear protein extracts of lung tissues after ovalbumin inhalation were decreased by the administration of PPARgamma agonists or AdPPARgamma. CONCLUSION: These results indicate that the effects of PPARgamma are mediated by the modulation of ROS generation and activation of redox-sensitive transcription factor nuclear factor-kappaB and HIF-1alpha in allergic airway disease of mice. CLINICAL IMPLICATIONS: Thus, these findings provide a pivotal molecular mechanism for the use of PPARgamma agonists to prevent and/or treat asthma and other airway inflammatory disorders.

Antioxidant down-regulates interleukin-18 expression in asthma.

An alteration in the balance between a T-helper type 2 cell (Th2) response and a Th1 response may predispose to the development of bronchial asthma. Interleukin-18 (IL-18) has an ability to promote both Th1 and Th2 responses, depending on the surrounding cytokine environment. Reactive oxygen species (ROS) play a crucial role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of asthma. In this study, we used a C57BL/6 mouse model of allergic asthma to examine the effects of antioxidants on the regulation of IL-18 expression. Our present study with ovalbumin-induced murine model of asthma revealed that ROS production in cells from bronchoalveolar lavage fluids was increased and that administration of L-2-oxothiazolidine-4-carboxylic acid or alpha-lipoic acid reduced the increased levels of ROS, the increased expression of IL-18 protein and mRNA, airway inflammation, and bronchial hyperresponsiveness. Our results also showed that antioxidants down-regulated a transcription factor, nuclear factor-kappaB (NF-kappaB), activity. These results indicate that antioxidants may reduce IL-18 expression in asthma by inhibiting the activity of NF-kappaB and suggest that ROS regulate the IL-18 expression.

An antioxidant modulates expression of receptor activator of NF-kappaB in asthma.

Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-kappaB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.

Hydrogen peroxide induces vascular permeability via regulation of vascular endothelial growth factor.

Oxidative stress plays critical roles in initiation and/or worsening of respiratory disease process. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce an increase in vascular permeability are not clearly understood. In this study, we have used a murine model to evaluate the effect of hydrogen peroxide (H(2)O(2)) to examine roles of ROS and the molecular mechanism in vascular permeability. The results have revealed that ROS levels, vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor-1alpha protein level, airway hyperresponsiveness, and vascular permeability are increased after inhalation of H(2)O(2). Administration of antioxidants markedly reduced plasma extravasation and VEGF levels in lungs treated with H(2)O(2). These results indicate that ROS may modulate vascular permeability via upregulation of VEGF expression.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) reduces vascular endothelial growth factor expression in allergen-induced airway inflammation.

Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of bronchial asthma. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway. The key role of PI3K in VEGF-mediated signal transduction is established. However, the effects of PTEN on VEGF-mediated signaling in asthma are unknown. This study aimed to determine the effect of PI3K inhibitors and PTEN on VEGF expression in allergen-induced airway inflammation. We have used a female C57BL/6 mouse model for asthma to determine the role of PTEN in allergen-induced airway inflammation, specifically in the expression of VEGF. Allergen-induced airway inflammation leads to increased activity of PI3K in lung tissue. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways; airway hyper-responsiveness; increased expression of interleukin (IL)-4, IL-5, IL-13, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, regulated on activation normal T cell expressed and secreted (RANTES), and eotaxin; increased vascular permeability; and increased levels of VEGF. Administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced the symptoms of asthma and decreased the increased levels of plasma extravasation and VEGF in allergen-induced asthmatic lungs. These results indicate that PTEN reduces VEGF expression in allergen-induced airway inflammation.

Pediatric radiofrequency catheter ablation: results of initial 100 consecutive cases including congenital heart anomalies.

Radiofrequency catheter ablation (RFCA) has recently become a management option for pediatric tachycardia. We reviewed the records of a total of 100 patients (aged 10 months to 19 yr) who had undergone RFCA, from March 2000 to June 2004. Types of arrhythmia (age, acute success rate) were as follows: atrioventricular reentrant tachycardia (AVRT, 9.0+/-3.7 yr, 66/67), atrioventricular nodal reentrant tachycardia (AVNRT, 13+/-2.5 yr, 16/16), ectopic atrial tachycardia (6.4+/-3.3 yr, 5/5), junctional ectopic tachycardia (10 month, 1/1), ventricular tachycardia (12+/-4.9 yr, 6/6), postsurgical intraatrial reentrant tachycardia (15.6+/-4.1 yr, 2/3), twin node tachycardia (4 yr, 0/1), and His bundle ablation (9 yr, 1/1). The age of AVNRT was older than that of AVRT (p=0.002). Associated cardiac disease was detected in 17 patients, including 6 univentricular patients, and 3 Ebstein's anomaly patients. RFCA for multiple accessory pathways required longer fluoroscopic times than did the single accessory pathway (53.9+/-4.8 vs. 36.2+/-24.1 min; p=0.03), and was associated with a higher recurrence rate (3/9 vs. 3/53; p=0.03). Regardless of the presence or absence of cardiac diseases, the overall acute success rate was 97% without major complications, the recurrence rate was 8.2%, and the final success rate was 97%. This experience confirmed the efficacy and safety of RFCA in the management of tachycardia in children.

Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling immune and inflammatory responses. Recent studies have demonstrated that activation of PPARgamma reduces airway hyper-responsiveness and activation of eosinophils that are increased by induction of asthma. We have used a mouse model of asthma to determine the role of PPARgamma in the regulation of the pulmonary immune response, more specifically in the involvement of immunoregulatory cytokine interleukin (IL)-10. Administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced eosinophilic airway inflammation and airway hyper-responsiveness. Expression of PPARgamma was increased by ovalbumin inhalation, and the increase was further enhanced by the administration of PPARgamma agonists or AdPPARgamma. The increased IL-10 levels in lung tissues after ovalbumin inhalation were further increased by the administration of rosiglitazone, pioglitazone, or AdPPARgamma. Levels of IL-4, IL-5, and ovalbumin-specific IgE were also increased after ovalbumin inhalation, and the increased levels were significantly reduced by the administration of the PPARgamma agonists or AdPPARgamma. The results also showed that inhibition of IL-10 activity with anti-IL-10 receptor antibody partially restored the inflammation. These findings suggest that a protective role of PPARgamma in the pathogenesis of the asthma is partly mediated through an IL-10-dependent mechanism.

A prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, regulates vascular permeability by reducing vascular endothelial growth factor expression in asthma.

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Oxidative stress plays critical roles in airway inflammation. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce increased vascular permeability are not clearly understood. We have used a murine model of asthma to evaluate the effect of l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine that acts as an antioxidant, more specifically in the increase of vascular permeability. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of vascular endothelial growth factor (VEGF). Administration of OTC markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that at 72 h after ovalbumin inhalation, increased levels of hypoxia-inducible factor-1alpha (a transcriptional activator of VEGF) in nuclear protein extracts of lung tissues were decreased by the administration of OTC. These results indicate that OTC modulates vascular permeability by lowering VEGF expression.