Publications

IL-6 is a biological marker of ventilator-associated lung injury that may contribute to alveolar barrier dysfunction in acute respiratory distress syndrome. To determine whether IL-6 affects alveolar barrier disruption in a model of ventilator-induced lung injury, we examined alveolar barrier albumin flux in wild-type (WT) mice given an IL-6-blocking Ab (IL6AB) and mice deficient in IL-6 (IL6KO). Albumin flux was significantly higher in mice given IL6AB compared with mice given a control Ab. Unexpectedly, albumin flux was similar in WT and IL6KO mice. To examine the mechanisms for these findings, lung neutrophil accumulation (myeloperoxidase activity) was compared, revealing a correlation between lung neutrophil accumulation and albumin flux. IL6AB mice had significantly more lung neutrophils than WT and IL6KO mice, which were similar. Therefore, to determine whether the cellular source of IL-6 influences neutrophil accumulation and alveolar barrier function, chimeric mice were compared. WT/KO chimeras (WT mice with IL6KO hematopoietic cells) showed significantly greater albumin flux and neutrophil accumulation with mechanical ventilation than WT/WT mice. Neutrophil depletion decreased albumin flux in WT and WT/KO mice. IL6KO neutrophils were more adherent in an in vitro assay compared with WT neutrophils. IL-6 from a hematopoietic cell source limits alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium. Modulation of IL-6 signaling in a cell type-specific fashion may be a therapeutic target for patients with acute lung injury.

BACKGROUND AND AIM

The endoscopic landmark of esophagogastric junction (EGJ) for diagnosis of Barrett's esophagus (BE) differs between Japan and Western countries. Japanese endoscopists use the distal end of the lower esophageal palisade vessels to localize EGJ. In the West, endoscopists use the proximal gastric folds because of concerns that palisade vessels may be difficult to recognize. We evaluated whether there were differences between American and Japanese endoscopists in the recognition of palisade vessels.

METHOD

A total of 82 patients were enrolled in this study. Patients were referred for diagnostic esophagogastroduodenoendoscopy (EGD) at the Veterans Affairs Palo Alto Health Care System, from May to July 2008. American and Japanese endoscopists evaluated the EGJ of patients undergoing diagnostic EGD. We analyzed the differences in the recognition of the distal end of palisade vessels. We calculated the kappa statistic to measure interobserver variability.

RESULTS

Based on localization using the distal end of the palisade vessels, American and Japanese endoscopists identified the EGJ in 87.8% (72/82) and 89.0% (73/82) of cases, respectively. The kappa statistic for visualization of EGJ was 0.88 [95% confidence interval (CI): 0.73-1.00].

CONCLUSION

American and Japanese endoscopists similarly recognized the distal end of palisade vessels as EGJ.

OBJECTIVE

To determine whether the flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin have abnormal pulmonary function.

METHODS

We administered questionnaires and performed pulmonary function testing in 61 never-smoking female flight attendants who worked in active air crews before the smoking ban on commercial aircraft (preban).

RESULTS

Although the preban flight attendants had normal FVC, FEV1, and FEV1/FVC ratio, they had significantly decreased flow at mid- and low-lung volumes, curvilinear flow-volume curves, and evidence of air trapping. Furthermore, the flight attendants had significantly decreased diffusing capacity (77.5% +/- 11.2% predicted normal) with 51% having a diffusing capacity below their 95% normal prediction limit.

CONCLUSIONS

This cohort of healthy never-smoking flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin showed pulmonary function abnormalities suggestive of airway obstruction and impaired diffusion.

We examined the ability of sphingosine-1-phosphate (S1P) to desensitize extracellular signal-related kinase (ERK), a mitogen-activated protein kinase linked to antiapoptotic responses in the heart. In isolated adult mouse cardiomyocytes, S1P (10 nM-5 microM) induced ERK phosphorylation in a time- and dose-dependent manner. S1P stimulation of ERK was completely inhibited by an S1P1/3 subtype receptor antagonist (VPC23019), by a Gi protein inhibitor (pertussis toxin) and by a mitogen-activated protein kinase/ERK kinase inhibitor (PD98059). A selective S1P3 receptor antagonist (CAY10444) had no effect on S1P-induced ERK activation. The selective S1P1 agonist SEW2871 also induced ERK phosphorylation. Activation of ERK by restimulation with 100 nM S1P was suppressed after 1 hour of preincubation with 100 nM S1P but recovered fully the next day, suggesting receptor recycling. Similar results were obtained in protein kinase C epsilon-null cardiomyocytes. Treatment with the nonselective S1P receptor agonist FTY720 for 1 hour also reduced phospho-ERK expression in response to subsequent S1P stimulation. In contrast to S1P, some desensitization to FTY720 persisted after overnight exposure. Cell death induced by hypoxia/reoxygenation was reduced by pretreatment with exogenous S1P. This enhanced survival was abrogated by pretreatment with PD98059, VPC23019, or pertussis toxin. Thus, exogenous S1P induces rapid and reversible S1P1-mediated ERK phosphorylation. S1P-induced adult mouse cardiomyocyte survival requires ERK activation mediated via an S1P1-Gi pathway.

The Informatics and Computational Safety Analysis Staff at the US FDA's Center for Drug Evaluation and Research has created a database of pharmaceutical adverse effects (AEs) linked to pharmaceutical chemical structures and estimated population exposures. The database is being used to develop quantitative structure-activity relationship (QSAR) models for the prediction of drug-induced liver and renal injury, as well as to identify relationships among AEs. The post-market observations contained in the database were obtained from FDA's Spontaneous Reporting System (SRS) and the Adverse Event Reporting System (AERS) accessed through Elsevier PharmaPendium software. The database contains approximately 3100 unique pharmaceutical compounds and 9685 AE endpoints. To account for variations in AE reports due to different patient populations and exposures for each drug, a proportional reporting ratio (PRR) was used. The PRR was applied to all AEs to identify chemicals that could be scored as positive in the training datasets of QSAR models. Additionally, toxicologically similar AEs were grouped into clusters based upon both biological effects and statistical correlation. This clustering created a weight of evidence paradigm for the identification of compounds most likely to cause human harm based upon findings in multiple related AE endpoints.