No abstract

Rationale: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism. Objectives: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement. Methods: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry. Measurements and Main Results: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis. Conclusions: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.

A simple technique of resident, nursing, and ancillary staff education, combined with alterations in order sets using electronic medical records, can lead to a sustained reduction in laboratory test utilization over time and to significant cost savings without affecting patient safety.

Intrapulmonary factor VII is an effective adjunctive treatment for DAH. We achieved treatment success with both smaller and less frequent doses than those described previously. This may be a good therapeutic option for DAH, particularly when standard therapies have failed or bleeding is immediately life threatening. It is possible that intrapulmonary rFVIIa could save costs, while improving the intensive care unit length of stay. Further prospective studies are needed to assess the optimal dose and frequency for adequate therapeutic efficacy.

IPCs represent a potential treatment for refractory HH and should be used with caution in patients eligible for liver transplantation. Ideally, IPC use for these patients would be evaluated by a multidisciplinary team. IPC use may lead to small decreases in BMI and serum albumin levels in patients over time.