Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-alpha transgenic mice.

We have developed a transgenic mouse model in which tumor necrosis factor (TNF)-alpha is overexpressed exclusively in the heart under the regulation of the alpha-myosin heavy chain promoter. These animals develop chronic heart failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role of adhesion molecules in mediating cardiac dysfunction in the TNF-alpha transgenic model. TNF-alpha transgenic mice were bred with mice null for intercellular adhesion molecule (ICAM)-1 and P-selectin genes to obtain a lineage of ICAM-1 and P-selectin null mice with selective overexpression of TNF-alpha in the heart. TNF-alpha transgenic animals showed marked upregulation of ICAM-1 mRNA and protein; however, P-selectin mRNA and protein remained undetectable despite chronic TNF overexpression. Cardiac function was markedly improved in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic group versus the ICAM(+/+), P-selectin(+/+), TNF-alpha transgenic group. Kaplan-Meier survival curves showed statistically significant prolonged survival in the ICAM-1(-/-), P-selectin(-/-), TNF-alpha transgenic animals. These data suggest that ICAM-1 mediates at least in part the cardiac dysfunction induced by TNF-alpha expression by cardiac myocytes.

Feasibility of asynchronous independent lung high-frequency oscillatory ventilation in the management of acute hypoxemic respiratory failure: a case report.

OBJECTIVE: To report the first case of the use of asynchronous independent lung high-frequency oscillatory ventilation (AIL-HFOV) in the management of acute hypoxemic respiratory failure in a large pediatric patient with markedly asymmetric lung disease. DESIGN: Case study. SETTING: Tertiary pediatric intensive care unit in a pediatric teaching hospital. PATIENT: A 17-yr-old, 87-kg male patient with trisomy 21 and with respiratory failure and progressive hypoxemia because of pneumonia. INTERVENTIONS: Intubation with a 37-Fr double-lumen endobronchial tube and ventilation with two oscillatory ventilators for a total of 16 days. MEASUREMENTS AND MAIN RESULTS: Hemodynamic data were obtained using a pulmonary artery catheter. Adequate oxygenation and ventilation were readily achieved after institution of AIL-HFOV. The F(IO2)/PaO2 ratio increased from 52 to 224, and the shunt fraction decreased from 40 to 9 after 30 mins of AIL-HFOV. F(IO2) was rapidly reduced from 1.0 to 0.4 on the right lung and to 0.6 on the left lung. Mean arterial pressure was maintained, the cardiac index increased from 3.5 to 5.4 L/min/m2, the systemic vascular resistance index decreased from 1513 to 1225 dyne x sec/cm5 x m2, and the pulmonary vascular resistance index decreased from 723 to 428 dyne x sec/cm5 x m2 without the need for additional fluid boluses or increases in inotropic support. No airleaks developed during the entire hospital stay. CONCLUSIONS: AIL-HFOV improved oxygenation and hemodynamic performance in this large patient. This case demonstrates that it is feasible to use two high-frequency oscillatory ventilators to independently ventilate the lungs of a large patient with markedly asymmetric lung disease. We believe that AIL-HFOV deserves future study and development for the treatment of large patients with acute hypoxemic respiratory failure and asymmetric lung disease when other choices are limited.

Mullerian duct regression and antiproliferative bioactivities of mullerian inhibiting substance reside in its carboxy-terminal domain.

A 25-kilodalton dimeric carboxy-terminal fragment of the recombinant human Mullerian inhibiting substance protein (rhMIS) was produced by proteolytic cleavage with plasmin and purified by size-exclusion chromatography. The identity of the isolated dimer as the carboxy-terminal fragment was confirmed by gel electrophoresis and Western analysis. As was true of every sample of the holo molecule, all preparations of the carboxy-terminal domain of rhMIS (n = 10), when added in the 0.5-5.0 micrograms/ml range, exhibited a dose-dependent partial to complete regression of the 14.5-day fetal rat Mullerian duct in an organ culture assay. The carboxy-terminal dimer also inhibited, in a dose-dependent manner, the growth of A431 cells in monolayer cultures. Daily addition of 5, 10, or 20 micrograms carboxy-terminus for 3 days resulted in 0%, 25%, and 100% inhibition of cell proliferation, respectively. Similar and higher doses of holo rhMIS had no or inconsistent antiproliferative activity (0-34% inhibition), even though the preparations caused Mullerian duct regression. All amino-terminal fragments prepared using this separation protocol were found to be inactive in these assays. These findings suggest that the bioactivity of rhMIS as a regressor of fetal Mullerian ducts and an inhibitor of A431 cell growth resides in its carboxy-terminal domain. These results indicate that the urogenital ridge tissue, but not A431 cells in culture, may be capable of cleaving intact MIS to a biologically active conformation.