Propylthiouracil-induced microscopic polyangiitis.

The use of propylthiouracil (PTU) has been associated with various forms of vasculitis. We herein describe the case of a patient with Grave's disease who, after years of PTU therapy, developed a necrotizing vasculitis with anti-serine protease-3 antibodies. Despite treatment with corticosteroids and cyclophosphamide, the patient died of intra-alveolar hemorrhage secondary to her vasculitis. Based on the vessel size involved, the organ distribution of pathologic findings, and lack of granulomas, autopsy findings were felt to be more consistent with microscopic polyangiitis (MPA) than with her original clinical diagnosis of Wegener's granulomatosis. Her case satisfied both clinical and pathologic criteria for MPA. An MPA diagnosis is important to consider in similar clinical presentations because therapy may just need to be early withdrawal of an inciting drug, such as PTU, and the initiation of corticosteroids without cytotoxic therapy.

Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice.

This study identified the organ and cellular distribution of cationic liposome-DNA complexes injected intravenously into CD-1 mice for gene delivery. DOTIM-cholesterol liposomes were labeled with the fluorescent dye CM-Dil and complexed with plasmid DNA encoding the chloramphenicol acetyltransferase reporter gene. The distribution of the complexes was examined in 29 organs and tissues by fluorescence, confocal, and electron microscopy from 5 min to 24 h after injection. The complexes formed clusters in blood, which were cleared within 20 min. Complexes visible by fluorescence microscopy were taken up by endothelial cells, leukocytes, and macrophages and did not leave the vasculature except in the spleen. At 5 min, the complexes formed a patchy coating on the endothelial surface, but by 4 h, they were internalized into endosomes and lysosomes in organ- and vessel-specific patterns. Uptake by capillary endothelial cells was greatest in the lung, ovary, and anterior pituitary, less in muscle and the heart, and nearly absent in the brain and pancreatic islets. In lymph nodes and intestinal Peyer's patches, the uptake was sparse in capillaries but abundant in high endothelial venules. In the liver and spleen, most of the uptake was in Kupffer cells and macrophages. Measurements of chloramphenicol acetyltransferase reporter gene expression were generally consistent with the pattern of uptake by endothelial cells. The uptake and gene expression were accompanied by a decrease in circulating leukocytes and platelets. Overall, our results showed that the complexes were internalized by endothelial cells in organ- and vessel-specific patterns that did not match any previously identified properties of the microvasculature. The unusual distribution of endothelial cell uptake may be explained by a heterogeneously distributed membrane receptor for which the complexes are ligands.

Salmeterol reduces early- and late-phase plasma leakage and leukocyte adhesion in rat airways.

We examined the effect of salmeterol, a long-acting beta2-adrenergic receptor agonist, on ovalbumin-induced plasma leakage and leukocyte adhesion in tracheal blood vessels of unanesthetized brown Norway rats. Ovalbumin challenge of sensitized rats resulted in both early and late phases of plasma leakage as measured with Evans blue. The early phase occurred during the challenge. The late phase began 2 h after the challenge, peaked at 4 h, and ended by 24 h. Ovalbumin challenge also increased the number of adherent leukocytes in mucosal blood vessels at 4 h. Nebulized salmeterol (5 mg/ml for 10 min) administered before the challenge inhibited the early-phase leak by 26%, 58%, or 85%, depending upon whether the interval between pretreatment and challenge was 0.5, 1, or 4.5 h, respectively. Similarly, salmeterol pretreatment (0.05 to 5 mg/ml for 10 min) reduced the late-phase leak at 4 h. Late-phase leakage was completely blocked at concentrations of 0.5 mg/ml or greater. This inhibitory effect was prevented by prior injection of the beta2-adrenergic receptor antagonist ICI-118,551. Salmeterol pretreatment also reduced the adherence of neutrophils, eosinophils, monocytes, and lymphocytes in mucosal blood vessels at 4 h. We conclude that salmeterol pretreatment can reduce the plasma leakage and leukocyte adhesion in early- and late-phase responses after antigen challenge through its action on beta2 receptors.