Metastatic cancer cells seed the lung via blood vessels. Because endothelial cells generate nitric oxide (NO) in response to shear stress, we postulated that the arrest of cancer cells in the pulmonary microcirculation causes the release of NO in the lung. After intravenous injection of B16F1 melanoma cells, pulmonary NO increased sevenfold throughout 20 minutes and approached basal levels by 4 hours. NO induction was blocked by N G -nitro-L-arginine methyl ester (L-NAME) and was not observed in endothelial nitric oxide synthase (eNOS)-deficient mice. NO production, visualized ex vivo with the fluorescent NO probe diaminofluorescein diacetate, increased rapidly at the site of tumor cell arrest, and continued to increase throughout 20 minutes. Arrested tumor cells underwent apoptosis with apoptotic counts more than threefold over baseline at 8 and 48 hours. Neither the NO signals nor increased apoptosis were seen in eNOS knockout mice or mice pretreated with L-NAME. At 48 hours, 83% of the arrested cells had cleared from the lungs of wild-type mice but only ϳ55% of the cells cleared from eNOS-deficient or L-NAME pretreated mice. eNOS knockout and L-NAME-treated mice had twofold to fivefold more metastases than wild-type mice, measured by the number of surface nodules or by histomorphometry. We conclude that tumor cell arrest in the pulmonary microcirculation induces eNOS-dependent NO release by the endothelium adjacent to the arrested tumor cells and that NO is one factor that causes tumor cell apoptosis, clearance from the lung, and inhibition of metastasis. In the lung, metastatic neoplasms are the most common malignant tumors. Their formation usually involves hematogenous seeding of metastatic cancer cells into the lung from remote primary tumors. Interactions between intravascular cancer cells and the endothelium are important determinants of metastatic outcome. 1,2 For example, the expression of constitutive and inducible microvascular adhesion molecules, and the release of reactive oxygen species (NO, O 2 Ϫ , and H 2 O 2 ) by endothelial cells or cancer cells can regulate the mechanisms that govern the metastatic process, including cancer cell adhesion and arrest, 3 the production of endothelial matrix metalloproteinases, 4 and cancer cell apoptosis. 5 Evidence from in vitro and in vivo studies has shown that reactive oxygen and nitrogen species can be cytotoxic to neoplastic cells 6 -9 and reduced their adhesion to postcapillary venules. 10 In vivo, we have recently demonstrated that the arrest of intravascular B16F1 melanoma cells in the liver induces the rapid local release of nitric oxide (NO) that causes apoptosis of the melanoma cells and inhibits their subsequent development into hepatic metastases. 5 Because pulmonary endothelial cells generate NO in response to shear stress, 11 we have postulated that there is a comparable cytotoxic mechanism in the lung.Here we provide data showing that the arrest of B16F1 melanoma cells in the pulmonary circulation of wild-type C57B1/6 mice (WT mice) induces the ...

Cyclosporine and nifedipine therapy produces gingival overgrowth in many patients. Neither the mechanism underlying this undesirable side effect nor the possibility of synergism between these drugs is known, although many renal transplant patients receive both drugs. This study compared the rates of 3H-glucosamine utilization by three groups of fibroblasts: untreated gingival fibroblasts, fibroblasts from gingival overgrowth tissue of a patient receiving both cyclosporine and nifedipine, and normal gingival fibroblasts exposed to cyclosporine-A in vitro. Significant differences in the rates of deposition of 3H-glucosamine into the extracellular matrix by each group of gingival fibroblasts were demonstrated, suggesting that increased rates of deposition of proteoglycans into the gingival extracellular matrix by fibroblasts should be further investigated as a biologic mechanism for gingival overgrowth.

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The elastic properties of the periodontal ligament have been attributed, in part, to oxytalan fibers, as no other types of elastic fibers are described there. It has been difficult to study the periodontal elastic meshwork by standard microscopic techniques because it is partially obscured by the adjacent periodontal ligament collagen fibers. Our study employed methods which either completely or partially removed mandibular molar periodontal ligament collagen fibers, exposing a previously undescribed periodontal elastic meshwork. The periodontal elastic meshwork was composed of many elastin lamellae containing both peripheral microfibrils of regular arrangement and central microfibrils of irregular arrangement, which could only be demonstrated in oxidized tissues. Peripheral, regularly arranged bundles of microfibrils resembled oxytalan fibers, which were often adherent to the border of the elastin lamella. Elastin lamellae containing irregular microfibrils resembled elaunin fibers. These fibers probably enclosed either blood vessels, nerves or collagen fiber bundles. Peripheral microfibrils attached elaunin to cementum, alveolar bone, blood vessels, and principal periodontal collagen fibers. Thus, the periodontal elastic meshwork is composed of both oxytalan and elaunin fibers. Microfibrils attach elaunin fibers to the adjacent non-elastic tissue and also form bundles which traverse the periodontal ligament space and are probably the oxytalan fibers demonstrable by light microscopic techniques. This meshwork of oxytalan and elaunin fibers probably contributes to tooth support and maintenance of periodontal homeostasis by dissipating chewing forces and maintaining patency of periodontal blood vessels.

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