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Tissue injury that accompanies hypoxemia/reoxygenation shares features with the host response in inflammation, suggesting that cytokines, such as IL-1, may act as mediators in this setting. Human endothelial cells (ECs) subjected to hypoxia (Po2 12-14 Torr) elaborated IL-1 activity into conditioned media in a time-dependent manner; this activity was completely neutralized by an antibody to IL-la. Production of IL-1 activity by hypoxic ECs was associated with an increase in the level of mRNA for IL-ia, and was followed by induction of endothelial-leukocyte adhesion molecule-1 and enhanced expression of intercellular adhesion molecule-1 (ICAM-1 ) during reoxygenation. During reoxygenation there was a three-to fivefold increased adherence of leukocytes, partly blocked by antibodies to endothelial-leukocyte adhesion molecule-1 and ICAM-1. Suppressing endothelial-derived IL-1, using either antibodies to IL-la, specific antisense oligonucleotides or the IL-1 receptor antagonist, decreased leukocyte adherence to reoxygenated ECs, emphasizing the integral role of IL-1 in the adherence phenomenon. Mice subjected to hypoxia (Po2 30-40 Torr) displayed increased plasma levels of IL-la, induction of IL-ia mRNA in the lung, and enhanced expression of ICAM-1 in pulmonary tissue compared with normoxic controls. These data suggest that hypoxia is a stimulus which induces EC synthesis and release of IL-la, resulting in an autocrine enhancement in the expression of adhesion molecules. (J.

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Prolonged exposure to hypoxia, as at high altitude, results in increased vascular permeability that may be ameliorated by administration of glucocorticoids. To understand mechanisms underlying these observations, cultured bovine aortic and pulmonary artery endothelial cells (ECs) were subjected to hypoxia, and changes in monolayer permeability and adenosine 3',5'-cyclic monophosphate (cAMP) levels were assessed. Exposure of both types of cultured ECs to hypoxia (PO2 approximately 14 Torr) led to a time- and dose-dependent increase in monolayer permeability, as measured by diffusion of radiolabeled solutes, which was associated with a progressive decrease in EC cAMP levels from 60 to 15 pmol/mg protein, and a decrease in EC adenylate cyclase activity. The change in endothelial barrier function was prevented by addition of cAMP analogues. Pertussis toxin protected EC monolayers from hypoxia-mediated increase in permeability while maintaining cAMP levels and adenylate cyclase activity. Addition of dexamethasone to EC monolayers before or simultaneously with their incubation under hypoxic conditions blocked the hypoxia-mediated increase in monolayer permeability. Dexamethasone pretreatment also prevented the decline in cAMP and adenylate cyclase levels in oxygen-deprived cultures. These data indicate that hypoxia decreases EC barrier function by lowering adenylate cyclase activity and cellular cAMP levels. They suggest that dexamethasone may exert its protective effect, in part, by preventing the hypoxia-induced decline in adenylate cyclase activity, leading to an increase in cellular cAMP and maintenance of EC barrier function.

IntroductionNitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1±0.4 uM for freshly explanted hearts to 0.7±0.2 and 0.2±0.08 gM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time-and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5 'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist NG-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. (Sigma Chemical Co.). Components were combined within 4 h of donor cardiectomy, and preservation solutions were kept at 4°C. All of these solutions were at the pH of LR (6.6). University of Wisconsin solution (UW) was purchased from Du Pont Co. Blood flow was restored to the graft exactly 1 h after removal from the cold preservation solution, and pulsation of the donor aortic stump was observed to assure patency of the anastomosis. 10 min after removal of the crossclamp, an electrocardiogram (ECG) was taken (polygraph from Grass Instrument Co., Quincy, MA), and the heart was judged by the same 1. Abbreviations used in this paper: 8-Br-cGMP, 8-bromoguanosine 3',5' monophosphate; EC, endothelial cell; HUVEC, human umbilical vein endothelial cell; L-arg, L-arginine; L-NMMA, NG-monomethyl-Larginine; LR, lactated Ringer's solution; NO, nitric oxide; NOS, nitric oxide synthase; NTG, nitroglycerin; UW, University of Wisconsin solution.Nitric Oxide Pathway and Cardiac Preservation for Transplantation 2291 Abstract blinded investigators throughout based on the presence...

To determine the prevalence and the impact of premenstrual symptoms among Japanese adolescent girls, a total of 618 high school students were assessed. Of them, 64.6% were found to suffer from premenstrual symptoms, which is lower than that in adult women. On the other hand, the rates of prevalence of moderate to severe PMS and PMDD in girls were higher than those in adult women. Premenstrual symptoms could have significant consequences by interfering with the daily functioning of adolescent girls.