Hypoxia-inducible factor-1 alpha has a key role in hypoxic preconditioning.

Sublethal hypoxia induces tolerance to subsequent hypoxic insults in a process known as hypoxic preconditioning (HP). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key transcription protein involved in the mechanism of HP. In this study, we investigated the effects of HP on tissue oxygenation and expression of HIF-1 alpha gene targets in the brain using neural cell-specific HIF-1 alpha-deficient mice. The animals were exposed to 8% oxygen for 3 hours. Twenty-four hours later, the oxygen partial pressure (pO(2)) of brain tissue and gene expression were measured during hypoxia. HP improved the pO(2) of brain tissue during subsequent hypoxia with upregulated inducible nitric oxide synthase in wild-type mice, whereas HP had no detectable effect in the mutant mice. Our results indicate that the protective effects of HP may be partially mediated by improving tissue oxygenation via HIF-1 alpha and inducible nitric oxide synthase.

Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development.

The thymus provides a microenvironment that induces the differentiation of T-progenitor cells into functional T cells and that establishes a diverse yet self-tolerant T-cell repertoire. However, the mechanisms that lead to the development of the thymus are incompletely understood. We report herein the results of screening for genes that are expressed in the third pharyngeal pouch, which contains thymic primordium. Polymerase chain reaction (PCR)-based cDNA subtraction screening for genes expressed in microdissected tissues of the third pharyngeal pouch rather than the second pharyngeal arch yielded one transcription factor, MafB, which was predominantly expressed in CD45(-)IA(-)PDGFRalpha(+) mesenchymal cells and was detectable even in the third pharyngeal pouch of FoxN1-deficient nude mice. Interestingly, the number of CD45(+) cells that initially accumulated in the embryonic thymus was significantly decreased in MafB-deficient mice. Alterations of gene expression in the embryonic thymi of MafB-deficient mice included the reduced expression of Wnt3 and BMP4 in mesenchymal cells and of CCL21 and CCL25 in epithelial cells. These results suggest that MafB expressed in third pharyngeal pouch mesenchymal cells critically regulates lymphocyte accumulation in the embryonic thymus.

D-allose protects against endotoxemic acute renal injury.

D-allose is a monosaccharide. We previously reported that D-allose attenuated renal injury by inhibiting the activation of neutrophils after renal ischemia/reperfusion. Lipopolysaccharide (LPS) triggers sepsis syndrome by activating monocytes to produce proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, which potently stimulates the activation of neutrophils. This study was undertaken to examine the effects of D-allose on renal injury in the systemic inflammatory response induced by LPS administration, with emphasis on systemic TNF-alpha and the activation of neutrophils in the rat kidney. Serum and renal TNF-alpha, renal cytokine-induced neutrophil chemoattractant (CINC)-1, and myeloperoxidase (MPO) concentrations, and renal function after LPS administration were evaluated. D-allose (400 mg/kg body weight) inhibited LPS-induced increases in serum and renal TNF-alpha concentrations and renal CINC-1 and MPO concentrations after LPS administration, as well as the subsequent neutrophil-mediated renal injury. These findings may have important implications in understanding the biologic functions of D-allose. D-allose may prove useful in protecting against acute renal injury in systemic inflammatory responses to LPS.

Urinary trypsin inhibitor ameliorates renal tissue oxygenation after ischemic reperfusion in rats.

PURPOSE: In order to determine the mechanism of the protective effect of a urinary trypsin inhibitor (UTI) on renal ischemic reperfusion injury, we measured the tissue oxygen partial pressure pO2 in both the renal cortex and medulla in rats, using electron paramagnetic resonance (EPR) oximetry. METHODS: We allocated the rats to three groups: normal saline (NS) group, a UTI 50,000 U x kg(-1) (LD) group, and a UTI 150,000 U x kg(-1) (HD) group, with the normal saline and UTI being administered 30 min before ischemia. Renal ischemia was achieved by inflating the balloon of a vascular occluder that had been placed around the abdominal aorta just above the bifurcation of the renal artery. Cortical and medullary pO2 were measured every 10 min during ischemia (30 min) and reperfusion (60 min) by EPR oximetry; also, systemic cardiopulmonary parameters were measured. RESULTS: The pO2 in the cortex and medulla decreased to less than 2 mmHg during ischemia in all groups. At 60 min after reperfusion, the pO2 values in the NS group were not fully restored, whereas those in the LD and HD groups were completely restored to the pre-ischemic values. There were no significant differences between the HD and LD groups. There were no differences between any groups in cardiopulmonary parameters. CONCLUSION: Because UTI improved renal oxygenation after reperfusion without changing cardiopulmonary parameters, the pharmacological properties of UTI, such as its renal protection and anti-shock activity, may be explained in part, by this improvement in tissue oxygenation.

Inhibitory effect of d-allose on neutrophil activation after rat renal ischemia/reperfusion.

D-Allose is one of the rare sugars produced from D-psicose. We examined whether d-allose reduces the extent of rat renal ischemia/reperfusion (I/R) injury by suppressing the activation of neutrophils. The renal concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1 and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by D-allose administration. Furthermore, D-allose significantly inhibited the increase in the concentrations of blood urea nitrogen (BUN), creatinine, N-acetyl beta-D-glucosaminidase (NAG) and histopathologic changes after renal I/R. These findings strongly suggest that D-allose protects against I/R-induced renal injury by inhibiting the activation of neutrophils that play an important role in I/R-induced renal injury. These findings may have important implications in understanding the biologic functions of D-allose. D-Allose may prove useful in renal surgery and transplantation.

Urinary trypsin inhibitor reduces inflammatory response in kidney induced by lipopolysaccharide.

Human urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used in Japan as a drug for patients with acute inflammatory disorders such as septic shock and pancreatitis. Lipopolysaccharide (LPS) triggers the sepsis syndrome by activating monocytes to produce proinflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), which potently stimulate the activation of neutrophils. The inhibitory mechanism of UTI on the systemic inflammatory response induced by the intraperitoneal injection of LPS in the kidney is unclear. This study was undertaken to examine the inhibitory effects of UTI on renal injury associated with the systemic inflammatory response induced by LPS stimulation, with emphasis on systemic TNFalpha and the activation of neutrophils in rat kidney. The systemic inflammatory response syndrome was induced by LPS treatment. Serum and renal TNFalpha, renal cytokine-induced neutrophil chemoattractant-1 (CINC-1) and myeloperoxidase (MPO) levels, as well as renal function after LPS stimulation, were evaluated. UTI (50,000 U/kg) inhibited LPS-induced increases in the serum and renal tissue levels of TNFalpha, as well as the renal tissue levels of CINC-1 and MPO after LPS stimulation. UTI (50,000 U/kg) also inhibited the production of serum TNFalpha associated with the systemic inflammatory response syndrome induced by LPS stimulation, thereby attenuating neutrophil infiltration into renal tissues and subsequent neutrophil-mediated renal injury. These findings may have important implications in understanding the biologic functions of UTI. UTI may prove useful in protecting against acute renal injury associated with a systemic inflammatory response.

[Survival after intraoperative pulmonary embolism of a patient with left adrenal tumor].

We report a case of severe shock associated with intraoperative pulmonary embolism (PE). A 15-year-old girl was scheduled to undergo left adrenalectomy and removal of vena cava tumor thrombi. She had suffered from preoperative PE and a temporary IVC filter had been inserted. After left adrenalectomy and removal of vena cava tumor thrombi, IVC was declamped. Forty-five minutes after IVC declamping, circulatory collapse developed with severe hypoxia. Transesophageal echocardiography (TEE) revealed right ventricular dysfunction. We diagnosed PE and immediately started cardiopulmonary resuscitation. Ten minutes later, a stable cardio-respiratory condition was reestablished. TEE findings showed the restoration of right ventricular function. She recovered without any neurological complications. TEE may be useful for diagnosis of acute PE by secondary signs of pulmonary artery obstruction. When intraoperative PE is suspected, TEE should be used for early diagnoss of PE and monitoring cardiac function. This case also suggests that cardiopulmonary resuscitation maneuvers may ameliorate PE itself.

Effects of aging and HIF-1alpha deficiency on permeability of hippocampal vessels.

We examined age-related changes in the blood-brain barrier (BBB) of neural cell-specific hypoxia inducible factor-1alpha (HIF-1alpha) deficient mice, which showed hydrocephalus with neuronal cell loss, to investigate an effect of neural cell-specific HIF-1alpha deficiency or hydrocephalus on vascular function. Vascular permeability of horseradish peroxidase (HRP) and binding of cationized ferritin (CF) particles to the endothelial cell luminal surface, as a marker of glycocalyx, were investigated. The thickness of CF-labeled glycocalyx was significantly decreased in the cortex in mutant mice compared with that of control mice, although it was not paralleled by increased vascular permeability. In addition, strong staining for HRP was seen around vessels located along the hippocampal fissure in 24-month-old mutant mice. The reaction product of HRP appeared in an increasing number of the endothelial cell abluminal vesicles and within the thickened basal lamina of arterioles in the hippocampus, showing increased vascular permeability. There were no leaky vessels in 10-week-old mutant mice or 10-week-old and 24-month-old control mice. These findings suggest the necessity of two factors, aging and hydrocephalus, for BBB dysfunction in HIF-1alpha deficient mice.

Two pathways of apoptosis are simultaneously induced in the embryonal brains of neural cell-specific HIF-1alpha-deficient mice.

The aim of this study was to clarify the mechanism of apoptosis seen in the cortex of neural cell-specific hypoxia inducible factor-1alpha (HIF-1alpha)-deficient embryos. A previous study showed that the neural cells in the cortical area of the mutant embryos underwent apoptosis coincident with vascular regression. Through histological, immunohistochemical, and electron microscopic technique, two kinds of apoptotic cells were detected in the mutant embryonal cortex. Apoptotic cells of one type were clustered in small round structures, 10-20 mum in diameter, whereas the others, present in large numbers, were distributed in a group at the cortical plate located more to the outer side than the round structures. The histochemical and electron microscopic findings indicate that the former represented the appearance of macrophages, in which cellular fragments including vascular cells underwent oxidative stress-related, TNF receptor-mediated, caspase-2-induced apoptosis, while the latter showed c-Myc-related, caspase-3-activated apoptosis of the neural cells. These results suggest that two pathways of apoptosis are induced in neuronal and vascular cells of the cortex in the neural cell-specific HIF-1alpha-deficient mouse.