Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed a decrease in ventilation. The precise mechanism of this decline in ventilation during sustained hypoxia is unknown. Recent studies hypothesized that the accumulation of dopamine in the central nervous system might have a major role in production of hypoxic respiratory depression. The purpose of this study was to examine whether dopamine has an effect on occurance of central ventilatory depression which is seen in acute hypoxia in peripheral chemoreceptors denervated animals. The experiment were conducted in rabbits anesthetized with Na-pentobarbital (25 mg·kg-1 i.v.). For intracerebroventricular (ICV) injections of dopamine (1 μg) in each animal, canula was placed in left lateral cerebral ventricle by stereotaxic method. Respiratory frequency (f·min-1), tidal volume (VT) ventilation minute volume (VE) and systemic arterial blood pressure (BP) were recorded during air and 3 minutes hypoxic gas mixture (8%O2-92%N2) breathing. ICV administration of dopamine during normoxia decreased VT, f, VE and BP, significantly. When rabbits were injected with an ICV dopamine on hypoxic gas mixture breathing in control animals, there was depression of hypoxic ventilatory responses. After ICV administration of dopamine antagonists haloperidol (0.1 mg) and domperidone (0.07 mg) in chemodenervated rabbits, the significant increases in VT, VE and BP were observed. On the breathing of hypoxic gas mixture of chemodenervated and ICV dopamine antagonists administrated rabbits, hypoxic depression was completely abolished. These results of this study show that accumulation of dopamine in the brain seems to reduce the response of the central control mechanisms to chemoreceptor impulses during normoxia and hypoxia. In conclusion present study suggests important role played by central dopaminergic pathways in the occurence of acute hypoxic ventilatory depression.
CD4+HLA-DR+ T cells are known to be increasing in broncho-alveolar lavage fluid (BALF) from patients with sarcoidosis, and related to disease activity. Although there are several reports that the number of γδ T cells in peripheral blood from patients with sarcoidosis are increasing, contradictory assertions can be seen about the number of γδ T cells in BALF, and the clinical significance on the presence of γδ T cells in disease site of patients with diffuse lung disease including sarcoidosis. The absolute number of γδ T cells and CD4+HLA-DR+ T cells in BALF were determined by flow cytometry in 107 patients with diffuse lung diseases; 56 with sarcoidosis, 36 with collagen vascular diseases with lung involvement and 15 with idiopathic pulmonary fibrosis. We also measured the number of the transferrin receptor-positive macrophages in BALF. The correlation between γδ T cells and activated (maybe antigen-specific) T cells and macrophages were evaluated. Sarcoidosis patients were also evaluated from the data of the number of γδ T cells in peripheral blood by flow cytometry and clinical backgrounds. A significant correlation between the numbers of these two cell types was detected in each of the three patient groups. The percentage of peripheral γδ T cells was markedly increased in 7 sarcoidosis patients, each of whom also showed affected organs other than lung, however, 5 individuals did not show an increased number of γδ T cells in BALF. The number of γδ T cells in BALf did not correlate with the number of transferrin receptor-positive macrophages in all three patient groups. These results suggest that the increased number of γδ T cells in diffuse lung diseases likely plays a role in immunosurveillance and contributes to the activation of antigen-specific αβ T cell.
Recently, a few genetic abnormalities were identified in congenital central hypoventilation syndrome (CCHS or Ondine’s curse). CCHS is often associated with other neurocristopathies, especially with Hirschsprung’s disease (HSCR). Mutations of the genes involved in the receptor tyrosine kinase RET (REarranged during Transfection) (RET)-glial cell line-derived neurotrophic factor (GDNF) and/or endothelin 3 (EDN3)-endothelin receptor-B (EDNRB) signaling pathway have been found in some of HSCR patients. In this study, we analyzed candidates for HSCR, namely the RET, GDNF, EDN3 and EDNRB genes in three isolated CCHS patients to confirm the hypothesis that some CCHS patients have a common genetic abnormality with patients having HSCR or other neurocristopathies. We found a novel R114H mutation of the RET gene in one patient. The R114H mutation is unlikely to be a polymorphism and appears to be associated with CCHS. In addition, we also examined the HOX11L2 (RNX) gene, for which knock-out mice showed CCHS-like syndrome in these isolated CCHS patients and did not detected any mutation. Further cases should be analyzed for more candidates to clarify the pathophysiology of CCHS.
The species-specific difference of the immunohistochemical localization of aquaporin-1 (AQP1) and aquaporin-4 (AQP4) was investigated in the cochleae of the 3 different species of rodents, including guinea pig, mouse and Monglian gerbil. In the guinea pig cochlea, intense AQP1-like immunoreactivity was present in the type III fibrocytes in the spiral ligament and the mesenchymal cells just below the basilar membrane. Immunostaining was also found in some type IV fibrocytes in the spiral ligament, fibrocytes in the spiral limbus and mesenchymal cells lining the perilymphatic space against the bony otic capsule. In contrast, no remarkable immunostaining was found in the basilar membrane of the mouse cochlea. The medial part of the Reissner’s membrane was positively immunostained with anti-AQP1 antibody only in the mouse cochlea. In the gerbil cochlea, AQP1-like immunoreactivity was weak compared with the other 2 species. AQP4 was found in the cochlear supporting cells, including Claudius cells, Hensen’s cells and inner sulcus cells of the 3 rodent species. AQP4 was also expressed in some interdental cells of the spiral limbus. Weak immunoreactivity was also found in the root cells only in the upper turns of the guinea pig cochlea. In contrast, no detectable immunoreactivity was found in the root cells of the other 2 species. The results obtained in the present study provide the first evidence for the existence of the species differences in the expression of the AQP1 and AQP4 proteins in the rodent cochlea.
Plasminogen activator inhibitor-1 (PAI-1) is one of the target genes of hypoxia inducible factor-1α (HIF-1α). Besides being an important physiological regulator of the fibrinolytic system PAI-1 is also involved in cancer invasiveness. HIF-1α is expressed in various types of pulmonary cells, but the relation of PAI-1 to HIF-1α under hypoxic condition in these cells are not fully elucidated. We, therefore, studied the effect of hypoxia on the expression of PAI-1 in a lung cancer cell line EBC-1. The expression of HIF-1α protein in EBC-1 cells was enhanced by hypoxia, and this was associated with increased secretion of PAI-1. Hypoxia did not affect the levels of HIF-1α mRNA but enhanced the PAI-1 mRNA. Pretreatment of the cells with MG132, which inhibits the proteasomal degradation of HIF-1α, increased the production of PAI-1 under both normoxia and hypoxia. We conclude that hypoxia induces PAI-1 expression, in EBC-1 cells, through the stabilization of HIF-1 complex and this may be related to cancer metastasis.
To evaluate the role of interleukin (IL)-18 in endotoxin-induced diaphragm muscle deterioration, we studied three treatment groups, namely, a saline+endotoxin group, an IL-18+endotoxin group and an IL-18 only group using Wistar rats. Five minutes after saline or IL-18 (0.25 μg) injection, E. coli endotoxin (30 mg/kg) was injected intraperitoneally. In the saline+endotoxin group, the force-frequency curves by ANOVA (p<0.01), twitch tension (TT) and slope during contraction time (TT/CT) were significantly lower at 4 hours than those at 0 hours due to endotoxin (p<0.01 and p<0.05, respectively) and nitric oxide (NO) production had increased at 4 hours as shown by NADPH diaphorase staining. In the IL-18+endotoxin group, the decrement of the force-frequency curves in a higher frequency range (50-120 Hz), and the decrements of TT and TT/CT observed at 4 hours in the saline+endotoxin group were significantly prevented, and NO production was blocked at 4 hours. In the IL-18 only group, the force-frequency curves did not change except for fatigability, and NO production did not occur. It is suggested that IL-18 itself naturally blocks NO production, even when endotoxin coexists, resulting in the prevention of deterioration of diaphragm muscle contraction by endotoxin.
Bicarbonate and nitric oxide levels are important humoral factors in the blood and are affected by the human body’s physical condition. There are few reports, however, on changes in blood bicarbonate and nitric oxide levels during exercise and rest. Since urinary bicarbonate and nitric oxide metabolites reflect the levels of bicarbonate and nitric oxide in the blood, we studied circadian changes in 6 female athletes by monitoring their urinary pH and their levels of urinary bicarbonate and nitric oxide metabolites. Measurements were taken during exercise, rest and sleep. Six female athletes participated in a 3-day team handball training camp where they followed a schedule of exercise, rest and sleep. Urinary samples were collected immediately before and after handball training, at bed-time and upon waking. The urinary pH and levels of urinary bicarbonate and nitric oxide metabolites, including nitrite and nitrate, were examined with a blood gas analyzer and a NOx analyzer. The samples collected after handball training, as compared to the samples taken before exercise, showed a decreased pH, a decrease in levels of bicarbonate and little change in NO metabolites. During rest, urinary bicarbonate, NO metabolites and pH increased markedly in all 6 subjects. The levels of urinary bicarbonate, NO metabolites and pH significantly decreased upon waking. This study took into account the subjects’ various physiological conditions when considering the significance of their changes in urinary bicarbonate, NO metabolites and pH during the 3 day handball training program. There were significant circadian changes in the urinary pH, and in the levels of urinary bicarbonate and nitric oxide metabolites, in the athletes involved in the exercise, rest and sleep program at team handball camp.
Two Japanese female adolescents with systemic lupus erythematosus (SLE), known cases of urinary tract involvements: one with biopsy-proven class II lupus nephritis and the other one with lupus cystitis without overt glomerulonephritis (silent lupus), who after more than 4 years’ observation presented with subsequent progression to membranous glomerulonephritis (MGN) following exacerbation of urticarial rash. Although it is well known that lupus nephritis shows histological transformation with time, the late progression to MGN from another World Health Organization histologic pattern has been reported to be less common in pediatric-onset SLE. Although pathogenesis of their MGN remains speculative, these clinical observation might suggest that a possible association between exacerbation of urticarial rash and subsequent progression to MGN in the selected patients with SLE.