Pathophysiological roles of human chymase

Angiotensin (Ang) II plays an important role in cardiovascular homeostasis such as regulation of blood pressure and tissue remodeling. Alternative Ang II-forming pathways, independent of Ang I converting enzyme (ACE), have been reported. Several serine proteinases including kallikrein, cathepsin G and chymase appear to be involved in ACE-independent Ang II formation in vivo. Among them, biochemical analysis revealed that chymase is a highly efficient Ang II-forming enzyme with a high substrate specificity against Ang I and is rich in various human tissues. However, the pathophysiological roles of chymase have not yet been clarified. Recent reports from us and others indicated that chymase seems to be related to development of atherosclerosis, cardiomyopathy, remodeling of cardiovascular tissues, rheumatoid arthritis and etc. In this review article, the recent findings for chymase related to cardiovascular diseases are summarized.     

Human trophoblast interferons: production and possible roles in early pregnancy

Human villous and extravillous trophoblast populations were isolated from first- and third-trimester placentae and were stimulated with viral and non-viral inducers to produce interferons (IFNs). Polyriboinosinic/polyribocytidylic acid [poly(I:C)] induced exclusively IFN-beta in trophoblast cultures, whereas viruses induced mixtures of IFN-alpha subtypes and -beta. The level of IFN production was dependent on the trophoblast population, type of inducer and the stage of differentiation of the trophoblast. First-trimester extravillous trophoblast cultures produced greater than five-fold more IFN than third-trimester villous trophoblast on a per cell basis, whereas term syncytiotrophoblast produced twice as much IFN as term mononuclear villous trophoblast when stimulated with the same inducer. Pretreatment of trophoblast cultures with platelet-derived growth factor and granulocyte/macrophage-colony stimulating factor (GM-CSF) increased the trophoblast IFN production. Tandem high-performance affinity chromatography of the virus-induced trophoblast IFNs resulted in the isolation of trophoblast IFN-alpha and -beta with specific antiviral activities of 0.75-2.73 x 10(8) IU/ml protein. The trophoblast-induced IFNs have antiproliferative and immunosuppressive properties, and, furthermore, activated natural killer cell activity. These data may suggest the possible roles of these IFNs during embryonic development with regard to protection of the fetus against viral infection and maternal immunity.     

Amylin: physiological roles in the kidney and a hypothesis for its role in hypertension

1. There are high-affinity binding sites for amylin in the renal cortex associated with proximal tubules. These appear to represent seven transmembrane (heptatopic) receptors that are known to form ternary complexes with G-proteins and activate second messenger systems. 2. Amylin stimulates sodium/water reabsorption from the basolateral side of the proximal tubules and plays a role in sodium homeostasis. 3. The transient expression of amylin-like mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. There it is thought to play a role as a growth factor for brush border epithelial cells in the developing kidney and in renal regrowth in the adult kidney. 4. In two models of hypertension, the spontaneously hypertensive rat (SHR) and one created surgically by subtotal nephrectomy, renal amylin receptors are activated. In the SHR, activation precedes the rise in blood pressure and suggests that activation of the amylin system may be an important event in the development of hypertension.     

Characterization and possible roles of fibroblast growth factors in retinal photoreceptor cells

There is increasing evidence that soluble polypeptide growth factors such as those belonging to the fibroblast growth factor (FGF) family play important roles in many aspects of photoreceptor cell biology, including differentiation, continued survival and pathology. At least two members of this family, acidic FGF and basic FGF, are synthesized by, bind to and have profound effects upon these highly specialized retinal first-order neurons. The present review presents an overview of the evidence accumulated to date and will try to suggest future directions for research.     

Role of kinins in basal and furosemide-stimulated renin secretion

OBJECTIVE: To determine risk factors predictive of outcomes to aid in the cost-effective preoperative evaluation and postoperative management of patients who are undergoing tonsillectomy and adenoidectomy for obstructed breathing during sleep. DESIGN: A historical cohort study with a nested case-control analysis that examined risk factors associated with postoperative respiratory complications. SETTING: Children's Medical Center of Dallas, Dallas, Tex, which is a pediatric referral hospital for secondary and tertiary pediatric care with both private and university-appointed physicians. PATIENTS: A convenience sample of 355 patients who were undergoing tonsillectomy and adenoidectomy for obstructed breathing during sleep throughout a 1-year period. INTERVENTION: None. MAIN OUTCOME MEASURE: The occurrence of postoperative complications, including airway obstruction, apneas with oxygen desaturations, airway interventions (e.g., endotracheal intubation), or administration of supplemental oxygen, as they related to associated medical conditions (e.g., cerebral palsy or prematurity) and diagnostic tests (e.g., chest x-ray film and electrocardiogram). RESULTS: Five associated medical conditions (cerebral palsy; seizures; age, < or = 3 years; congenital heart disease; and prematurity) were identified as important predictors of a complicated postoperative course using stepwise logistic regression analysis. Those children with an abnormal chest x-ray film or electrocardiogram were also identified as having an associated medical condition that was predictive of postoperative complications. CONCLUSIONS: Children with 1 or more of the associated risk factors identified should be considered candidates for postoperative inpatient observation. A preoperative chest x-ray film and electrocardiogram were found to be of little predictive value, and they are probably not cost-effective screening tests for postoperative respiratory complications.     

Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone

Mice, homozygous for disrupted ganglioside GM2/GD2 synthase (EC 2.4. 1.94) gene and lacking all complex gangliosides, do not display any major neurologic abnormalities. Further examination of these mutant mice, however, revealed that the males were sterile and aspermatogenic. In the seminiferous tubules of the mutant mice, a number of multinuclear giant cells and vacuolated Sertoli cells were observed. The levels of testosterone in the serum of these mice were very low, although testosterone production equaled that produced in wild-type mice. Testosterone was found to be accumulated in interstitial Leydig cells, and intratesticularly injected testosterone was poorly drained in seminiferous fluid in the mutant mice. These results suggested that complex gangliosides are essential in the transport of testosterone to the seminiferous tubules and bloodstream from Leydig cells. Our results provide insights into roles of gangliosides in vivo.     

Identification of early postmitotic cells in distinct embryonic sites and their possible roles in morphogenesis

This article reviews MRI findings of parasitic diseases of the central nervous system (CNS), with emphasis on neurocysticercosis, which is by far the most common CNS parasitic infection worldwide. MRI findings of neurocysticercosis are various, depending on the location (parenchymal, cisternal, ventricular, and spinal forms), and temporal evolutional stages (vesicular, colloid vesicular, granular nodular, and nodular calcified stages) of the worm. Classical findings of each location and stage are presented. Characteristic MRI findings of cerebral toxoplasmosis frequently seen in patients with acquired immunodeficiency syndrome (AIDS), paragonimiasis, and sparganosis that have most commonly been reported in East Asia are also illustrated. MRI is superior to CT scan in the evaluation of most CNS parasitic infections and is nearly diagnostic, particularly in endemic areas. Contrast-enhanced study is essential not only for specific diagnosis of the disease, but also for assessment of the inflammatory activity.     

Pathophysiological and pathomorphological aspects of pulmonology

The tendency for the wide use of the term "obstructive" in chronic nonspecific lung diseases, which has contemplated in the literature on pulmonology and practice, is discussed. In the author's opinion, the term is invalid since it corresponds neither to the pathomorphological nor pathophysiological essence of data on the diseases and entails poor treatment results.     

Pathophysiological mechanisms of genetic absence epilepsy in the rat

Generalized non-convulsive absence seizures are characterized by the occurrence of synchronous and bilateral spike and wave discharges (SWDs) on the electroencephalogram, that are concomitant with a behavioral arrest. Many similarities between rodent and human absence seizures support the use of genetic rodent models, in which spontaneous SWDs occur. This review summarizes data obtained on the neurophysiological and neurochemical mechanisms of absence seizures with special emphasis on the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). EEG recordings from various brain regions and lesion experiments showed that the cortex, the reticular nucleus and the relay nuclei of the thalamus play a predominant role in the development of SWDs. Neither the cortex, nor the thalamus alone can sustain SWDs, indicating that both structures are intimely involved in the genesis of SWDs. Pharmacological data confirmed that both inhibitory and excitatory neurotransmissions are involved in the genesis and control of absence seizures. Whether the generation of SWDs is the result of an excessive cortical excitability, due to an unbalance between inhibition and excitation, or excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of inhibitory GABAergic mechanisms, remains controversial. The thalamo-cortical activity is regulated by several monoaminergic and cholinergic projections. An alteration of the activity of these different ascending inputs may induce a temporary inadequation of the functional state between the cortex and the thalamus and thus promote SWDs. The experimental data are discussed in view of these possible pathophysiological mechanisms.     

Peripheral benzodiazepine receptors: molecular pharmacology to possible physiological significance in stress-induced hypertension

Simultaneous to the discovery of binding sites for benzodiazepines in the central nervous system (CNS) was the observation that [3H]diazepam also bound to sites in peripheral tissues, including liver, heart, lung, adrenal, and kidney. These "peripheral" benzodiazepine receptors (PBR) have been well characterized, but their physiological significance remains elusive. Researchers have discovered candidates that may serve as endogenous ligands for the PBR. The PBR is both tonically and phasically regulated by neural and hormonal mechanisms. This site also appears to be a critical factor in the rate-limiting step of steroid synthesis, the conversion of cholesterol to pregnenolone in a variety of tissues. In addition, the tissue-specific, stress-induced regulation of renal PBR coupled with the pharmacological simulation of these effects by angiotensin II suggest that the physiological significance of this site in kidney may be related to the pathophysiology of hypertension. The potential relevance of these findings for the development of novel pharmacotherapies for stress-related disorders in humans such as hypertension is discussed.     

Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat

OBJECTIVE: To investigate the pathophysiologic roles of endogenous bradykinin (BK) and des-Arg9-BK on local and systemic inflammatory responses in a rat model of acute arthritis induced by peptidoglycan-polysaccharide (PG-APS). METHODS: Female Lewis rats were injected intraperitoneally with PG-APS. Selective antagonists of B1 (Lys-[Leu8]-des-Arg9-BK) and B2 (Hoe 140) receptors were infused at 500 microg/kg and 5 mg/kg per day for 6 days, starting 3 days before induction of inflammation, with subcutaneous micro-osmotic pumps. The local inflammatory response was assessed by paw edema, joint swelling, and tissue content of BK and des-Arg9-BK. These peptides were measured by highly sensitive and specific chemiluminescent enzyme immunoassays. Systemic inflammatory reaction was evaluated by the hepatic concentration of the type 2 acute-phase protein T-kininogen. RESULTS: PG-APS induced significant paw edema and joint swelling 24-72 hours after intraperitoneal injection. The maximal responses to PG-APS observed at 72 hours were significantly reduced (31-38%) by the combination of both B1 and B2 receptor antagonists at 5 mg/kg per day. PG-APS induced a significant increase of BK (up to 5.3-fold) and des-Arg9-BK (up to 4.1-fold) 72 hours after challenge. Liver T-kininogen content was increased by 5.3-, 7.7-, and 5.8-fold at 24, 48, and 72 hours, respectively, after PG-APS injection. At 24 hours, Hoe 140 and Lys-[Leu8]-des-Arg9-BK increased liver T-kininogen content by 43% and 45%, respectively, but they had no effect at 72 hours. CONCLUSION: The results indicate that endogenous kinins are involved in local and systemic acute inflammatory responses, through both B1 and B2 kinin receptors, in the model of PG-APS-induced arthritis.     

Role of kinins in the acute antihypertensive effect of enalapril in hypertensive rats

1. We used the kinin antagonist HOE 140 to investigate the role of endogenous kinins in the acute antihypertensive effect of the angiotensin converting enzyme inhibitor enalapril in chronic and acute renal hypertensive rats. 2. In normotensive rats, treatment with HOE 140 (33 micrograms/kg, sc) caused a complete blockade of the depressor effect of bradykinin (100 ng, ia) without affecting the depressor effect of sodium nitroprusside (1 microgram, i.v.) or the basal blood pressure. 3. HOE 140 treatment (33 micrograms/kg, sc, plus 330 ng/min, i.v.) did not affect basal blood pressure of chronic (6-7 weeks) one-kidney, one clip and two-kidney, one clip hypertensive rats and in rats with acute hypertension, elicited by unclamping the renal pedicle that had been occluded for 5 h, but HOE 140 completely blocked the hypotensive response to bradykinin (100 ng, ia) during the 60-min period after enalapril administration (2 mg/kg, i.v.). 4. Acutely hypertensive rats treated or not with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) presented a similar fall in blood pressure after enalapril (165 +/- 5 to 137 +/- 6 mmHg and 166 +/- 5 to 136 +/- 6 mmHg, respectively). 5. Untreated two-kidney, one clip hypertensive rats presented a rapid and sustained fall in blood pressure after enalapril (177 +/- 4 to 148 +/- 4 mmHg) that did not differ from the HOE 140-treated (33 micrograms/kg, sc, plus 330 ng/min, i.v.) group (177 +/- 6 to 154 +/- 4 mmHg). 6. One-kidney, one clip hypertensive rats treated with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) showed a significantly smaller fall in blood pressure after enalapril (204 +/- 7 to 179 +/- 9 mmHg) compared to the untreated rats (197 +/- 7 to 149 +/- 2 mmHg). 7. These results indicate that kinin potentiation plays an important role in the antihypertensive effect of acutely administered angiotensin converting enzyme inhibitor in the one-kidney, one clip model of hypertension.     

Pathophysiological response of the blood coagulation system in acute glomerulonephritis

1. The effects of clonidine on blood pressure, cerebral norepinephrine content and vascular structures of the kidneys were investigated in 21 SHR. Although the body weight was not affected by long term clonidine treatment up to 36 weeks, the syatolic blood pressure was significantly reduced. The reduction of the blood pressure was already obvious after 1 week administration of clonidine but the effect was more prominent after long term treatment of 30 weeks or longer. 2. The cerebral norepinephrine content was significantly lower in SHR, regardless of with or without clonidine treatment, than in the control Wistar rats. Although the cerebral norepinephrine content was slightly increased following clonidine treatment SHR, the increase was not statistically significant. 3. Angiographic study of the kidneys revealed a poor opacification of the blood vessels and glomeruli in SHR compared with the control Wistar rats. There was no difference in the sizes of the arcuate and interlobular arteries in SHR and the control Wistar rats, although the medial muscular hypertrophy of the arteries was slightly more prominent in the SHR histologically. The more prominent in the SHR histologically. The angiographic and histologic findings of the renal arteries were not altered following long term clonidine treatment. A possibility was considered that the renal arterioles are mainly functionally affected in SHR.     

Pathophysiological role of the cytokine network in the anterior pituitary gland

Recent evidence has demonstrated that cytokines and other growth factors act in the anterior pituitary gland. Using the traditional criteria employed to determine autocrine or paracrine functions our review shows that, in addition to their role as lymphocyte messengers, certain cytokines are autocrine or paracrine regulators of anterior pituitary function and growth. The cytokines known to regulate and/or be expressed in the anterior pituitary include the inflammatory cytokine family (IL-1 and its endogenous antagonist, IL-1ra; TNF-alpha, and IL-6), the Th1-cytokines (IL-2 and IFN-gamma), and other cytokines such as LIF, MIF, and TGF-beta. This review examines at the cellular, molecular, and physiological levels whether: (1) each cytokine alters some aspect of pituitary physiology; (2) receptors for the cytokine are expressed in the gland; and (3) the cytokine is produced in the anterior pituitary. Should physiological stimuli regulate pituitary cytokine production, this would constitute additional proof of their autocrine/paracrine role. In this context, we analyze in this review the current literature on the actions of cytokines known to regulate anterior pituitary hormone secretion, selecting the in vivo studies that support the direct action of the cytokine in the anterior pituitary. Further support for direct regulatory action is provided by in vitro studies, in explant cultures or pituitary cell lines. The cytokine receptors that have been demonstrated in the pituitary of several species are also discussed. The endogenous production of the homologous cytokines and the regulation of this expression are analyzed. The evidence indicating that cytokines also regulate the growth and proliferation of pituitary cells is reviewed. This action is particularly important since it suggests that intrinsically produced cytokines may play a role in the pathogenesis of pituitary adenomas. The complex cell to cell communication involved in the action of these factors is discussed.     

Interaction between growth factors and kinins in arterial smooth muscle cells

Bradykinin receptors are present on vascular smooth muscle cells; however, the regulation and biological function of these receptors is unclear. To address these questions the interaction between growth factors and kinins in cultured arterial smooth muscle cells has been examined. Based upon the data a hypothesis is presented that platelet-derived growth factor (PDGF) upregulates cell surface bradykinin B2 receptors on arterial smooth muscle cells. The biological effect of the increase in B2 receptors is currently unclear but under certain conditions they may enhance mitogenesis. These mitogenic effects however, are strongly opposed by the effects of bradykinin acting via a B1-type of receptor which mediates potent inhibition of growth factor-induced mitogenesis.