Mast cell stabilizing compound FPL 55618 reduces right ventricular hypertrophy and lung mast cell hyperplasia in chronically hypoxic rats

Summary Rats treated with chronic hypobaric hypoxia (21 days, 380 Torr) and mast cell stabilizing compund FPL 55618 had significantly less right ventricular hypertrophy and lung mast cell hyperplasia than rats subjected to chronic hypoxia alone. Right ventricular blood pressure was not reduced.Compound FPL 55618 was kindly donated by Mr P. Sheard of Fisons Ltd Pharmaceutical Division, Loughborough, Leicestershire, LE11 OQY England.This study was supported by grants from the Medical Research Council of Canada and St. Joseph's Hospital Foundation.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction.

There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.     

Biological implications of preformed mast cell mediators

Mast cells store an impressive array of preformed compounds (mediators) in their secretory granules. When mast cells degranulate, these are released and have a profound impact on any condition in which mast cell degranulation occurs. The preformed mast cell mediators include well-known substances such as histamine, proteoglycans, proteases, and preformed cytokines, as well as several recently identified compounds. Mast cells have recently been implicated in a large number of novel pathological settings in addition to their well-established contribution to allergic reactions, and there is consequently a large current interest in the molecular mechanisms by which mast cells act in the context of a given condition. In many cases, preformed mast cell mediators have been shown to account for functions ascribed to mast cells, and these compounds are hence emerging as major players in numerous pathologies. In this review we summarize the current knowledge of preformed mast cell mediators.     

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction

Summary There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.This work was supported by NIH grant No. HL14985.     

Quantitative cytophotometric analyses of mesenteric mast cell granulation in acute soman intoxicated rats

Effects of the organophosphate neurotoxin soman on rat mesenteric mast cell granule content were determined using scanning-integrating microdensitometric analysis of individual cell metachromasia. Mast cell degranulation was evidenced both with sublethal (0.5 LD50) and lethal (1.5 LD50) dosages and as early as 3-10 min post-injection. These data indicate a possible contribution of mast cell autacoids in the genesis of organophosphate-induced respiratory and circulatory collapse.     

Mast cell tryptase,a still enigmatic enzyme

Tryptases constitute a subfamily of trypsin-like proteinases, stored in the mast cell secretory granules of all mammalian organisms. These enzymes are released along with other mediators into the extracellular medium upon mast cell activation/degranulation. Among the trypsin-like enzymes, tryptases are unique: they are present as active enzymes in the mast cell granules, but display activity only extracellularly, and have a specificity which is much more restricted than trypsin. Tryptases are mostly tetrameric, and in only few organisms (not in humans) are they inhibited by endogenous inhibitors in vitro. The enzymatic and molecular properties of tryptases are far better characterized that any of their plausible biological functions. On the basis of its structural and functional features it could be predicted that tryptase would not degrade a large number of proteins in vivo due to low accessibility to the tetramer central pore where the active sites face inwards. Although their biological function has not yet been clarified, tryptases seem to be involved in a number of mast cell-mediated allergic and inflammatory diseases. In particular, the involvement of tryptase in asthma, an inflammatory disease of the airways often caused by allergy, has been proposed. Here we review the present knowledge on the structure-function relationship of tryptases from different organisms, with special emphasis on human enzymes, and on their role in a variety of pathophsyiological processes.Received 29 October 2003; received after revision 3 December 2003; accepted 11 December 2003     

A comparative study of the gastric ulcerogenic effects of stress and reserpine in rats with decreased stomach wall mast cell populations

Summary Stress-induced gastric glandular ulcers in rats appeared less severe than those evoked by reserpine, although glandular mucosal mast cell counts were equally decreased. Prior depletion of the glandular mucosal mast cell population confirmed the hypothesis that an additional mechanism contributes to reserpine ulceration.     

Quantitative cytophotometric analyses of mesenteric mast cell granulation in acute soman intoxicated rats

Summary Effects of the organophosphate neurotoxin soman on rat mesenteric mast cell granule content were determined using scanning-integrating microdensitometric analysis of individual cell metachromasia. Mast cell degranulation was evidenced both with sublethal (0.5 LD₅₀) and lethal (1.5 LD₅₀) dosages and as early as 3–10 min post-injection. These data indicate a possible contribution of mast cell autacoids in the genesis of organophosphate-induced respiratory and circulatory collapse.Supported by U.S. Army Medical Research and Development Command Contract DAMD-17-81-C-1202.     

Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia

Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.     

Studies on the role of the mast cell in local calcergy

Summary The treatment of animals with disodium chromoglycate and/or cytochalasins which inhibit mast cell degranulation has no influence on the development of local calcergy induced in the mouse by the s.c. injection of lead acetate.     

The exercising heart at altitude

Maximal cardiac output is reduced in severe acute hypoxia but also in chronic hypoxia by mechanisms that remain poorly understood. In theory, the reduction of maximal cardiac output could result from: (1) a regulatory response from the central nervous system, (2) reduction of maximal pumping capacity of the heart due to insufficient coronary oxygen delivery prior to the achievement of the normoxic maximal cardiac output, or (3) reduced central command. In this review, we focus on the effects that acute and chronic hypoxia have on the pumping capacity of the heart, particularly on myocardial contractility and the molecular responses elicited by acute and chronic hypoxia in the cardiac myocytes. Special emphasis is put on the cardioprotective effects of chronic hypoxia. (Part of a multi-author review.)     

The effect of combined chronic hypoxia and N-ethyl-N-nitrosourea on the carotid bodies of rats.

We measured the carotid body volume of rats treated with chronic hypoxia alone and chronic hypoxia together with a single neonatal injection of N-ethyl-N-nitrosourea (10 mg/kg). All the animals so treated showed enlargement of their carotid bodies, but no carotid body chemodectomas occurred.     

The effect of combined chronic hypoxia and N-ethyl-N-nitrosourea on the carotid bodies of rats

Summary We measured the carotid body volume of rats treated with chronic hypoxia alone and chronic hypoxia together with a single neonatal injection of N-ethyl-N-nitrosourea (10 mg/kg). All the animals so treated showed enlargement of their carotid bodies, but no carotid body chemodectomas occurred.This work was supported by a grant from the North West Cancer Research Fund.     

Degranulating activity in hybrid cells derived from rat peritoneal mast cells and ehrlich ascites tumor cells

Summary Fusion of rat mast cells and Ehrlich ascites tumor cells was mediated by HVJ. Compound 48/80-induced degranulation occurred in the fused cells formed from two mast cells and one tumor cell, but not in the fused cells from one mast cell and two or more tumor cells.I am grateful to DrK. Utsumi for valuable discussions and for the donation of HVJ.     

On maximal oxygen consumption in hypoxic humans

The present paper discusses the factors affecting maximal O2 consumption (VO2max) in hypoxia (4300 m above sea level) along the following lines: 1) In acute hypoxia, the fractional limitation to VO2max imposed by circulatory O2 transport (FQ') is 50%, instead of 70% as in normoxia. This is due to the increase in the blood O2 transport coefficient (beta b) as PO2 decreases, as a consequence of the sigmoidal shape of the O2 dissociation curve of hemoglobin. The remaining 50% is assumed to be equally partitioned between tissue O2 transfer (Ft') and mitochondria O2 utilization (Fm'). 2) In chronic hypoxia, FQ' = 0.45, Ft' = 0.20 and Fm' = 0.35, as a consequence of reduced muscle fiber size and muscle mitochondrial density following acclimatization. 3) The relationship between VO2max and PIO2 in both acute and chronic hypoxia reflects the O2 dissociation curve. 4) Acclimatization to chronic hypoxia does not have the function of preserving VO2max.     

Targeting mitochondria by α-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment

Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, α-tocopheryl succinate (α-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by α-TOS was even enhanced. Thus, α-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes α-TOS an attractive candidate for antitumor therapy via mitochondrial targeting.     

Histamine H1- and H2-receptor-mediated gastric microcirculatory effects in the aetiology of stress ulceration in the rat stomach

Stress produced severe mucosal ulcers, increased mucosal microcirculation and lowered mast cell counts in the glandular wall of rat stomachs. Mepyramine i.m. or metiamide i.p. effectively prevented both ulceration and microcirculatory changes but not stress-reduced mast cell counts.     

Imaging of oxygen and hypoxia in cell and tissue samples

Molecular oxygen (O₂) is a key player in cell mitochondrial function, redox balance and oxidative stress, normal tissue function and many common disease states. Various chemical, physical and biological methods have been proposed for measurement, real-time monitoring and imaging of O₂ concentration, state of decreased O₂ (hypoxia) and related parameters in cells and tissue. Here, we review the established and emerging optical microscopy techniques allowing to visualize O₂ levels in cells and tissue samples, mostly under in vitro and ex vivo, but also under in vivo settings. Particular examples include fluorescent hypoxia stains, fluorescent protein reporter systems, phosphorescent probes and nanosensors of different types. These techniques allow high-resolution mapping of O₂ gradients in live or post-mortem tissue, in 2D or 3D, qualitatively or quantitatively. They enable control and monitoring of oxygenation conditions and their correlation with other biomarkers of cell and tissue function. Comparison of these techniques and corresponding imaging setups, their analytical capabilities and typical applications are given.     

Die Leucinaminopeptidaseaktivität des Rattenharnes nach Verabreichung einer mastzellerschöpfenden Substanz

Summary LAP activity was determined in rat urine under normal conditions and following mast cell depletion by compound 48/80. A statistically significant increase in urinary LAP activity is found after administration of compound 48/80. This increase is due to mast cell depletion and the resulting anaphylactoid reaction.