Modest Hypoxia Research Articles

COVID-19-Related Spontaneous Aortic Arch Thrombus With Delayed Embolization.

Presentation of a 62-year-old man with baseline chronic obstructive pulmonary disease admitted to the hospital with dyspnea and newly diagnosed COVID-19 infection. CT scan of the chest was obtained to rule out pulmonary embolism. This revealed a mural thrombus of the inner curvature of the aortic arch with a floating component. Therapeutic full dose anticoagulation was initiated in combination with close clinical observation and treatment for modest hypoxia. He did well for 1month and then returned with ischemic rest pain of the right foot. Angiography revealed thrombosis of all 3 tibial arteries in the right leg. Percutaneous mechanical thrombectomy with tissue plasminogen activator injection and angioplasty was performed with success in 1 tibial artery to achieve in line flow to the foot. After continued anticoagulation, the remainder of the tibial arteries autolysed and the aortic thrombus was noted to be resolved 4 months later. A brief pathophysiology discussion is included.

Effects of Modest Hypoxia and Exercise on Cardiac Function, Sleep-Activity, Negative Geotaxis Behavior of Aged Female Drosophila.

Mild normobaric hypoxia (NH) and modest exercise have multiple beneficial effects on health, but the changes in physiological function induced by NH and/or exercise remain unclear. The purpose of this investigation was to examine the specific effects of NH and/or exercise on cardiac function and myocardial structure and behavior including sleep-activity and negative geotaxis in aged Drosophila. We also assessed the survival rate of flies after hypoxia and/or exercise. One-thousand wild-type w1118 virgin female flies were randomly divided into four groups and treated with NH and/or exercise from ages 3–6 weeks. We found that exercise remarkably delayed the decline of actin and myosin and the age-related changes in cardiac structure, improved abnormal cardiac contraction, and enhanced the cardiac pumping force by inducing cardiac hypertrophy and delaying deterioration of cardiac contractility and diastolic compliance, and improved abnormal heart contraction. NH also increased the content of actin and myosin, but induced a decrease in heart diameter and heart rate, as well as an increase in the number of mitochondria and deeper sleep, which may be the manifestation of energy saving under long-term hypoxia. Both NH and exercise improved sleep quality and climbing ability of aged flies, as well as extended the maximum life span, which shows the benefits of hypoxia and exercise. Finally, the superposition of NH and exercise did not impart any obvious physiological and behavior improvement. Therefore, it is necessary to further explore the appropriate combination of hypoxia and exercise.

Perfluorocarbon Nanocapsules Improve Hypoxic Microenvironment for the Tumor Ultrasound Diagnosis and Photodynamic Therapy.

Amelioration of hypoxia is an important factor increasing the effects of anti-tumor therapies. In the present experiments, nanocapsules of poly(lactide-co-glycolide)-poly(ethylene glycol)/perfluorooctyl bromide (PFOB)/photosensitizers (IR780) have been developed to increase oxygen concentration inside the tumor and improve the outcome of photodynamic therapy (PDT). PFOB has high oxygen solubility, and IR780 is a photosensitizer particularly suited for a highly effective photodynamic therapy under the 808-nm laser irradiation. Thus, PFOB provides sufficient oxygen for the reaction with the photosensitizer, producing more singlet oxygen to induce cell apoptosis. The photodynamic effect of nanocapsules was confirmed to be enhanced after addition of PFOB through simulation experiments in vitro in the hypoxic microenvironment. The results have demonstrated that due to the addition of PFOB the nanocapsules can provide a contrast-enhanced ultrasound diagnosis and ensure more notable inhibition of the growth of lung tumors following the 808 nm laser irradiation. Furthermore, the nanocapsules allowed the photosensitizers to achieve sufficient therapeutic potential, which was optimal under the conditions of modest hypoxia with about 5% oxygen concentration.

Chick embryos have the same pattern of hypoxic lower-brain activation as fetal mammals.

cFos expression (indicating a particular kind of neuronal activation) was examined in embryonic day (E) 18 chick embryos after exposure to 4 h of either normoxia (21% O2), modest hypoxia (15% O2), or medium hypoxia (10% O2). Eight regions of the brainstem and hypothalamus were surveyed, including seven previously shown to respond to hypoxia in late-gestation mammalian fetuses (Breen et al., 1997; Nitsos and Walker, 1999b). Hypoxia-related changes in chick embryo brain activation mirrored those found in fetal mammals with the exception of the medullary Raphe, which showed decreased hypoxic activation, compared with no change in mammals. This difference may be explained by the greater anapyrexic responses of chick embryos relative to mammalian fetuses. Activation in the A1/C1 region was examined in more detail to ascertain whether an O2-sensitive subpopulation of these cells containing heme oxygenase 2 (HMOX2) may drive hypoxic brain responses before the maturation of peripheral O2-sensing. HMOX2-positive and -negative catecholaminergic cells and interdigitating noncatecholaminergic HMOX2-positive cells all showed significant changes in cFos expression to hypoxia, with larger population responses seen in the catecholaminergic cells. Hypoxia-induced activation of lower-brain regions studied here was significantly better correlated with activation of the nucleus of the solitary tract (NTS) than with that of HMOX2-containing A1/C1 neurons. Together, these observations suggest that (1) the functional circuitry controlling prenatal brain responses to hypoxia is strongly conserved between birds and mammals, and (2) NTS neurons are a more dominant driving force for prenatal hypoxic cFos brain responses than O2-sensing A1/C1 neurons.

Therapeutic potential of intermittent hypoxia: a matter of dose.

Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9-16% inspired O2) and low cycle numbers (3-15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2-8% inspired O2) and more episodes per day (48-2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that "low dose" IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders.

Crosstalk between Nitrite, Myoglobin and Reactive Oxygen Species to Regulate Vasodilation under Hypoxia

The systemic response to decreasing oxygen levels is hypoxic vasodilation. While this mechanism has been known for more than a century, the underlying cellular events have remained incompletely understood. Nitrite signaling is critically involved in vessel relaxation under hypoxia. This can be attributed to the presence of myoglobin in the vessel wall together with other potential nitrite reductases, which generate nitric oxide, one of the most potent vasodilatory signaling molecules. Questions remain relating to the precise concentration of nitrite and the exact dose-response relations between nitrite and myoglobin under hypoxia. It is furthermore unclear whether regulatory mechanisms exist which balance this interaction. Nitrite tissue levels were similar across all species investigated. We then investigated the exact fractional myoglobin desaturation in an ex vivo approach when gassing with 1% oxygen. Within a short time frame myoglobin desaturated to 58±12%. Given that myoglobin significantly contributes to nitrite reduction under hypoxia, dose-response experiments using physiological to pharmacological nitrite concentrations were conducted. Along all concentrations, abrogation of myoglobin in mice impaired vasodilation. As reactive oxygen species may counteract the vasodilatory response, we used superoxide dismutase and its mimic tempol as well as catalase and ebselen to reduce the levels of reactive oxygen species during hypoxic vasodilation. Incubation of tempol in conjunction with catalase alone and catalase/ebselen increased the vasodilatory response to nitrite. Our study shows that modest hypoxia leads to a significant nitrite-dependent vessel relaxation. This requires the presence of vascular myoglobin for both physiological and pharmacological nitrite levels. Reactive oxygen species, in turn, modulate this vasodilation response.

Transcriptional divergence of the duplicated hypoxia-inducible factor alpha genes in zebrafish

Oxygen availability has been a major force in shaping the physiological evolution of animals. Under reduced oxygen availability (hypoxia) major changes in gene expression are mediated by hypoxia-inducible factors (HIF alphas). Tetrapods have three hif alpha genes, whereas zebrafish (Danio rerio) and other cyprinids have six due to a teleost lineage-specific genome duplication. We studied the transcriptional divergence of the six teleost-specific hif alphas by inspecting the tissue-specific transcription patterns in adult zebrafish and by monitoring the early developmental transcription of normoxia- and hypoxia-grown zebrafish embryos. Overall we observed the highest hif alpha mRNA levels in tissues that are important for hypoxic survival, including the brain, gill and heart. Of the paralogs that have not previously received attention (hif alpha-1A, hif alpha-2B and hif alpha-3B) especially the hif alpha-2B transcription levels suggest functional relevance. The hif alpha-1A/B paralogs that have considerable coding sequence divergence displayed more overall transcriptional divergence than the hif alpha-2A/B paralog pair. The hif alpha-2A/B paralogs that are similarly conserved in coding sequence had a divergent transcription pattern during early development. When zebrafish grown in modest hypoxia were compared to normoxia grown fish, only hif alpha-3A transcription was significantly altered. These results suggest that, in zebrafish, the evolutionary retention of each hif alpha paralog pair has involved unique patterns of coding sequence divergence, adult tissue-specific transcriptional divergence or developmental transcriptional divergence.

Modest hypoxia significantly reduces triglyceride content and lipid droplet size in 3T3-L1 adipocytes

BackgroundA previous study has demonstrated that endurance training under hypoxia results in a greater reduction in body fat mass compared to exercise under normoxia. However, the cellular and molecular mechanisms that underlie this hypoxia-mediated reduction in fat mass remain uncertain. Here, we examine the effects of modest hypoxia on adipocyte function. MethodsDifferentiated 3T3-L1 adipocytes were incubated at 5% O2 for 1week (long-term hypoxia, HL) or one day (short-term hypoxia, HS) and compared with a normoxia control (NC). ResultsHL, but not HS, resulted in a significant reduction in lipid droplet size and triglyceride content (by 50%) compared to NC (p<0.01). As estimated by glycerol release, isoproterenol-induced lipolysis was significantly lowered by hypoxia, whereas the release of free fatty acids under the basal condition was prominently enhanced with HL compared to NC or HS (p<0.01). Lipolysis-associated proteins, such as perilipin 1 and hormone-sensitive lipase, were unchanged, whereas adipose triglyceride lipase and its activator protein CGI-58 were decreased with HL in comparison to NC. Interestingly, such lipogenic proteins as fatty acid synthase, lipin-1, and peroxisome proliferator-activated receptor gamma were decreased. Furthermore, the uptake of glucose, the major precursor of 3-glycerol phosphate for triglyceride synthesis, was significantly reduced in HL compared to NC or HS (p<0.01). ConclusionWe conclude that hypoxia has a direct impact on reducing the triglyceride content and lipid droplet size via decreased glucose uptake and lipogenic protein expression and increased basal lipolysis. Such an hypoxia-induced decrease in lipogenesis may be an attractive therapeutic target against lipid-associated metabolic diseases.

Early Ventilation-Heart Rate Breakpoint during Incremental Cycling Exercise

Previous observations having reported a transient hypoxia at the onset of incremental exercise, we investigated the existence of concomitant ventilatory and heart rate (HR) breakpoints.33 subjects executed a maximal cycling exercise with averaging for successive 5-s periods of HR, ventilation, tidal volume (VT), mean inspiratory flow rate (VT/Ti), and end-tidal partial pressures of O2 (PETO2) and CO2. In 10 subjects, the transcutaneous partial pressure of O2 (PtcO2) was recorded and the venous blood lactic acid (LA) concentration measured.At the beginning of exercise, PETO2 decreased, reaching a nadir, then progressively increased until the exercise ended. PtcO2 varied in parallel. Whether or not a 0-W cycling period preceded the incremental exercise, the rate of changes in VE, VT, VT/Ti and HR significantly increased when the nadir PO2 was reached. The ventilatory/ HR breakpoint was measured at 33±4% of VO2max, whereas the ventilatory threshold (VTh) was detected at 67±4% of VO2max and LA began to increase at 45 to 50% of VO2max.During incremental cycling exercise, we identified the existence of HR and ventilatory breakpoints in advance of both lactate and ventilatory thresholds which coincided with modest hypoxia and hypercapnia.

Single-electron reduction of quinone and nitroaromatic xenobiotics by recombinant rat neuronal nitric oxide synthase.

We examined the kinetics of single-electron reduction of a large number of structurally diverse quinones and nitroaromatic compounds, including a number of antitumour and antiparasitic drugs, and nitroaromatic explosives by recombinant rat neuronal nitric oxide synthase (nNOS, EC 1.14.13.39), aiming to characterize the role of nNOS in the oxidative stress-type cytotoxicity of the above compounds. The steady-state second-order rate constants (kcat/Km) of reduction of the quinones and nitroaromatics varied from 10² M⁻¹s⁻¹ to 10⁶ M⁻¹s⁻¹, and increased with an increase in their single-electron reduction potentials (E¹₇). The presence of Ca²⁺/calmodulin enhanced the reactivity of nNOS. These reactions were consistent with an 'outer sphere' electron-transfer mechanism, considering the FMNH∙/FMNH₂ couple of nNOS as the most reactive reduced enzyme form. An analysis of the reactions of nNOS within the 'outer sphere' electron-transfer mechanism gave the approximate values of the distance of electron transfer, 0.39-0.47 nm, which are consistent with the crystal structure of the reductase domain of nNOS. On the other hand, at low oxygen concentrations ([O₂] = 40-50 μM), nNOS performs a net two-electron reduction of quinones and nitroaromatics. This implies that NOS may in part be responsible for the bioreductive alkylation by two-electron reduced forms of antitumour aziridinyl-substituted quinones under a modest hypoxia.

Hypoxic level and duration differentially affect embryonic organ system development of the chicken (Gallus gallus)

Hypoxia inhibits avian embryonic development, as well as increases embryonic mortality. However, the key organ systems affected by hypoxia, and their critical windows for development, are poorly understood. Consequently, chicken embryos were continuously exposed to 3 levels of oxygen (21, 15, or 13% O2) throughout d 0 to 10, d 11 to 18, or d 0 to 18 of incubation, followed by morphometric and blood physiological measurements. Hypoxia occurring early during incubation (d 0 to 10) had larger effects on embryonic mortality and organ growth than hypoxia occurring at later stages (d 10 to 18). Growth of the heart and chorioallantoic membrane was stimulated by chronic hypoxia, whereas the lung, brain, eye, liver, stomach, beak, and toes showed no disruption. Sustained hypoxia from the beginning of incubation decreased blood hemoglobin, hematocrit, and red blood cell concentration of embryos at d 10, but the values among hypoxic and normoxic groups were not significantly different at d 18. Blood partial pressure of O2 and partial pressure of CO2 were dependent upon incubation O2 level at a given day of development. These results indicated that either modest hypoxia (15% O2) throughout development, or hypoxia at any level during the late stages (d 11 to 18), increased the heart and chorioallantoic membrane weight, which partly compensated for the detrimental effects of hypoxia on embryonic development. We conclude that the first half of embryonic development contained the critical windows for the detrimental effects of hypoxia, and the second half contained the critical windows for the compensatory response of hypoxia in key organs.

HIF-1α in Epidermis: Oxygen Sensing, Cutaneous Angiogenesis, Cancer, and Non-Cancer Disorders

Besides lung, postnatal human epidermis is the only epithelium in direct contact with atmospheric oxygen. Skin epidermal oxygenation occurs mostly through atmospheric oxygen rather than tissue vasculature, resulting in a mildly hypoxic microenvironment that favors increased expression of hypoxia-inducible factor-1α (HIF-1α). Considering the wide spectrum of biological processes, such as angiogenesis, inflammation, bioenergetics, proliferation, motility, and apoptosis, that are regulated by this transcription factor, its high expression level in the epidermis might be important to HIF-1α in skin physiology and pathophysiology. Here, we review the role of HIF-1α in cutaneous angiogenesis, skin tumorigenesis, and several skin disorders.

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

Autophagy is a highly regulated cellular mechanism that leads to degradation of long-lived proteins and dysfunctional organelles. The process has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. Recent studies show the existence of autophagy in cerebral ischemia, but no consensus has yet been reached regarding the functions of autophagy in this condition. This article highlights the activation of autophagy during cerebral ischemia and/or reperfusion, especially in neurons and astrocytes, as well as the role of autophagy in neuronal or astrocytic cell death and survival. We propose that physiological levels of autophagy, presumably caused by mild to modest hypoxia or ischemia, appear to be protective. However, high levels of autophagy caused by severe hypoxia or ischemia and/or reperfusion may cause self-digestion and eventual neuronal and astrocytic cell death. We also discuss that oxidative and endoplasmic reticulum (ER) stresses in cerebral hypoxia or ischemia and/or reperfusion are potent stimuli of autophagy in neurons and astrocytes. In addition, we review the evidence suggesting a considerable overlap between autophagy on one hand, and apoptosis, necrosis and necroptosis on the other hand, in determining the outcomes and final morphology of damaged neurons and astrocytes.

Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension

Adipose tissue becomes hypoxic in obesity, and cell culture studies have demonstrated that hypoxia leads to major changes in adipocyte function. Studies on the response of adipocytes to low O₂ tension have employed marked hypoxia (1% O₂). Here, we have examined the effects of modest hypoxia, utilising differing concentrations of O₂ (1-21%), on adipokine production and glucose uptake by human adipocytes. Incubation with 10% O₂ (24 h) increased expression of the leptin, vascular endothelial growth factor (VEGF) and Angptl4 genes, while leptin expression was elevated even at 15% O₂ (compared to 'normoxia'-21% O₂). Overall, there was a concentration-dependent increase in the expression of these genes as O₂ fell, with the highest mRNA level evident at 1% O₂. Parallel changes were observed in the secretion of leptin, VEGF and IL-6 into the medium, an increased release being evident at 10% O₂ (15% O(2) for leptin). Adiponectin gene expression was reduced at 15% O₂ and below, while adiponectin release was significantly reduced at 5% O₂. Both 2-deoxy-D: -glucose uptake and lactate release showed progressive increases as O₂ concentration fell, being significantly raised at 10% and 5% O₂, respectively. The alterations in substrate transport were accompanied by parallel changes in transporter gene expression, GLUT1 and MCT1 mRNA level increasing from 15% and 10% O₂, respectively. These results indicate that marked responses to reduced O₂ concentration are exhibited by human adipocytes at O₂ levels well above those associated with hypoxia and employed in cell culture studies. Adipocytes are sensitive to small changes in O₂ tension.

Oxygen consumption of the chicken embryo: interaction between temperature and oxygenation

We measured the effects of hypoxia and changes in ambient temperature (T) on the oxygen consumption (VO2) of chicken embryos at embryonic days 11, 16 and 20 (E11, E16 and E20, respectively), and post-hatching day 1 (H1). Between 30 and 39 degrees C, at E11 and E16, VO2 changed linearly with T, as in ectothermic animals, with a Q10 of about 2.1. At E20, VO2 did not significantly change with T, indicating the onset of endothermy. At H1, a drop in T increased VO2, a clear thermogenic response. Hypoxia (11% O2 for 30 min) decreased VO2, by an amount that varied with T and age. At H1, hypoxia lowered VO2 especially at low T. At E20, hypoxic hypometabolism was similar at all T. At E11 and E16, hypoxia lowered VO2 only at the higher T. In fact, at E11, with T=39 degrees C even a modest hypoxia (15-18% O2) decreased VO2. Upon return to normoxia after 40 min of 11% O2, VO2 did not rise above the pre-hypoxic level, indicating that the hypometabolism during hypoxia did not generate an O2 debt. At E11, during modest hypoxia (16% O2) at 36 degrees C, the drop in VO2 was lifted by raising the T to 39 degrees C, suggesting that the hypoxic hypometabolism at 36 degrees C was not due to O2-supply limitation. In conclusion, the hypometabolic effects of hypoxia on the chicken embryo's VO2 depend on the development of the thermogenic ability, occurring predominantly at high T during the early (ectothermic phase) and at low T during the late (endothermic) phase. At E11, both low T and low oxygen force VO2 to drop. However, at a near-normal T, modest hypoxia promotes a hypometabolic response with the characteristics of regulated O2 conformism.

Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning.

Mesotelencephalic dopamine (DA) pathways are exquisitely vulnerable to ischemic-anoxic insult. These insults are known to produce long-term derangements in DA signaling and have been hypothesized to contribute, at least in part, to pathologic behaviors such as cerebral palsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Whether modest intermittent hypoxia, such as that encountered with repetitive apneas in premature infants, contributes to clinically significant impairments in DA signaling, and how these impairments manifest at a systems level, is unknown. To address these voids there is a need to develop animal models emulating features of a common disorder of prematurity, namely, apnea with hypoxia. Behavioral traits exhibited by such models include disturbed sleep-wake architecture, excessive locomotion, and impaired working memory persisting 1 to 2 months post-insult. Western-blot analysis of expression patterns of proteins involved in DA signaling (e.g., DA and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptors) are consistent with that which might be expected from hyper- or hypodopaminergic functioning in DA-responsive prefrontal cortex and striatal circuits, respectively. These novel observations suggest that intermittent hypoxia occurring during a period of critical brain development disrupts development of those mesotelencephalic pathways modulating the expression of sleep and wakefulness, locomotion, and executive functioning.

Erythropoietin Regulates theIn VitroandIn VivoProduction of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells

Recent studies have shown that neurogenesis is enhanced after hypoxia and that erythropoietin (EPO), an inducible cytokine, is produced in the brain as part of the intrinsic hypoxia response. Thus, we asked whether EPO might regulate neurogenesis by forebrain neural stem cells (NSCs). We found that EPO receptors are expressed in the embryonic germinal zone during neurogenesis as well as in the adult subventricular zone, which continues to generate neurons throughout adulthood. Cultured NSCs exposed to a modest hypoxia produced two- to threefold more neurons, which was associated with an elevation in EPO gene expression. The enhanced neuron production attributable to hypoxia was mimicked by EPO and blocked by coadministration of an EPO neutralizing antibody. EPO appears to act directly on NSCs, promoting the production of neuronal progenitors at the expense of multipotent progenitors. EPO infusion into the adult lateral ventricles resulted in a decrease in the numbers of NSCs in the subventricular zone, an increase in newly generated cells migrating to the olfactory bulb, and an increase in new olfactory bulb interneurons. Infusion of anti-EPO antibodies had the opposite effect: an increase in the number of NSCs in the subventricular zone and a decrease in the number of newly generated cells migrating to the bulb. These findings suggest that EPO is an autocrine-paracrine factor, capable of regulating the production of neuronal progenitor cells by forebrain NSCs.

Modulation of oxygen consumption rate and vascular endothelial growth factor mRNA expression in human malignant glioma cells by hypoxia.

Cellular responses to hypoxia include modulation of respiration rate and up-regulation of genes which encode for angiogenesis factors. We tested whether human malignant glioma cells vary in their response to hypoxic stress over the range of oxygen concentrations which exist in tumours. In five cell lines tested, decreased oxygen availability resulted in decreased rates of oxygen utilization, however substantial differences in the magnitude of the response were observed. Northern blot analysis was used to study induction of vascular endothelial growth factor mRNA in response to hypoxia. In two cell lines, modest hypoxia increased vascular endothelial growth factor mRNA levels compared with those of aerobic controls. In two additional cell lines, vascular endothelial growth factor mRNA was constituitively expressed under aerobic conditions and was not further increased by hypoxia. These findings demonstrate that differences in the response to hypoxia exist among human malignant glioma cell lines and suggest that therapies designed to exploit tumour hypoxia may have varying effects in tumours with different hypoxic stress responses. © 1999 Cancer Research Campaign

Pulmonary hypertension induced by amosite asbestos: A physiological and morphologic study in the guinea pig

Although there is increasing evidence that mineral dust exposure will produce obstructive lung disease, there is little information on the effects of mineral dust on the pulmonary vascular system. To examine whether exposure to amosite asbestos would affect the pulmonary vasculature and produce pulmonary hypertension, we instilled 5 mg amosite asbestor intratracheally into guinea pigs. After periods of 3 and 6 months, we examined their pulmonary and pulmonary vascular function, and compared these data to those obtained from groups of control animals. We found that, at both time periods, there was pulmonary arterial hypertension, with alteration of the vascular pressure-flow relationships. This was accompanied by abnormalities in the structure of the small pulmonary arterioles. The animals also showed airflow obstruction, with air trapping and an upward shift of the pressure-volume curve. There was evidence of emphysema, and the animals were moderately hypoxic. We found no consistent increase in inflammatory cells either in lavage or peripheral blood, and the histamine dose-response curves were similar in control and asbestos-exposed animals at 6 months. We conclude that intratracheal instillation of asbestos in the guinea pig produces pulmonary hypertension associated with modest hypoxia, emphysema, and airflow obstruction. Whether pulmonary hypertension reflects emphysema-induced hypoxia and loss of vascular bed, or is related to the brief but intense inflammatory infiltrate induced by asbestos, is unclear.

Regulation of muscle lactate production

It is not possible to make accurate measurements of muscle lactic acid net exchange during exercise by application of the Fick relationship. To make accurate measurements of lactic acid net exchange, preparations with isolated circulations have been used. Since such preparations utilize relatively small muscles or groups of muscles, the data apply to muscle contractions, not exercise. In exercise, external influences may affect lactate exchange. The net lactic acid exchange (L) of the isolated dog gastrocnemius-plantaris muscle group has been quantified for repetitive twitch and tetanic contractions, progressive contractions, and four repetitions of 30-s intense contractions with 3.5 min of recovery between each. Epinephrine has been infused during repetitive and progressive contractions; modest ischemia and hypoxic hypoxia, and the oxidation-reduction state of mitochondrial cytochrome a-a3 have been investigated. After the initiation of repetitive contractions, L rises transiently to a peak at 3-5 min and then declines to net uptake after 30 min of contractions. The peak L is roughly proportional to VO2. L rises progressively during progressive contractions to levels lower than the peak in repetitive contractions. Epinephrine increases L transiently during repetitive contractions and increases L during progressive contractions. L rises to levels similar to the repetitive peak during the four repeated 30-s bouts. Cytochrome a-a3 was more oxidized during contractions than when at rest. Ischemia has little or no effect on L. Hypoxic hypoxia sufficient to produce hypoxidosis increased L sharply, but transiently. Muscle L reflects the balance between the production of the products of glycolysis and their removal into the mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)