Small airway and alveolar tissue changes in nocturnal asthma.
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Airway Resistance↗
Biomedical subjects
R J Martin
Publications and source records attributed to R J Martin.
Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma.
Infection with Mycoplasma pneumoniae has been shown to exacerbate asthma in humans. However, the role of M. pneumoniae in the pathogenesis of chronic asthma has not been defined. Eighteen asthmatics with chronic, stable asthma and 11 nonasthmatic control subjects underwent evaluation of the upper and lower airways and serologic analysis to determine the presence of M. pneumoniae, Chlamydia pneumoniae, and seven respiratory viruses through culture, enzyme-linked immunoassay (EIA) and polymerase chain reaction (PCR). M. pneumoniae was detected by PCR in 10 of 18 asthmatics and one of 11 control subjects (p = 0.02). In nine of the 10 patients, the organism was detected in bronchoalveolar lavage or bronchial biopsies. Seven of 18 asthmatics and one of 11 control subjects were also positive for M. fermentans and M. genitalium by PCR. All patients' cultures, EIAs, and serology were negative for M. pneumoniae. All PCR and cultures were negative for C. pneumoniae, and all EIAs for respiratory viruses were negative in all subjects. Nine asthmatics and one control subject exhibited positive serology for C. pneumoniae (p = 0.05). M. pneumoniae was present in the lower airways of chronic, stable asthmatics with greater frequency than control subjects, and may play a role in the pathogenesis of chronic asthma.
Adult↗
Chronobiology of asthma.
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Activities of Daily Living↗
Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease.
Chronic airway inflammation and remodeling, including fibrosis, have been proposed as important contributors to asthma pathophysiology. Previous studies of airway fibrosis have been performed mainly in mild and moderate asthmatics at the subepithelial "basement membrane" (SBM) level. The current study was designed to evaluate the large airway SBM thickness and submucosal collagen deposition, as measured by three different collagen staining methods, in endobronchial biopsies from 17 severe, nine moderate, and seven mild asthmatics, as well as eight normal control subjects. Tissue eosinophils and transforming growth factor-beta (TGF-beta) immunoreactivity were also examined. There were no statistically significant differences in the SBM thickness, submucosal collagen deposition, eosinophil numbers, or TGF-beta positive cells among the three groups of asthmatics and the normal control subjects. It was only when examining all asthmatics (n = 33) together, that a modestly thickened SBM (p = 0.04), as evaluated by collagen type III immunostaining, was observed as compared with normal control subjects. Despite this difference, no significant differences were found in the amount of submucosal collagen deposition and the number of eosinophils or TGF-beta expressing cells when comparing total asthmatics and normal control subjects. Additionally, no significant correlations were found between collagen deposition and eosinophil count, TGF-beta expression level, FEV1, or duration of asthma. These results suggest that although increased collagen deposition in the SBM at the large airway level is a characteristic of asthma, it may not explain the differences in severity of asthma.
Adult↗
Bronchodilators and corticosteroids in the treatment of asthma.
Despite advancements in treatment, the incidence of asthma, asthma-related deaths and hospitalizations for asthma have increased significantly during the past decade. Although asthma mortality may now be decreasing, reasons for the worsening of morbidity and mortality in asthma remain unclear. These unexpected changes in asthma severity have sparked renewed interest in research into the pathogenesis and treatment of the condition. Beta(2)-Adrenergic agonists are the most commonly used class of drugs for the treatment of asthma. Recent concerns about safety issues for beta-agonists caused reevaluation of prescribing practices, and using them on an as-needed basis is now more frequently accepted and recommended. In acute asthma, a beta(2)-adrenergic agonist is still the medication of choice. Long-acting salmeterol and formoterol, administered only twice daily, can decrease symptoms of asthma during day and nighttime. On the other hand, the role of tolerance to their bronchodilator and bronchoprotective effects is still to be determined in the treatment of asthma. Theophylline, whose use has been limited by the potential for serious toxicity, may regain an important position in asthma treatment with the development of the knowledge about its antiinflammatory actions. Dosing theophylline on a time- related basis also improves the risk/benefit ratio and makes it a useful drug for nocturnal asthma. Ipratropium bromide, an anticholinergic drug, still awaits a defined role in the treatment of asthma. Studies on its use for acute asthma have not achieved consensus and, for nocturnal asthma, the short duration of effect limits the benefits. Corticosteroids, including inhaled steroids, have measurable effects on symptoms, lung function, bronchial responsiveness and inflammation associated with asthma. Side effects of chronic use limit systemic, but not inhaled administration. Newer preparations, like budesonide, flunisolide and fluticasone, decrease the incidence of possible side effects related to inhaled steroids by having better ratio of topical to systemic potency. Daily doses up to 1600 micro g of beclomethasone (or equivalent) are considered safe and higher doses should be reserved for patients with moderate to severe asthma. Although future trials are necessary to clarify many issues related to dosing of inhaled steroids, chronotherapy studies have shown that single administration between 3 and 5:30 p.m. may be as effective as 4 times a day dosing.
Journal Article↗
Recent innovations in asthma therapy.
Guidelines for the diagnosis and management of asthma have been published since 1990 and already new versions are being published. The recommendations for the treatment of asthma were organized around four components of effective asthma management: i) use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy, ii) environmental control measures to avoid or eliminate factors that precipitate asthma symptoms or exacerbations, iii) comprehensive pharmacologic therapy for long-term management designed to reverse and prevent the airway inflammation characteristic of asthma as well as pharmacologic therapy to manage asthma exacerbations, and iv) patient education that fosters a partnership among the patient, family and clinicians. Newly released medications include anti-leukotriene (LTs) agents which function either by blocking the interaction of LTs with receptors (receptor antagonists) or by inhibiting leukotriene synthesis (synthesis inhibitors). Representatives of the antagonists discussed here are zafirlukast, pranlukast and montelukast. Zafirlukast (20 mg twice daily) improves pulmonary function indices and days without symptoms and decreases the asthma exacerbation frequency. Pranlukast, the first leukotriene receptor antagonist to be marketed, improves lung function and symptoms when 450 mg twice daily is used. A study with montelukast demonstrated similar positive results irrespective of the use of concomitant inhaled corticosteroid. This indicates that leukotriene receptor antagonists may have additive effects to steroid therapy. They may also be a potential alternative to inhaled steroids, although more studies need to be performed before defining the role of receptor antagonists in the treatment of asthma. Zileuton, a leukotriene synthesis inhibitor, has been shown to improve lung function, reduce symptoms and reduce use of beta-agonists and asthma exacerbations. These positive effects are dose-dependent and liver function abnormalities seem to be a relevant issue during zileuton use in some patients. Other compounds that inhibit LTs synthesis are in development and, like zileuton, need more tests. Phosphodiesterases (PDE), enzymes that break down cAMP and cGMP, have been a target for new compounds developed to treat asthma. Inhibition of PDE enzymes increases intracellular cAMP or cGMP which then produces bronchodilation. Recent studies have also shown antiinflammatory effects by suppressing some PDE isoenzymes, including PDE III and PDE IV. These effects were detected by studies in vitro and in animal models. Clinical trials are necessary to determine which PDE inhibitors can be useful for the treatment of asthma.
Journal Article↗
Human corticotropin-releasing hormone improves overnight FEV1 in nocturnal asthma.
Corticotropin-releasing hormone (CRH) exhibits anti-inflammatory properties independent of its effect on adrenal function. We investigated the safety and effect of CRH in nocturnal asthma, a disease where inflammation is prominent. Five subjects underwent an overnight infusion of placebo on the first night, CRH at a 2.5 micrograms/kg/hr on the second night, and three subjects received CRH at 4.0 micrograms/kg/hr on the third night. A significant improvement occurred in overnight change in forced expiratory volume 1 sec. % (delta FEV1) with CRH (+17.4 +/- 9.1%) as opposed to placebo (-25.9 +/- 7.1%), p = 0.024, CRH was well tolerated. Further research with CRH may clarify the pathophysiology of nocturnal asthma.
Adult↗
Serum cortisol in asthma: marker of nocturnal worsening of symptoms and lung function?
UNLABELLED: Changes in the hormone cortisol have been implicated in the pathogenesis of nocturnal worsening of asthma, or nocturnal asthma (NA). We studied 45 patients, 15 with NA, 15 subjects with non-nocturnal asthma (NNA), and 15 controls over a 24h period, measuring forced expiratory volume in 1 second (FEV1) and serum cortisol at 08:00, 12:00, 16:00, 20:00, 23:00, 04:00, and 08:00 the following day. Evaluation of the time response curves for cortisol revealed a significant difference in the shape of the curves (p = 0.04 by mixed-effects model). Evaluation of individual time points revealed that the cortisol levels in the NNA and control groups were significantly lower than in the NA group at 20:00 (NNA: 3.5 +/- 0.8 mg/mL; CONTROLS: 3.4 +/- 0.8 mg/mL; NA: 4.9 +/- 0.8 mg/mL; p = 0.007). The percentage (%) predicted FEV1 was significantly different among the three groups over the 24h period (p < 0.001). The percentage predicted FEV1 was significantly lower in the NA group compared to the control group at all time points and significantly lower than the NNA group at 16:00, 23:00, and 04:00. The difference among the groups was most pronounced at 04:00, when the percentage predicted FEV1 was 58.9 +/- 2.2% in the NA group, 76.8 +/- 2.9% in the NNA group, and 91.6 +/- 2.8% in the control group (p = 0.001, where each group is significantly different from the others). Although the time response curves for cortisol were significantly different among the three groups, the differences in serum levels of cortisol do not appear to be clinically significant. Therefore, serum levels of cortisol may not be the appropriate measurement to assess the role of cortisol in nocturnal asthma.
Adult↗
Longer-term fourth ventricular 5-thioglucose infusion increases body fat in the rat.
5-Thioglucose (5-TG) has been shown to increase food intake after acute administration. To determine the longer-term effects of 5-TG on feeding and body composition, thirty-four female Sprague-Dawley rats were cannulated into the fourth ventricle and infused with artificial CSF and either 0.01 M 5-TG or 0.1 M 5-TG using osmotic pumps. Food intake and body weight were monitored daily. Rats were killed after 14 days of infusion. Carcass and fatpad weights were measured, and body compositions were determined. Food intake was not different during the first week of infusion; however, cumulative food intake was decreased in the 0.1 M 5-TG group during the second week as compared to the CSF control group. Body weight and carcass weight of this group also decreased as compared to the control. The group receiving the higher dose of 5-TG (0.1 M) had increased fatpad weights in all three depots examined (inguinal, retroperitoneal, and perimetrial depot); the group with lower dose of 5-TG infusion (0.01 M) increased the fatpad weights in the retroperitoneal and perimetrial depot, as compared to the CSF group. Data from the body composition analysis were consistent with the results of the fatpad weights. In conclusion, the present study demonstrated that chronic fourth ventricular 5-TG infusion increased body fat without increasing food intake, suggesting that energy expenditure is decreased under this condition. The results of this study indicate that glucose metabolism in the hindbrain is important in the control of energy expenditure, body fat deposition, and thus energy balance regulation.
Adipose Tissue↗
Dietary fat type and level influence adiposity development in obese but not lean Zucker rats.
The development of obesity is influenced by a variety of factors including genetics and dietary fat type and level. To examine the interaction between these factors, male lean and obese Zucker rats (5 weeks initial age) were fed either a low-fat (15% calories) or one of two high-fat diets (65% calories; predominant fat source of either soybean oil or palm olein) for 8 weeks. Body weight, food intake, indirect calorimetry, and body composition determinations were performed. As expected, food intake, body weight, feed efficiency, oxygen consumption, heat production and carcass lipid were all significantly higher in obese compared to lean rats. Dietary fat level and/or type influenced body weight gain, oxygen consumption, heat production, energy balance, and carcass weight and lipid content in the obese but not in the lean Zucker rats. Oxygen consumption and carcass weight were increased approximately 25% and 10% respectively in obese rats fed either of the two high-fat diets as compared to those fed the low-fat diet. The type of fat fed in the high-fat diets also influenced body weight gain, heat production, energy balance, and carcass lipid content of the obese rats. Body weight gain and carcass lipid content were increased (16%-17%; P < 0.005) in obese rats fed the high-fat palm olein diet as compared to those fed the low-fat diet. These parameters were not increased in obese rats fed the high-fat soybean oil diet. In contrast, indirect calorimetry measurements indicated a moderate increase in heat production (Kcal/effective body mass/day; 14.5%) and decrease in energy balance (44.8%) in the obese rats fed the high-fat soybean oil diet as compared to those fed the low-fat diet. Energy expenditure and lipid accumulation were negligibly influenced by dietary fat level or type in the lean Zucker rats. The differential response of the lean and obese Zucker rats to this short-term dietary manipulation demonstrate that genetic background can influence an individual's response to dietary fat type and level. The genetically obese Zucker rat appears to be a good model for further studies of high-fat diet-induced obesity.
Adipose Tissue↗
Regulation of adipose cell development in utero.
The condition of obesity is impacted by increases in fat cell number, fat cell size, or a combination of the two. It is generally believed that fat cell number is dependent on the age of onset and the degree of obesity. This review provides an update on intrauterine growth of fetal adipose tissue, the earliest period of proliferation onset, and the factors that interact to enhance or suppress development. Fetal adipose tissue development is regulated by the complex interaction of maternal, endocrine, and paracrine influences that initiate specific changes in angiogenesis, adipogenesis, and metabolism. Developmental stages and metabolic processes influenced by specific hormones and paracrine factors have been identified through examination of the offspring of obese and diabetic pregnancies, hormonal manipulation during late pregnancy in animal models, and the use of cell culture. Collectively, the results of the studies cited herein delineate the basis for imprinting or conditioning of fetal preadipocytes at the paracrine/autocrine level and a role of thyroxine, glucocorticoids, and other hormones in fetal adipose tissue development and metabolism.
Adipose Tissue↗
Nocturnal asthma and the use of theophylline.
The nocturnal worsening of asthma is a common event in asthma patients. Some studies have shown the prevalence of nocturnal asthma to be as high as 75% of patients. It is important to understand this phenomenon as nocturnal asthma is associated with decreased daytime cognitive function and increased morbidity and mortality. The exact mechanism for decrements in overnight lung function is not known. However, there are many different processes associated with nocturnal asthma. Day-to-night change in both circulating bronchodilating and bronchoconstricting mediators occur which favour airway narrowing and increased bronchial hyperresponsiveness at night. The beta2 adrenergic receptors decrease in both number and function at night which is associated with a genetic polymorphism, a glycine 16 substitution. Neuroinfluences such as increased nocturnal cholinergic tone also contribute to nocturnal asthma, and a hallmark of nocturnal asthma is increased airway inflammation during sleep. Long-acting theophylline preparations have long been associated with improvement in overnight lung function. Some of these agents can be used in a chronotherapeutic modality, that is, higher blood levels at night when the disease is worse and lower blood levels during the day when lung function is routinely better. Theophylline works as both a bronchodilator and an anti-inflammatory agent to improve nocturnal asthma.
3',5'-Cyclic-AMP Phosphodiesterases↗
Elevated hypothalamic neuropeptide Y levels in rats with dorsomedial hindbrain lesions.
Lesions centered on the area postrema (AP) and adjacent nucleus of the solitary tract (AP/mNTS-lesions) are reported to result in increased consumption of highly palatable diets. Recent studies suggest that neuropeptide Y (NPY) may cause a preference for carbohydrate-rich diets. Thus, it is possible that NPY may play a role in the enhanced intake of highly palatable diets by AP/mNTS-lesioned rats. In the studies reported here, we found that lesions centered on the AP result in increased levels of NPY-immunoreactivity in the paraventricular nucleus of the hypothalamus. Additionally, steady-state NPY mRNA in the basomedial hypothalamus including the arcuate nucleus was elevated. Enhanced NPY was not found throughout the hypothalamus however, as NPY-immunoreactivity was not elevated in the lateral hypothalamus or the tissue bordering the anteroventral third ventricle. These data suggest the possibility that elevated hypothalamic NPY, particularly in the arcuate and paraventricular nuclei, may contribute to the altered food intake and energy balance observed in rats with lesions centered on the AP.
Animals↗
Heterogeneous levamisole receptors: a single-channel study of nicotinic acetylcholine receptors from Oesophagostomum dentatum.
A muscle vesicle preparation from Oesophagostomum dentatum, a 5 mm parasitic nematode, was developed for single-channel recording. Properties of nicotinic acetylcholine receptors activated by the anthelmintic levamisole (10 microM) were investigated using cell-attached and isolated inside-out patches. The current-voltage relationships of the single-channel currents were linear with conductances in the range 24.6-57.7 pS (mean 39.5 pS). The distributions of open times were fitted with a single exponential and mean open times were in the range 0.98-4.43 ms (mean 2.2 ms). The distributions of conductances and open times of the channels showed that the receptors could not be described as a single homogeneous population. There were two main channel subtypes: one subtype, designated G35, had a mean conductance of 35.2 pS and mean open time of 1.6 ms: another subtype designated G45, had a mean conductance of 44.6 pS and mean open time of 2.7 ms. A channel with a conductance near 25 pS. designated G25, and a channel with a conductance near 55 pS. designated G55, were also observed. The designations were based on the mean conductances. G. of the channel subtypes. A model for the heterogeneous population of nicotinic acetylcholine channels predicting four subtypes of receptor separated by their conductance is discussed and related to the development of levamisole resistance.
Animals↗
Assessment of tidal volume over time in preterm infants using respiratory inductance plethysmography, The CHIME Study Group. Collaborative Home Infant Monitoring Evaluation.
Non-invasive techniques for monitoring ventilation in infants are widely used in short-term laboratory-studies but have not been evaluated in routine clinical settings. To determine whether respiratory inductance plethysmography (RIP) can provide reproducible measurements of tidal volume (VT) in premature infants over an extended period of time, we monitored respiration in eight healthy preterm infants over 4.9 +/- 1.0 hours (mean +/- SD). The algebraic sum (Sum) of rib cage (RC) and abdominal (AB) motion signals (obtained by RIP) was calculated and presented over the entire recording period as percent of an initial 5 minute calibration period. VT was simultaneously measured with a nasal mask pneumotachometer with infants in prone and supine positions during active and quiet sleep. Infants were studied in the morning (AM) and again in the afternoon (PM). Between these studies they were returned to the nursery wearing the RIP in a continuous record mode. For all patients there was a significant linear relationship between VT (in mL measured by pneumotachometer) and Sum (in % of calibration value, RIP). Neither the slope of the relationship (0.074 +/- 0.03 in AM vs. 0.071 +/- 0.02 in PM), nor its variability as measured by standard error of the estimate (SEE) (2.3 +/- 0.5 in AM vs. 2.5 +/- 0.8 in PM) changed significantly from AM to PM. The relationship between VT and Sum, as well as the variability of that relationship, was not altered by position, asynchrony of RC and AB, respiratory rate, or percent RC contribution to Sum. We conclude that RIP produces consistent measurements of respiratory effort over 5 hours in healthy preterm infants without need for recalibration and is not affected by routine care.
Female↗
Characteristics of hypoxemic episodes in very low birth weight infants on ventilatory support.
OBJECTIVE: To characterize hypoxemic episodes in very low birth weight infants with mechanically ventilated lungs and to describe their natural history and the effect of body position. STUDY DESIGN: Tidal volume, respiratory rate, oxygen saturation, heart rate, and body movement were continuously recorded in 10 very low birth weight infants who exhibited episodes of hypoxemia during mechanical ventilation (birth weight, 810 +/- 133 gm; postconceptional age at study, 30 +/- 1.6 weeks). Frequency of hypoxemic episodes was compared in both prone and supine positions. RESULTS: Seventy-eight percent of hypoxemic episodes began in association with body movement as well as heart rate acceleration. Thereafter the spontaneous and delivered minute ventilation both decreased during the first 15 seconds of hypoxemia. The former decrease was due to a significant decrease in frequency of spontaneous respiration, whereas the latter was associated with a significant decrease in delivered tidal volume. Minute ventilation returned to normal before recovery of oxygenation. A change in body position from supine to prone significantly decreased the frequency of hypoxemic episodes. CONCLUSION: Hypoxemic episodes in infants who are on ventilatory support are characterized by (1) movement and cardioacceleration at initiation; (2) a decrease in both spontaneous and delivered minute ventilation, and (3) a lower incidence in the prone position. We speculate that spontaneous movement during sleep can trigger cardiopulmonary reflex responses that initiate and propagate these episodes.
Heart Rate↗
Effect of glucose and 2-deoxyglucose on hypothalamic GABA release in lactating rats.
Gamma-amino butyric acid (GABA), an inhibitory neurotransmitter, has been implicated in the control of feeding behavior. This study was conducted to investigate the in vitro release of GABA in the basal medial hypothalamus (BMH) of hyperphagic lactating (L) and control nonlactating (NL) rats. Pregnant Sprague-Dawley rats (n = 10) were ad lib fed a semipurified powdered diet during the last 6 days of pregnancy until day 19 of lactation. Nonpregnant (n = 10) animals served as controls. Body weights and food intake were recorded every other day. Lactating rats demonstrated an increase in body weight as well as food intake as compared to nonlactating animals. At sacrifice, the BMH was removed and perfused (0.1 ml/min) with Kreb's Ringer buffer (KRB) ("basal" medium) using a Brandel perifusion system. KRB containing glucose (100 mM) or 2-deoxyglucose (2DG) (100 mM) was also applied to the tissue. Potassium stimulation was carried out to test for the viability of the tissues. Samples were collected every 10 min, derivatized with O-Phthalaldehyde and analyzed via HPLC. Glucose depressed, and 2DG enhanced GABA release compared to basal levels. There were no significant differences in GABA release between lactating and nonlactating groups. These data suggest that GABA release is responsive to metabolic changes in the brain.
Animals↗
ICV beta-hydroxybutyrate: effects on food intake, body composition, and body weight in rats.
This study examined the effect of long-term intracerebroventricular (ICV) infusion of beta-hydroxybutyrate (beta HB) on food intake, diet selection, body weight, and body composition in rats. Female rats were divided into 2 groups and implanted with a 28-day osmotic pump connected to a lateral cerebroventricular cannula. One group was infused with artificial cerebrospinal fluid (aCSF) and the other with beta HB for 28 days. The rats had free access to both a high-fat/low-carbohydrate and a low-fat/high-carbohydrate diet (isocaloric) for the 28-day infusion period. The group infused with beta HB had a significantly lower body weight gain during the infusion period. Cumulative food intake increased in the same manner in both groups. Fat pad weights and carcass lipid content were significantly higher in beta HB rats, despite the equivalent caloric intake in both groups and the decreased body weight. Our observations are in accord with earlier studies indicating that beta HB infused ICV reduces body weight, but not necessarily food intake. Increased adiposity in association with decreased body weight change in beta HB-infused rats strongly suggests that energy is being partitioned to fat deposition at the expense of lean tissue growth when ketone bodies are infused into the cerebroventricles.
3-Hydroxybutyric Acid↗