Corticosteroids and Leukotrienes: Chronobiology and Chronotherapy

Corticosteroids and leukotrienes play opposite roles in asthma. Corticosteroids, both endogenously secreted and exogenously administered, are antiinflammatory and are very effective in the treatment of asthma. They have also been evaluated chronotherapeutically and have been found to be very effective in reducing the enhanced airway inflammation and decrement in lung function associated with nocturnal worsening of asthma. Leukotrienes are potent proinflammatory and spasmogenic mediators that have been shown to be increased at night in patients with nocturnal asthma (NA). Leu-kotriene modifiers, a new class of medications to treat asthma, improve, but do not abolish, the symptoms and decrement in lung function associated with nocturnal asthma. However, they have not been evaluated chronotherapeutically. This article addresses the roles of corticosteroids and leukotrienes in nocturnal asthma and their position as therapeutic agents or targets for therapy.     

Corticosteroids 21-glucuronides: Synthesis and complete characterization by H and C NMR

Despite the important physiological role of the corticosteroids glucuronides, very poor NMR data for this class of compounds are reported. For this reason we prepared a set of corticosteroids and submitted them to a detailed NMR study. A complete assignment of ¹H and ¹³C signals was accomplished arranging mono- and two-dimensional NMR techniques.     

Neuropsychological Outcomes of Nocturnal Asthma

In spite of frequent reports that nocturnal asthma results in fatigue and impaired cognitive performance, there exists little objective evidence as to the daytime consequences of this disorder. Treatment studies have established that the symptoms of nocturnal asthma improve with medication intervention, but performance does not. Studies of obstructive sleep apnea (OSA), a source of generally more severe sleep fragmentation, have demonstrated that measurement of sleep-deprivation effects is limited to tasks requiring heightened alertness and rapid information processing, and that the degree of score change is related to the degree of sleep disruption. Studies of normal, but sleep-deprived, subjects indicate that (1) utilization of repetitive measures sustained for long duration can potentiate motivation to overcome the effects of fatigue in the laboratory, and (2) even when average scores do not change significantly, performance becomes more irregular. These collective findings about the measurement of performance impairment secondary to sleep deprivation can be used to guide new studies of nocturnal asthma. Finally, children must be included in future investigations because they may be at even greater risk for daytime consequences of nocturnal asthma than adults.     

Neuropsychological Outcomes of Nocturnal Asthma

In spite of frequent reports that nocturnal asthma results in fatigue and impaired cognitive performance, there exists little objective evidence as to the daytime consequences of this disorder. Treatment studies have established that the symptoms of nocturnal asthma improve with medication intervention, but performance does not. Studies of obstructive sleep apnea (OSA), a source of generally more severe sleep fragmentation, have demonstrated that measurement of sleep-deprivation effects is limited to tasks requiring heightened alertness and rapid information processing, and that the degree of score change is related to the degree of sleep disruption. Studies of normal, but sleep-deprived, subjects indicate that (1) utilization of repetitive measures sustained for long duration can potentiate motivation to overcome the effects of fatigue in the laboratory, and (2) even when average scores do not change significantly, performance becomes more irregular. These collective findings about the measurement of performance impairment secondary to sleep deprivation can be used to guide new studies of nocturnal asthma. Finally, children must be included in future investigations because they may be at even greater risk for daytime consequences of nocturnal asthma than adults.     

Leukotriene B4 is essential for selective eosinophil recruitment following allergen challenge of CD4+ cells in a model of chronic eosinophilic inflammation

Subcutaneous heat-coagulated egg white implants (EWI) induce chronic, intense local eosinophilia in mice, followed by asthma-like responses to airway ovalbumin challenge. Our goal was to define the mechanisms of selective eosinophil accumulation in the EWI model. EWI carriers were challenged i.p. with ovalbumin and the contributions of cellular immunity and inflammatory mediators to the resulting leukocyte accumulation were defined through cell transfer and pharmacological inhibition protocols. Eosinophil recruitment required Major Histocompatibility Complex Class II expression, and was abolished by the leukotriene B4 (LTB4) receptor antagonist CP 105.696, the 5-lipoxygenase inhibitor BWA4C and the 5-lipoxygenase activating protein inhibitor MK886. Eosinophil recruitment in EWI carriers followed transfer of: a) CD4+ (but not CD4-) cells, harvested from EWI donors and restimulated ex vivo; b) their cell-free supernatants, containing LTB4. Restimulation in the presence of MK886 was ineffective. CC chemokine receptor ligand (CCL)5 and CCL2 were induced by ovalbumin challenge in vivo. mRNA for CCL17 and CCL11 was induced in ovalbumin-restimulated CD4+ cells ex vivo. MK886 blocked induction of CCL17. Pretreatment of EWI carriers with MK886 eliminated the effectiveness of exogenously administered CCL11, CCL2 and CCL5. In conclusion, chemokine-producing, ovalbumin-restimulated CD4+ cells initiate eosinophil recruitment which is strictly dependent on LTB4 production.     

Thermoregulatory and endocrine responses to light pulses in short-day acclimated social voles (Microtus socialis)

In mammals, nocturnal light pulses (NLP) have been demonstrated to affect physiology and behavior. However, the impact of NLP as a stressor has been less broadly examined. The purpose of this study was to examine the effect of NLP (three 15 min 450 lux light pulses) during each scotophase on both thermoregulation and endocrine stress responses under short-day (SD; 8L:16D) acclimation. Voles were acclimated to either SD (SD voles) or SD+NLP (NLP voles). Resistance to cold was estimated by measurements of body temperature (T_b) during cold exposure (5°C). Daily rhythms of energy expenditure (calculated from oxygen consumption), urine production, and urinary adrenaline and serum cortisol levels were measured. T_b values of SD voles were generally unaffected by the cold stimulus, whereas in NLP voles, resistance to cold was markedly lowered. While SD- and NLP voles showed similar ultradian characteristics in energy expenditure with a period of 3.5 h, mean energy expenditure levels were lowest for voles exposed to NLP-treatment. In SD voles, but not in NLP voles, urine production rates showed clear time variations and were consistently highest for SD voles, with significant differences during the scotophase. Both mean total urinary adrenaline and serum cortisol levels were significantly elevated in NLP-treated voles compared with the control group. Taken together, the results suggest that NLP negatively affects winter acclimatization of thermoregulatory mechanisms of M. socialis, probably by mimicking summer acclimatization, and consequently the thermoregulatory mechanisms respond inappropriately to ambient conditions. One important finding of this study is that NLP may act as a stressor and correspondingly impose a major threat to the physiological homeostasis of M. socialis, such that over-winter survival might be compromised.     

Seasonal Variation in the Orcadian Rhythm of Pulmonary Function in Stable Astthmatic Children who have Nearly Outgrown their Asthma

To study whether nocturnal bronchial obstruction changes during the year, we assessed the circadian FEV₁ variation during four consecutive seasons in 20 children (12 boys; aged 9–12 years) with episodic asthma who were outgrowing their asthma. FEV₁ was determined every 4 h between 10:00 and 10:00 during two consecutive days. The last six FEV₁ values were submitted to cosinor and coefficient of variation (CV) analyses. The seasonal means (SD) in the group 24 h percent predicted FEV₁ was 85.5 (11.4), 81.2 (10.6), 86.0 (11.6), and 82.2 (14.0)% during spring, summer, autumn, and winter, respectively. The difference between the summer and autumn FEV₁ values was statistically significant (p < 0.05). The mean (SD) of the circadian amplitude values was 4.1 (4.3), 6.0 (3.8), 4.9 (3.4), and 7.2 (4.1)% during spring, summer, autumn, and winter, respectively. The difference in amplitude between the spring and winter and between the autumn and winter values was statistically significant (p<0.05). CV values of 48 of the 80 (60%) circadian FEV, time series exceeded the average CV of 5% observed in non-asthmatic children studied in our laboratory. There was an unequal distribution during the year in elevated CV values; 6, 17, 10, and 15 of the high CV values occurred, respectively, in the spring, summer, autumn, and winter. These results suggest that nocturnal bronchial obstruction may change seasonally in terms of severity and amplitude in children who have nearly outgrown their asthma. (Chronobiology International, 13(4), 295–303, 1996)     

Thermoregulatory and Endocrine Responses to Light Pulses in Short‐Day Acclimated Social Voles (Microtus socialis)

In mammals, nocturnal light pulses (NLP) have been demonstrated to affect physiology and behavior. However, the impact of NLP as a stressor has been less broadly examined. The purpose of this study was to examine the effect of NLP (three 15 min 450 lux light pulses) during each scotophase on both thermoregulation and endocrine stress responses under short‐day (SD; 8L:16D) acclimation. Voles were acclimated to either SD (SD voles) or SD+NLP (NLP voles). Resistance to cold was estimated by measurements of body temperature (T_b) during cold exposure (5°C). Daily rhythms of energy expenditure (calculated from oxygen consumption), urine production, and urinary adrenaline and serum cortisol levels were measured. T_b values of SD voles were generally unaffected by the cold stimulus, whereas in NLP voles, resistance to cold was markedly lowered. While SD‐ and NLP voles showed similar ultradian characteristics in energy expenditure with a period of 3.5 h, mean energy expenditure levels were lowest for voles exposed to NLP‐treatment. In SD voles, but not in NLP voles, urine production rates showed clear time variations and were consistently highest for SD voles, with significant differences during the scotophase. Both mean total urinary adrenaline and serum cortisol levels were significantly elevated in NLP‐treated voles compared with the control group. Taken together, the results suggest that NLP negatively affects winter acclimatization of thermoregulatory mechanisms of M. socialis, probably by mimicking summer acclimatization, and consequently the thermoregulatory mechanisms respond inappropriately to ambient conditions. One important finding of this study is that NLP may act as a stressor and correspondingly impose a major threat to the physiological homeostasis of M. socialis, such that over‐winter survival might be compromised.     

Location of Airway Inflammation in Asthma and the Relationship to Orcadian Change in Lung Function

Nocturnal asthma is an important part of asthma as the majority of patients with asthma have nocturnal worsening in lung function. The etiology of this process is multifactorial and interactive. There are many naturally occurring circadian rhythms, which for the normal individual have only a minor effect on lung function. However, in the asthmatic patient, these day-to-night alterations produce increased airway inflammation and worsening of asthma. Although asthma is considered an airway disease, the location of the inflammatory response may be greater in the alveolar tissue area. If correct, this could alter the therapeutic approach to this disease.     

Expression of dual Nucleotides/Cysteinyl‐Leukotrienes Receptor GPR17 in early trafficking of cardiac stromal cells after myocardial infarction

GPR17 is a G_i-coupled dual receptor activated by uracil-nucleotides and cysteinyl-leukotrienes. These mediators are massively released into hypoxic tissues. In the normal heart, GPR17 expression has been reported. By contrast, its role in myocardial ischaemia has not yet been assessed. In the present report, the expression of GPR17 was investigated in mice before and at early stages after myocardial infarction by using immunofluorescence, flow cytometry and RT-PCR. Before induction of ischaemia, results indicated the presence of the receptor in a population of stromal cells expressing the stem-cell antigen-1 (Sca-1). At early stages after ligation of the coronary artery, the receptor was expressed in Sca-1⁺ cells, and cells stained with Isolectin-B4 and anti-CD45 antibody. GPR17⁺ cells also expressed mesenchymal marker CD44. GPR17 function was investigated in vitro in a Sca-1⁺/CD31⁻ cell line derived from normal hearts. These experiments showed a migratory function of the receptor by treatment with UDP-glucose and leukotriene LTD4, two GPR17 pharmacological agonists. The GPR17 function was finally assessed in vivo by treating infarcted mice with Cangrelor, a pharmacological receptor antagonist, which, at least in part, inhibited early recruitment of GPR17⁺ and CD45⁺ cells. These findings suggest a regulation of heart-resident mesenchymal cells and blood-borne cellular species recruitment following myocardial infarction, orchestrated by GPR17.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist,Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist, Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

Background

There is large variation in the therapeutic response to inhaled corticosteroids (ICS) in COPD patients. We present a pooled analysis of our previous studies investigating the effects of corticosteroids on lung macrophages, in order to robustly determine whether corticosteroid sensitivity in COPD cells is reduced compared to controls, and also to evaluate the degree of between individual variation in drug response.

Methods

Data from 20 never smokers (NS), 27 smokers (S) and 45 COPD patients was used. Lung macropahges had been stimulated with lipopolysaccharide (LPS), with or without the corticosteroid dexamethasone, and tumour necrosis factor (TNF)-α, interleukin (IL)-6 and chemokine C-X-C motif ligand (CXCL) 8 production was measured.

Results

There was no difference in the anti-inflammatory effects of corticosteroids when comparing group mean data of COPD patients versus controls. The inhibition of TNF-α and IL-6 was greater than CXCL8. The effects of corticosteroids varied considerably between subjects, particularly at lower corticosteroid concentrations.

Conclusions

We confirm that overall corticosteroid sensitivity in COPD lung macrophages is not reduced compared to controls. The varied effect of corticosteroids between subjects suggests that some individuals have an inherently poor corticosteroid response. The limited suppression of lung macrophage derived CXCL8 may promote neutrophilic inflammation in COPD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0260-0) contains supplementary material, which is available to authorized users.     

吸入激素对ACOS患者的临床疗效及对内皮细胞功能的影响

目的:探讨吸入激素治疗哮喘-慢阻肺重叠综合征(ACOS)患者的临床疗效及对内皮细胞功能的影响。方法:收集2013年3月至2016年3月在我院接受治疗的95例ACOS患者,随机分为对照组48例和观察组47例。对照组患者给予西医综合治疗,观察组患者在对照组基础上给予丙酸氟替卡松雾化吸入剂治疗。观察治疗前后两组的肺功能指标(包括最大肺活量(FVC)、1 s用力呼吸容积(FEV1)、吸气分数(IC/TLC)、残总比(RV/TLC)以及一氧化碳弥散量(DLCO))、内皮细胞功能指标(包括可溶性细胞间黏附因子(SICAM-1)、血清NO及内皮素1(ET-1))、症状评分(包括哮喘症状评分(ACT)及慢阻肺症状评分(CAT))的变化以及临床疗效。结果:观察组的临床总有效率为89.4%,显著高于对照组的77.1%(P0.05)。治疗后,两组的FEV1、FEV1/FVC、IC/TLC及RV/TLC均较治疗前明显改善(P0.05),且观察组的FEV1、FEV1/FVC、IC/TLC、RV/TLC及DLCO改善幅度大于对照组(P0.05)。治疗后,两组的血清SICAM和ET-1水平均较治疗前明显降低,血清NO水平显著升高(P0.05),且观察组的血清SICAM和ET-1水平显著低于对照组,血清NO水平明显高于对照组(P0.05)。治疗后,两组的ACT评分和CAT评分均较治疗前明显改善(P0.05),且观察组的ACT评分显著高于对照组,CAT评分低于对照组(P0.05)。结论:吸入糖皮质激素治疗ACOS的临床疗效显著,可有效改善患者的临床症状、肺功能和内皮细胞功能。     

The effects of food and density on the nocturnal behaviour ofArion ater andAriolimax columbianus (Pulmonata: Stylommatophora)

The effects of food supply and population density on the nocturnal behaviour of Arion ater and Ariolimax columbianus were investigated. Density did not significantly affect A. ater's level of activity or short-term movement, resting, or feeding. A. columbianus was more active and moved, rested, and fed more frequently when slug density was high. A. ater foraged and rested more often, but fed less when good food was unavailable. Ariolimax's only response to the food regime was to feed more when good food was available. Seasonal changes in the level of activity and behaviour of Arion were evident, whereas Ariolimax's activity and behavioural repertoire were not similarly affected. Arion ater's nightly activity appeared to be mainly food oriented, while Ariolimax columbianus seemed most responsive to slug density during its nocturnal activity periods.     

The two faces of mast cells in food allergy and allergic asthma: The possible concept of Yin Yang

The purpose of this review is to discuss the role of mast cells in allergic inflammation. We have focused on inflammation associated with allergic asthma and food allergy. Mast cells are ‘first line of defense’ innate/adaptive immune cells and are widely distributed in tissues in surfaces exposed to the environment. Especially in allergic settings mast cells are extensively studied, as they can be activated to release a wide range of mediators by allergen-IgE specific triggers. In addition, in allergic inflammation mast cells can also be activated non-allergic triggers. Recent studies revealed that mast cells, besides the classical role of pro-inflammatory effector cell, have also emerged as modulators of allergic sensitization and down-regulators of allergic inflammation. Therefore, mast cells can be regarded as ‘Ying Yan’ modulators in allergic responses in intestinal tract and airways. This article is part of a Special Issue entitled: Mast Cells in Inflammation.