Headliner in Physiology and Management of Childhood Asthma: Hypothalamic-Pituitary-Adrenal Axis

2020 ◽  
Vol 16 (1) ◽  
pp. 43-52 ◽  
Author(s):  
Nese Akcan ◽  
Nerin N. Bahceciler

Asthma is the most common chronic inflammatory disease of children. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy which are the most effective, commonly used treatment of persistent asthma. Mostly, studies on the relationship between asthma and cortisol have focused on side effects of treatment. Recently, asthmatic patients not treated with ICS have been reported to have an attenuated activity and/or responsiveness of their Hypothalamic-Pituitary- Adrenal (HPA) axis. Moreover, it has been proposed that asthma worsening with stress may be due to a dysfunctional HPA axis, or cortisol insensitivity due to chronic psychological stress through impaired glucocorticoid receptor expression or function. Although long-term ICS treatment might produce adrenal suppression or iatrogenic Cushing syndrome, improvement of adrenal function has also been detected in some of asthmatic cases. Thus, the response scheme of HPA axis still contains undiscovered features in asthma. The management of asthma can be improved by increasing knowledge on the role of HPA axis in asthma pathophysiology. The risk for side effects of ICS can be minimized through increased awareness, early recognition of at-risk patients and regular patient follow-up. This review was written to draw attention to the role of HPA axis in both asthma and its treatment and to illustrate a follow up algorithm of HPA axis in the management of asthma.

2005 ◽  
Vol 289 (5) ◽  
pp. E857-E863 ◽  
Author(s):  
Anastasia Kariagina ◽  
Svetlana Zonis ◽  
Mahta Afkhami ◽  
Dmitry Romanenko ◽  
Vera Chesnokova

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 μg/mouse, ip) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.


Author(s):  
Susanne Fischer ◽  
Tabea Schumacher ◽  
Christine Knaevelsrud ◽  
Ulrike Ehlert ◽  
Sarah Schumacher

Abstract Background Less than half of all individuals with post-traumatic stress disorder (PTSD) remit spontaneously and a large proportion of those seeking treatment do not respond sufficiently. This suggests that there may be subgroups of individuals who are in need of augmentative or alternative treatments. One of the most frequent pathophysiological findings in PTSD is alterations in the hypothalamic–pituitary–adrenal (HPA) axis, including enhanced negative feedback sensitivity and attenuated peripheral cortisol. Given the role of the HPA axis in cognition, this pattern may contribute to PTSD symptoms and interfere with key processes of standard first-line treatments, such as trauma-focused cognitive behavioural therapy (TF-CBT). Methods This review provides a comprehensive summary of the current state of research regarding the role of HPA axis functioning in PTSD symptoms and treatment. Results Overall, there is preliminary evidence that hypocortisolaemia contributes to symptom manifestation in PTSD; that it predicts non-responses to TF-CBT; and that it is subject to change in parallel with positive treatment trajectories. Moreover, there is evidence that genetic and epigenetic alterations within the genes NR3C1 and FKBP5 are associated with this hypocortisolaemic pattern and that some of these alterations change as symptoms improve over the course of treatment. Conclusions Future research priorities include investigations into the role of the HPA axis in day-to-day symptom variation, the time scale in which biological changes in response to treatment occur, and the effects of sex. Furthermore, before conceiving augmentative or alternative treatments that target the described mechanisms, multilevel studies are warranted.


2017 ◽  
Vol 16 (3) ◽  
pp. 103-103
Author(s):  
Chris Roseveare ◽  

The role of consultants in the referral process for acute medicine has been a subject of discussion for as long as I have been involved with the speciality. This journal has previously published data from individual sites which demonstrated benefits on a local level when consultants were directly involved in taking referral phone calls from general practitioners. This was further evaluated as part of the Society for Acute Medicine’s 2016 Benchmarking Audit, (SAMBA16), which generated some National data around outcomes according to the seniority of clinician receiving the referral. This is presented in the current edition. The authors acknowledge the limitations of the data, particularly the difficulty in comparing units with different facilities for assessment, treatment and follow-up, which may have influenced the options available for consultants when taking referrals. As with previous research in this area, the paper focuses on the quantitative benefits in terms of the admissions ‘avoided’ as a result of telephone advice given; the data collection does not allow any analysis of what subsequently happened to these patients, and it is possible that some were subsequently admitted to hospital. It is important also to remember the qualitative benefits of direct communication with GPs: the ability to glean important nuggets of information which may be omitted from a referral letter, as well as the value of regular conversations in building relationships between primary and secondary care. My own experiences over the past 2 decades suggest that these benefits are often at least as great, albeit more difficult to measure, than ‘admission avoidance’. Infections represent a large proportion of the acute medical intake, and this is reflected in many of the case reports we receive for consideration of publication. Three such cases are included in this edition. When the case history includes ‘visiting sewage-contaminated land’, many clinicians would be thinking along the lines of leptospirosis while awaiting serological testing. However in the case presented by Sarah Lawrence and colleagues from the Manchester area, it turned out to be the family pet which was responsible for their patient’s disseminated intravascular coagulation. Captocytophaga carnimorsis is not an organism with which I was previously familiar, but this case has reinforced my view that allowing your dog to lick your mucus membranes is something to be avoided. Lemierr’s syndrome is another condition which I have not previously encountered; however the authors of our third case report suggest this may be worth considering when a patient’s ‘simple sore throat’ fails to improve. In this case, it was the finding of another unusual bacterium – fusebacterium necrophorum – in the blood culture which led to the further investigation and diagnosis of this condition. Early recognition and initiation of appropriate antibiotic therapy is associated with an improved outcome, so this represents an important reminder of a condition which might otherwise be forgotten. Although this is technically the ‘autumn edition’, I suspect that Winter may already have arrived with a vengeance by the time it has been printed and mailed, so I hope that readers working in the NHS’ busy Acute Medical Units are managing to keep their spirits up, and have battened down the necessary hatches for whatever the months ahead choose to throw at us.


2021 ◽  
Vol 8 (3) ◽  
pp. 554
Author(s):  
Krutika Gangdev ◽  
Hemant Jain ◽  
Atul Luhadia

Background: Asthma is characterized by hyperresponsiveness of airways to various stimuli, manifested by widespread narrowing of airways causing paroxysmal dyspnoea, wheezing or cough. Most asthma medications are inhalational and compliance is difficult. So, development of an orally active and once daily drug with additional bronchodilator properties would lead to a major advance for managing young patients with asthma.Methods: Children between 6-18 years with not well controlled asthma on daily controller therapy were enrolled. Their personal data and history regarding the duration of asthma symptoms, frequency and severity of exacerbations was noted. Diagnosis and grading of severity of asthma was confirmed by spirometry. Then subjects were started on montelukast as add on to their daily controller therapy and were reassessed at 4, 8 and 12 weeks by clinical symptoms and PEFR. The change in frequency of symptoms and PEFR at the end of 12 weeks gave the outcome of efficacy of montelukast. Side effects of montelukast were also assessed.Results: Among total 64 subjects, at 4 weeks, 52 improved to well-controlled asthma. The remaining 12 did not improve, so required an increase in dose of their daily controller medication. Out of those 12 subjects, 10 subjects improved to well-controlled asthma at 8 weeks and 2 subjects still did not improve, so, their inhaled corticosteroids (ICS) dose was further increased. All 64 subjects showed improvement at 12 weeks. No serious side effects were observed.Conclusions: 81.25% subjects showed improvement at the 1st follow up itself and no serious complications were observed. So, it can be suggested that montelukast is a safe drug.


2009 ◽  
Vol 1 ◽  
pp. CMT.S2133
Author(s):  
Daniel Gonzalez ◽  
Hartmut Derendorf

Ciclesonide is a novel inhaled corticosteroid (ICSs) approved in most countries for the management of persistent asthma. Although inhaled corticosteroids are first-line therapy in the treatment of asthma, long term use and high-doses of these products may result in significant side effects. When developing a new ICSs, the goal is to identify a drug with comparable (or superior) efficacy to active comparators, and an improved safety profile. Ciclesonide is a prodrug which is administered through a hydrofluoroalkane-propellant metered dose inhaler (HFA-MDI). Once it reaches the lungs, the parent compound is metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. Ciclesonide has a unique pharmacokinetic-pharmacodynamic profile which confers an improved therapeutic ratio. Several clinical trials have shown that its efficacy is superior to placebo and similar to several active comparators. However, its high pulmonary deposition and on-site activation minimizes the risk for local side effects. Also, its low oral bioavailability, high hepatic clearance, and extensive plasma protein binding, among other factors, decrease the risk for systemic side effects. Doses of ciclesonide as high as 1280 μg/day (ex-actuator) result in minimal hypothalamic-pituitary-adrenal (HPA) axis suppression, a measure commonly used to assess systemic bioavailability for an ICSs. This review will provide a summary of ciclesonide's role in the management of asthma, including a discussion of relevant clinical trials designed to evaluate its efficacy and safety.


2008 ◽  
Vol 197 (2) ◽  
pp. 421-427 ◽  
Author(s):  
Mathias V Schmidt ◽  
Claudia Liebl ◽  
Vera Sterlemann ◽  
Karin Ganea ◽  
Jakob Hartmann ◽  
...  

The function of the hypothalamic–pituitary–adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPY-deficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.


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