The airway smooth muscle (ASM) surrounding the airways is dysfunctional in both asthma and chronic obstructive pulmonary disease (COPD), exhibiting; increased contraction, increased mass, increased ...inflammatory mediator release and decreased corticosteroid responsiveness. Due to this dysfunction, ASM is a key contributor to symptoms in patients that remain symptomatic despite optimal provision of currently available treatments.
There is a significant body of research investigating the effects of oxidative stress/ROS on ASM behaviour, falling into the following categories; cigarette smoke and associated compounds, air pollutants, aero-allergens, asthma and COPD relevant mediators, and the anti-oxidant Nrf2/HO-1 signalling pathway. However, despite a number of recent reviews addressing the role of oxidative stress/ROS in asthma and COPD, the potential contribution of oxidative stress/ROS-related ASM dysfunction to asthma and COPD pathophysiology has not been comprehensively reviewed.
We provide a thorough review of studies that have used primary airway, bronchial or tracheal smooth muscle cells to investigate the role of oxidative stress/ROS in ASM dysfunction and consider how they could contribute to the pathophysiology of asthma and COPD. We summarise the current state of play with regards to clinical trials/development of agents targeting oxidative stress and associated limitations, and the adverse effects of oxidative stress on the efficacy of current therapies, with reference to ASM related studies where appropriate. We also identify limitations in the current knowledge of the role of oxidative stress/ROS in ASM dysfunction and identify areas for future research.
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•Airway smooth muscle (ASM) is dysfunctional in asthma and COPD.•Cigarette smoke, pollutants, aero-allergens and mediators induce oxidative stress in ASM.•Nrf2/HO-1 antioxidant defences are compromised in ASM in asthma and by TGF-β.•ASM dysfunction relevant to asthma and COPD is increased by oxidative stress stimuli.•Oxidative stress effects on ASM could contribute to AHR, airflow obstruction and inflammation.
Airway smooth muscle (ASM) contributes to asthma pathophysiology via hypercontractility, increased mass, and inflammatory mediator release.1 Clinical studies and animal models demonstrate a role for ...high-mobility group box 1 (HMGB1) and its receptors in airway inflammation and asthma.2,3 HMGB1's activity and receptor interactions is determined by its redox state, with oxidation rendering HMGB1 inactive.4 We have investigated the redox state of airway HMGB1 and the role of HMGB1 in ASM function. Reduced recombinant HMGB1, at concentrations equivalent to those in sputum, caused a concentration-dependent increase in intracellular ROS production in ASMCs from controls, but not in ASMCs from those with asthma (Fig 2, D), which was reduced by the RAGE decoy receptor soluble RAGE (sRAGE) and the Toll-like receptor (TLR) 4 antagonist LPS from Rhodobacter sphaeroides (LPS-RS) (Fig 2, E). Characteristic Healthy control(n = 10) Asthma severe(n = 19) t test/χ2 test∗ GINA classification, n GINA 4, n = 11GINA 5, n = 5 Age (y)† 46.7 ± 6.2 55 ± 2.8 P = .17 Sex: male, n (%) 5 (50) 8 (42.1) P = .71∗ Smoking status, current smoker, n (%) 1 (10) 5 (26.3) P = .63∗ ICS (μg/d BDP equivalent)‡ 0 (0) 1600 (125)§ P < .001 Pre-BD FEV1 % predicted‡ 93.5 (28.6) 76.0 (54.7) P = .065 Pre-BD FEV1/FVC‡ 90.5 (13.3) 71.1 (24.9)§ P = .0009 % Sputum neutrophils† 50.5 ± 18.7 52.6 ± 6.1 P = .9 % Sputum eosinophils‡ 0.4 (0.8) 5.3 (16.8)§ P = .002 1 D.C. Doeing, J. Solway, Airway smooth muscle...
Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to ...temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70°C) for 10 s to mimic thermoplasty.
we developed a mathematical model of airway heat distribution post-thermoplasty.
we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.
airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C.
simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm.
at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured
Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1-1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0-10; p=0.03) and epithelial integrity increased (14%, IQR 6-29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated
and
modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.
Carnosine was first discovered in skeletal muscle, where its concentration is higher than in any other tissue. This, along with an understanding of its role as an intracellular pH buffer has made it ...a dipeptide of interest for the athletic population with its potential to increase high-intensity exercise performance and capacity. The ability to increase muscle carnosine levels via β-alanine supplementation has spawned a new area of research into its use as an ergogenic aid. The current evidence base relating to the use of β-alanine as an ergogenic aid is reviewed here, alongside our current thoughts on the potential mechanism(s) to support any effect. There is also some emerging evidence for a potential therapeutic role for carnosine, with this potential being, at least theoretically, shown in ageing, neurological diseases, diabetes and cancer. The currently available evidence to support this potential therapeutic role is also reviewed here, as are the potential limitations of its use for these purposes, which mainly focusses on issues surrounding carnosine bioavailability.
Objective
Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID‐19) are similar to those found with clinical hormone deficiencies. We ...hypothesised that people with severe acute COVID‐19 and with post‐COVID symptoms have glucocorticoid and sex hormone deficiencies.
Design/Patients
Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID‐19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation WHO Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow‐up 5 months after hospitalisation (Post‐hospitalisation COVID‐19 study).
Measurements
Plasma steroids were quantified by liquid chromatography–mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD).
Results
In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 1.6 vs. 429.2 1.7 nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 2.2 vs. 6.9 1.9 nmol/L in fatal vs. least severe, p < .001). In the follow‐up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 121–192 days postdischarge), plasma cortisol concentrations (275.6 1.5 nmol/L) did not differ with in‐hospital severity, perception of recovery, or patient‐reported symptoms. Male testosterone concentrations (12.6 1.5 nmol/L) were not related to in‐hospital severity, perception of recovery or symptom scores.
Conclusions
Circulating glucocorticoids in patients hospitalised with COVID‐19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post‐COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.
Objectives
We investigated patients with
Clostridioides difficile
-associated diarrhoea to see if clinical resolution correlated with faecal concentrations of metronidazole or markers of ...inflammation.
Methods
Faecal metronidazole, lactoferrin and serum CRP were measured daily. These were then compared with clinical progress.
Results
Metronidazole concentration correlated with lactoferrin (
ρ
= 0.17,
p
= 0.015), CRP (
ρ
= 0.23,
p
< 0.001) and number of diarrhoeal stools per day (
ρ
= 0.29,
p
< 0.001). Lactoferrin correlated with CRP (
ρ
= 0.57,
p
< 0.001) and the number of diarrhoeal stools per day (
ρ
= 0.52,
p
< 0.001) as did CRP (
ρ
= 0.52,
p
< 0.001).
Conclusions
We found no association between cessation of diarrhoea and metronidazole or lactoferrin concentrations. There was a relationship between metronidazole concentrations and markers of inflammation and stool frequency.
The authors argue on the effectiveness of bronchial thermoplasty (BT) in asthma. Here, presents caution when interpreting predictions of computational models at the organ level in the context of ...tissuescale effects. Examined are the few points about the use of modeling to understand the mechanisms underlying the therapeutic action of BT in asthma control. The authors postulate a fixed airway smooth muscle (ASM) reduction after BT. However, relative reductions in ASM mass in reported in vivo biopsy studies, is cited. Other works have also highlighted the relative resilience of fibroblasts to thermal injury.
Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is ...limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group.
This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care.
Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority.
The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study ...aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms. One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators. Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean + or - SD of 14.9 + or - 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 + or - 1.7 h/day spent inactive and 7.2 + or - 1.1 h/day asleep. The values for men were 21.0 + or - 22.3 and 12.6 + or - 1.7 h /day and 6.9 + or - 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant.
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