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BioRxiv : the Preprint Server For... Aug 2023Pulmonary disorders impact 40-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely...
Pulmonary disorders impact 40-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs)-mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing effects of dietary challenge on diaphragms of wild-type (WT) and knockout ( ) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGFβ-related expression signatures, and augmentation of a -expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, mice were protected from these transcriptomic changes, and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition, and potential therapeutic target in obesity-associated respiratory dysfunction.
PubMed: 37645822
DOI: 10.1101/2023.08.17.553733 -
The Journal of Comparative Neurology Dec 2023The diaphragm is a multifunctional muscle that mediates both autonomic and volitional inspiration. It is critically involved in vocalization, postural stability, and...
The diaphragm is a multifunctional muscle that mediates both autonomic and volitional inspiration. It is critically involved in vocalization, postural stability, and expulsive core-trunk functions, such as coughing, hiccups, and vomiting. In macaque monkeys, we used retrograde transneuronal transport of rabies virus injected into the left hemidiaphragm to identify cortical neurons that have multisynaptic connections with phrenic motoneurons. Our research demonstrates that representation of the diaphragm in the primary motor cortex (M1) is split into two spatially separate and independent sites. No cortico-cortical connections are known to exist between these two sites. One site is located dorsal to the arm representation within the central sulcus and the second site is lateral to the arm. The dual representation of the diaphragm warrants a revision to the somatotopic map of M1. The dorsal diaphragm representation overlaps with trunk and axial musculature. It is ideally situated to coordinate with these muscles during volitional inspiration and in producing intra-abdominal pressure gradients. The lateral site overlaps the origin of M1 projections to a laryngeal muscle, the cricothyroid. This observation suggests that the coordinated control of laryngeal muscles and the diaphragm during vocalization may be achieved, in part, by co-localization of their representations in M1. The neural organization of the two diaphragm sites underlies a new perspective for interpreting functional imaging studies of respiration and/or vocalization. Furthermore, our results provide novel evidence supporting the concept that overlapping output channels within M1 are a prerequisite for the formation of muscle synergies underlying fine motor control.
Topics: Animals; Motor Cortex; Diaphragm; Motor Neurons; Macaca; Respiration; Neural Pathways
PubMed: 37723869
DOI: 10.1002/cne.25540 -
Australian Critical Care : Official... Jan 2024Diaphragm and lung ultrasound (DLUS) is emerging as an important point-of-care respiratory assessment tool and is being used in clinical care by trained respiratory... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Diaphragm and lung ultrasound (DLUS) is emerging as an important point-of-care respiratory assessment tool and is being used in clinical care by trained respiratory physiotherapists, both in Australia and internationally. However, the impact of DLUS on physiotherapists' clinical decision-making remains largely unknown. This systematic review aims to review the evidence for implementing DLUS in acute respiratory physiotherapy management.
REVIEW METHOD USED
We conducted a systematic review.
DATA SOURCES
We searched PubMed, Embase, CINAHL, CENTRAL, and Scopus from inception to 18th April 2023 for all original clinical studies reporting on the physiotherapy clinical decision-making, following a DLUS examination and/or where DLUS was used to evaluate the effect of respiratory physiotherapy, in adults over 18 years of age.
REVIEW METHODS
Two authors independently performed study selection and data extraction. Individual study risk of bias was assessed using the Newcastle-Ottawa Scale, and certainty in outcomes was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework.
RESULTS
A total of seven observational studies (n = 299) were included, all of which were in the intensive care setting. DLUS changed physiotherapy diagnosis, management, and treatment in 63.9% (50-64%), 16.8% (15-50%), and 48.4% (25-50%) of patients, respectively. There was a significant improvement in the lung ultrasound score post respiratory physiotherapy treatment (mean difference -2.31, 95% Confidence Interval (95% CI) -4.42 to -0.21; very low certainty) compared to before respiratory physiotherapy treatment. Moderate risk of bias was present in six studies, and there was variance in the DLUS methodology across included studies.
CONCLUSIONS
The findings of this review suggest DLUS influences physiotherapy clinical decision-making and can be used to evaluate the effects of acute respiratory physiotherapy treatment. However, the available data is limited, and further high-quality studies are needed.
TRIAL REGISTRATION
This study is registered with the International Prospective Register of Systematic Reviews; CRD42023418312.
Topics: Adult; Humans; Adolescent; Diaphragm; Lung; Physical Therapy Modalities; Clinical Decision-Making; Australia
PubMed: 38036384
DOI: 10.1016/j.aucc.2023.10.001 -
Respiratory Medicine Sep 2023Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We...
BACKGROUND
Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters.
METHODS
All consecutive CTD-ILD and IPF patients followed in our center (March-October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded.
RESULTS
Eighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients' functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021).
CONCLUSION
The prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment.
Topics: Humans; Diaphragm; Prevalence; Lung Diseases, Interstitial; Idiopathic Pulmonary Fibrosis; Connective Tissue Diseases; Dyspnea
PubMed: 37271302
DOI: 10.1016/j.rmed.2023.107293 -
Journal of Intensive Care Medicine Sep 2023We aimed to analyze the prognostic value of muscle volume (MV), bone mineral density (BMD), and diaphragm diameter (DD) in COVID-19. The study included 498 patients...
We aimed to analyze the prognostic value of muscle volume (MV), bone mineral density (BMD), and diaphragm diameter (DD) in COVID-19. The study included 498 patients admitted to the intensive care unit (ICU) with a positive polymerase chain reaction test for COVID-19 from March 11, 2020, through August 31, 2022. The patients' laboratory and demographic data of the patients at the time of ICU admission were recorded. MV, DD, and BMD measurements were performed using computed tomography examinations. Muscle index (MI) was calculated as MV/height. Quartiles were determined for all 4 measurements. Patients in the lowest quartile were recorded as having low MV, MI, DD, and BMD values. The parameters were evaluated for the whole group and compared according to gender and mortality. The multiple regression analysis was performed for the prediction of mortality. In the mortality group, the male and female patients had significantly statistically lower values in MV ( < .001 and = .002, respectively), MI ( < .001 and = .005, respectively), DD ( < .001 and < .001, respectively), and BMD ( = .002 and < .001, respectively). In the multiple regression analysis, low MI (OR: 2.03, 95% CI: 1.14-3.61, = .016) and DD (OR: 10.47, 95% CI: 5.59-19.59, < .001) values remained significant for the prediction of mortality. BMD is a risk factor for mortality in patients with severe COVID-19, but cannot be used as an independent predictor. However, MI and DD can be used as independent predictors of mortality even in severe cases.
Topics: Humans; Male; Female; Diaphragm; Bone Density; COVID-19; Critical Illness; Prognosis; Intensive Care Units; Retrospective Studies
PubMed: 37050868
DOI: 10.1177/08850666231169494 -
American Journal of Physiology. Cell... Apr 2024Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this...
Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analog, ALY688-SR, remodels the diaphragm of murine model of DMD on DBA background (D2.) mice treated from of age during early stages of disease. ALY688-SR also lowered interleukin-6 (IL-6) mRNA but increased IL-6 and transforming growth factor-β1 (TGF-β1) protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated HO emission. Treatment also attenuated fibrosis, fiber type-specific atrophy, and in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling, and force-generating properties during the very early stages of disease progression in murine model of DMD on DBA background (D2.) mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2. mice partially prevents fibrosis and fiber type-specific atrophy and lowers force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations. There are limited therapies for the treatment of Duchenne muscular dystrophy. As fibrosis involves an accumulation of collagen that replaces muscle fibers, antifibrotics may help preserve muscle function. We report that the novel adiponectin receptor agonist ALY688-SR prevents fibrosis in the diaphragm of D2. mice with short-term treatment early in disease progression. These responses were related to altered inflammation and mitochondrial functions and serve as a foundation for the development of this class of therapy.
Topics: Animals; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; Adiponectin; Disease Models, Animal; Interleukin-6; Mice, Inbred C57BL; Hydrogen Peroxide; Receptors, Adiponectin; Mice, Inbred DBA; Muscle, Skeletal; Diaphragm; Fibrosis; Inflammation; Disease Progression; Atrophy
PubMed: 38145301
DOI: 10.1152/ajpcell.00638.2023 -
Cells Jul 2023Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive...
Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced changes in diaphragm muscle, which manifest as impaired muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) administered in the drinking water throughout exposure to CIH. In separate studies, we examined sham and CIH-exposed NOX2-null mice (B6.129S-). Apocynin co-treatment or NOX2 deletion proved efficacious in entirely preventing diaphragm muscle dysfunction following exposure to CIH. Exposure to CIH had no effect on NOX2 expression. However, NOX4 mRNA expression was increased following exposure to CIH in wild-type and NOX2 null mice. There was no evidence of overt CIH-induced oxidative stress. A NOX2-dependent increase in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy was evident following exposure to CIH. We suggest that NOX-dependent CIH-induced diaphragm muscle weakness has the potential to affect ventilatory and non-ventilatory performance of the respiratory system. Therapeutic strategies employing NOX2 blockade may function as an adjunct therapy to improve diaphragm muscle performance and reduce disease burden in diseases characterised by exposure to CIH, such as obstructive sleep apnoea.
Topics: Mice; Male; Animals; NADPH Oxidase 2; Diaphragm; Mice, Inbred C57BL; Hypoxia; Muscle Weakness
PubMed: 37508499
DOI: 10.3390/cells12141834 -
Neurogastroenterology and Motility Jan 2024Gastroesophageal reflux (GER) is known to be associated with chronic lung diseases. The driving force of GER is the transdiaphragmatic pressure (Pdi) generated mainly by...
BACKGROUND
Gastroesophageal reflux (GER) is known to be associated with chronic lung diseases. The driving force of GER is the transdiaphragmatic pressure (Pdi) generated mainly by costal and crural diaphragm contraction. The latter also enhances the esophagogastric junction (EGJ) pressure to guard against GER.
METHODS
The relationship between Pdi and EGJ pressure was determined using high resolution esophageal manometry in patients with interstitial lung disease (ILD, n = 26), obstructive lung disease (OLD, n- = 24), and healthy subjects (n = 20).
KEY RESULTS
The patient groups did not differ with respect to age, gender, BMI, and pulmonary rehabilitation history. Patients with ILD had significantly higher Pdi but lower EGJ pressures as compared to controls and OLD patients (p < 0.001). In control subjects, the increase in EGJ pressure at all-time points during inspiration was greater than Pdi. In contrast, the EGJ pressure during inspiration was less than Pdi in 14 patients with ILD and 7 patients with OLD. The drop in EGJ pressure was usually seen after the peak Pdi in ILD group (p < 0.0001) and before the peak Pdi in OLD group, (p = 0.08). Nine patients in the ILD group had sliding hiatus hernia, compared to none in control subjects (p = 0.003) and two patients in the OLD, (p = 0.04).
CONCLUSIONS AND INFERENCES
A higher Pdi and low EGJ pressure, and dissociation between Pdi and EGJ pressure temporal relationship suggests selective dysfunction of the crural diaphragm in patients with chronic lung diseases and may explain the higher prevalence of GERD in ILD as seen in previous studies.
Topics: Humans; Diaphragm; Gastroesophageal Reflux; Esophagogastric Junction; Manometry; Lung Diseases, Obstructive; Lung Diseases, Interstitial
PubMed: 37882102
DOI: 10.1111/nmo.14699 -
Neurocritical Care Dec 2023Patients in the neurointensive care unit (NICU) fail extubation despite successful weaning from mechanical ventilation. Parameters currently used in the general... (Observational Study)
Observational Study
BACKGROUND
Patients in the neurointensive care unit (NICU) fail extubation despite successful weaning from mechanical ventilation. Parameters currently used in the general intensive care unit do not accurately predict extubation success in the NICU. In this study, peak cough expiratory flow rate, ultrasound-based diaphragm function assessment, and comprehensive clinical scoring systems were measured to determine whether these new variables, in isolation or combination, could predict extubation failure successfully in the NICU.
METHODS
All adult patients extubated after 48 h of mechanical ventilation in the NICU of a single tertiary care center were recruited into the prospective cohort. The patient's cough peak expiratory flow rate (C-PEFR), diaphragm function, and clinical scores were measured before extubation. C-PEFR was measured using a hand-held spirometer, diaphragm function (excursion, thickness fraction, and diaphragm contraction velocity on coughing) was assessed using ultrasound, and the clinical scores included the visual pursuit, swallowing, age, Glasgow Coma Scale for extubation (VISAGE) and respiratory insufficiency scale-intubated (RIS-i) scores. The patients requiring reintubation within 48 h were considered as extubation failure. Univariate and multivariate logistic regression analyses were done to identify predictors of extubation failure.
RESULTS
Of the 193 patients screened, 43 were recruited, and 15 had extubation failure (20.9%). Patients with extubation failure had higher RIS-i scores (p < 0.001) and lower VISAGE scores (p = 0.043). The C-PEFR and diaphragm function (excursions and contraction velocity on coughing) were lower in patients with extubation failure but not statistically significant. The variables with p < 0.2 in univariate analysis (RIS-i, VISAGE, and diaphragm cough velocity) were subjected to multivariate regression analysis. RIS-I score remained an independent predictor (odds ratio 3.691, 95% confidence interval 1.5-8.67, p = 0.004). In a receiver operating characteristic analysis, the area under the curve for RIS-i was 0.963. An RIS-i score of 2 or more had 94% specificity and 89% sensitivity for predicting extubation failure.
CONCLUSIONS
The RIS-i score predicts extubation failure in NICU patients. The addition of ultrasound-based diaphragm measurements to the RIS-i score to improve prediction accuracy needs further study. Clinical trial registration Clinical Trials Registry of India identifier CTRI/2021/03/031923.
Topics: Adult; Humans; Diaphragm; Ventilator Weaning; Cough; Prospective Studies; Airway Extubation; Respiration, Artificial; Respiratory Insufficiency
PubMed: 36859489
DOI: 10.1007/s12028-023-01695-4 -
Respiratory Physiology & Neurobiology Mar 2024There is increasing clinical interest in understanding the contribution of the diaphragm in early expiration, especially during mechanical ventilation. However, current...
BACKGROUND
There is increasing clinical interest in understanding the contribution of the diaphragm in early expiration, especially during mechanical ventilation. However, current experimental evidence is limited, so essential activity of the diaphragm during expiration and diaphragm segmental differences in expiratory activity, are unknown.
OBJECTIVES
To determine if: 1) the diaphragm is normally active into expiration during spontaneous breathing and hypercapnic ventilation, 2) expiratory diaphragmatic activity is distributed equally among the segments of the diaphragm, costal and crural.
METHODS
In 30 spontaneously breathing male and female canines, awake without confounding anesthetic, we measured directly both inspiratory and expiratory electrical activity (EMG), and corresponding mechanical shortening, of costal and crural diaphragm, during room air and hypercapnia.
RESULTS
During eupnea, costal and crural diaphragm are active into expiration, showing significant and distinct expiratory activity, with crural expiratory activity greater than costal, for both magnitude and duration. This diaphragm segmental difference diverged further during progressive hypercapnic ventilation: crural expiratory activity progressively increased, while costal expiratory activity disappeared.
CONCLUSION
The diaphragm is not passive during expiration. During spontaneous breathing, expiratory activity -"braking"- of the diaphragm is expressed routinely, but is not equally distributed. Crural muscle "braking" is greater than costal muscle in magnitude and duration. With increasing ventilation during hypercapnia, expiratory activity -"braking"- diverges notably. Crural expiratory activity greatly increases, while costal expiratory "braking" decreases in magnitude and duration, and disappears. Thus, diaphragm expiratory "braking" action represents an inherent, physiological function of the diaphragm, distinct for each segment, expressing differing neural activation.
Topics: Female; Male; Animals; Dogs; Diaphragm; Hypercapnia; Electromyography; Respiration; Thorax
PubMed: 38135107
DOI: 10.1016/j.resp.2023.104205