Airway diameter at different transpulmonary pressures in ex vivo sheep lungs: Implications for deep-inspiration-induced bronchodilation and bronchoprotection

2021 ◽  
Author(s):  
Shou-Jin Dong ◽  
Lu Wang ◽  
Pasquale Chitano ◽  
Harvey O. Coxson ◽  
Peter D. Paré ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Ex Vivo ◽  
Transpulmonary Pressure ◽  
Significant Loss ◽  
Clear Understanding ◽  
Deep Inspiration ◽  
Central Question ◽  
First Line ◽  
Lung Volumes ◽  
Lung Resistance

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology. It has been postulated that straining airway smooth muscle (ASM) during a DI could lead to bronchodilation and bronchoprotection. The hypothesis is currently under debate, and a central question is whether ASM is sufficiently stretched during a DI for its contractility to be compromised. Besides bronchoconstriction, another contributor to lung resistance is airway heterogeneity. The present study examines changes in airway diameter and heterogeneity at different lung volumes. Freshly explanted sheep lungs were used in plethysmographic measurements of lung resistance and elastance at different lung volumes while the airway dimensions were measured by computed tomography (CT). The change in airway diameter informed by CT measurements was applied to isolated airway ring preparations to determine the strain-induced loss of ASM contractility. We found that changing the transpulmonary pressure from 5 to 30 cmH2O led to a 51%-increase in lung volume, accompanied by a 46%-increase in the airway diameter with no change in airway heterogeneity. When comparable airway strains measured in the whole lung were applied to isolated airway rings in either relaxed or contracted state, a significant loss of ASM contractility was observed, suggesting that DI-induced bronchodilation and bronchoprotection can result from strain-induced loss of ASM contractility.

Nonlinear increases in diffusing capacity during exercise by seated and supine subjects

1981 ◽  
Vol 51 (4) ◽  
pp. 858-863 ◽  
Author(s):  
D. L. Stokes ◽  
N. R. MacIntyre ◽  
J. A. Nadel
Keyword(s):  
Carbon Monoxide ◽  
Oxygen Consumption ◽  
Healthy Subjects ◽  
Vital Capacity ◽  
Maximal Exercise ◽  
Sitting Position ◽  
Diffusing Capacity ◽  
Heavy Exercise ◽  
Lung Volumes ◽  
Rate Of Increase

To study the effects of exercise on pulmonary diffusing capacity, we measured the lungs' diffusing capacity for carbon monoxide (DLCO) during exhalation from 30 to 45% exhaled vital capacity in eight healthy subjects at rest and during exercise while both sitting and supine. We found that DLCO at these lung volumes in resting subjects was 26.3 +/- 3.2% (mean +/- SE) higher in the supine than in the sitting position (P less than 0.001). We also found that, in both positions, DLCO at these lung volumes increased significantly (P less than 0.001) with increasing exercise and approached similar values at maximal exercise. The pattern of increase in DLCO with an increase in oxygen consumption in both positions was curvilinear in that the rate of increase in DLCO during mild exercise was greater than the rate of increase in DLCO during heavy exercise (P = 0.02). Furthermore, in the supine position during exercise, it appeared that DLCO reached a physiological maximum.

scholarly journals Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 356 ◽  
Author(s):  
Alessia Lo Curto ◽  
Simona Taverna ◽  
Maria Assunta Costa ◽  
Rosa Passantino ◽  
Giuseppa Augello ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fabry Disease ◽  
Healthy Subjects ◽  
Aging Process ◽  
Replicative Senescence ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Quantitative Polymerase Chain Reaction ◽  
Premature Aging

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) “young” and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process.

Inflection point on transpulmonary pressure-volume curves and closing volume

1975 ◽  
Vol 38 (2) ◽  
pp. 228-235 ◽  
Author(s):  
M. Demedts ◽  
J. Clement ◽  
D. C. Stanescu ◽  
K. P. van de Woestijne
Keyword(s):  
Inflection Point ◽  
Vital Capacity ◽  
Transpulmonary Pressure ◽  
Bronchial Obstruction ◽  
Closing Volume ◽  
Lung Volumes ◽  
Nitrogen Washout ◽  
Single Breath ◽  
Space Effect ◽  
Washout Curves

In 20 healthy subjects and 18 patients with bronchial obstruction, closing volume (CV) on single-breath nitrogen washout curves and inflection point (IP) on transpulmonary pressure-volume curves were recorded simultaneously during slow expiratory vital capacity maneuvers. IP and CV did not occur at identical lung volumes, IP being systematically larger than CV for small CV values. This discrepancy could not be attributed to an esophageal or mediastinal artifact. It is suggested that, though CV and IP both express “airway closure,” their sensitivity to closure may differ: CV underestimates closure because of a dead space effect; the latter may vary individually. On the other hand, IP may not reflect the true beginning of closure, particularly when it occurs at higher lung volumes.

High lung volume increases stress failure in pulmonary capillaries

1992 ◽  
Vol 73 (1) ◽  
pp. 123-133 ◽  
Author(s):  
Z. Fu ◽  
M. L. Costello ◽  
K. Tsukimoto ◽  
R. Prediletto ◽  
A. R. Elliott ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Lung Volume ◽  
Autologous Blood ◽  
Physiological Mechanism ◽  
Transpulmonary Pressure ◽  
Lung Volumes ◽  
Lung Inflation ◽  
Pulmonary Capillaries ◽  
Scanning Electron

We previously showed that when pulmonary capillaries in anesthetized rabbits are exposed to a transmural pressure (Ptm) of approximately 40 mmHg, stress failure of the walls occurs with disruption of the capillary endothelium, alveolar epithelium, or sometimes all layers. The present study was designed to test whether stress failure occurred more frequently at high than at low lung volumes for the same Ptm. Lungs of anesthetized rabbits were inflated to a transpulmonary pressure of 20 cmH2O, perfused with autologous blood at 32.5 or 2.5 cmH2O Ptm, and fixed by intravascular perfusion. Samples were examined by both transmission and scanning electron microscopy. The results were compared with those of a previous study in which the lung was inflated to a transpulmonary pressure of 5 cmH2O. There was a large increase in the frequency of stress failure of the capillary walls at the higher lung volume. For example, at 32.5 cmH2O Ptm, the number of endothelial breaks per millimeter cell lining was 7.1 +/- 2.2 at the high lung volume compared with 0.7 +/- 0.4 at the low lung volume. The corresponding values for epithelium were 8.5 +/- 1.6 and 0.9 +/- 0.6. Both differences were significant (P less than 0.05). At 52.5 cmH2O Ptm, the results for endothelium were 20.7 +/- 7.6 (high volume) and 7.1 +/- 2.1 (low volume), and the corresponding results for epithelium were 32.8 +/- 11.9 and 11.4 +/- 3.7. At 32.5 cmH2O Ptm, the thickness of the blood-gas barrier was greater at the higher lung volume, consistent with the development of more interstitial edema. Ballooning of the epithelium caused by accumulation of edema fluid between the epithelial cell and its basement membrane was seen at 32.5 and 52.5 cmH2O Ptm. At high lung volume, the breaks tended to be narrower and fewer were oriented perpendicular to the axis of the pulmonary capillaries than at low lung volumes. Transmission and scanning electron microscopy measurements agreed well. Our findings provide a physiological mechanism for other studies showing increased capillary permeability at high states of lung inflation.

scholarly journals Encapsulated cyclosporine does not change the composition of the human microbiota when assessed ex vivo and in vivo

2020 ◽  
Vol 69 (6) ◽  
pp. 854-863
Author(s):  
Catherine O'Reilly ◽  
Órla O’Sullivan ◽  
Paul D. Cotter ◽  
Paula M. O’Connor ◽  
Fergus Shanahan ◽  
...  
Keyword(s):  
Pilot Study ◽  
Gut Microbiota ◽  
Targeted Delivery ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Microbiota Composition ◽  
Faecal Samples

Introduction. Management of steroid-refractory ulcerative colitis has predominantly involved treatment with systemic cyclosporine A (CyA) and infliximab. Aim. The purpose of this study was to assess the effect of using a colon-targeted delivery system CyA formulation on the composition and functionality of the gut microbiota. Methodology. Ex vivo faecal fermentations from six healthy control subjects were treated with coated minispheres (SmPill) with (+) or without (−) CyA and compared with a non-treated control in a model colon system. In addition, the in vivo effect of the SmPill+CyA formulation was investigated by analysing the gut microbiota in faecal samples collected before the administration of SmPill+CyA and after 7 consecutive days of administration from eight healthy subjects who participated in a pilot study. Results. Analysis of faecal samples by 16S rRNA gene sequencing indicated little variation in the diversity or relative abundance of the microbiota composition before or after treatment with SmPill minispheres with or without CyA ex vivo or with CyA in vivo. Short-chain fatty acid profiles were evaluated using gas chromatography, showing an increase in the concentration of n-butyrate (P=0.02) and acetate (P=0.32) in the faecal fermented samples incubated in the presence of SmPill minispheres with or without CyA. This indicated that increased acetate and butyrate production was attributed to a component of the coated minispheres rather than an effect of CyA on the microbiota. Butyrate and acetate levels also increased significantly (P=0.05 for both) in the faecal samples of healthy individuals following 7 days’ treatment with SmPill+CyA in the pilot study. Conclusion. SmPill minispheres with or without CyA at the clinically relevant doses tested here have negligible direct effects on the gut microbiota composition. Butyrate and acetate production increased, however, in the presence of the beads in an ex vivo model system as well as in vivo in healthy subjects. Importantly, this study also demonstrates the relevance and value of using ex vivo colon models to predict the in vivo impact of colon-targeted drugs directly on the gut microbiota.

scholarly journals Obesity alters the topographical distribution of ventilation and the regional response to bronchoconstriction

2020 ◽  
Vol 128 (1) ◽  
pp. 168-177 ◽  
Author(s):  
S. Rutting ◽  
S. Mahadev ◽  
K. O. Tonga ◽  
D. L. Bailey ◽  
J. R. Dame Carroll ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Body Mass Index ◽  
Body Mass ◽  
Respiratory System ◽  
Healthy Subjects ◽  
Airway Closure ◽  
Ventilation Distribution ◽  
Lung Volumes ◽  
Topographical Distribution ◽  
Lung Zone

Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity ( n = 9) and subjects without obesity ( n = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Ventnon), low ventilated (Ventlow), or well ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Ventnon and Ventlow for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Ventnon (17.5 ± 10.6% vs. 34.7 ± 7.8%, P < 0.001) and Ventlow (25.7 ± 6.3% vs. 33.6 ± 5.1%, P < 0.05) were decreased in subjects with obesity, with a consequent increase in Ventwell (56.8 ± 9.2% vs. 31.7 ± 10.1%, P < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index ( rs = 0.74, P < 0.001), respiratory system resistance ( rs = 0.72, P < 0.001), and respiratory system reactance ( rs = −0.64, P = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Ventnon increased similarly in both groups; however, in subjects without obesity, Ventnon only increased in the lower zone, whereas in subjects with obesity, Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes. NEW & NOTEWORTHY Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.

scholarly journals A10 Presence and frequency of M184V mutation in the MOBIDIP trial

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
A Armero ◽  
M L Chaix ◽  
M L Nere ◽  
E Delaporte ◽  
M Peeters ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Dual Therapy ◽  
Significant Loss ◽  
Resistance Mutations ◽  
Hiv Reverse Transcriptase ◽  
First Line ◽  
Bioinformatics Pipeline ◽  
Peripheral Blood Mononuclear ◽  
Number Of Patients ◽  
M184v Mutation

Abstract The MOBIDIP trial evaluated the simplification by protease (PI/r) monotherapy for HIV infection versus dual therapy and boosted protease inhibitor plus lamivudine (PI/r + 3TC) in controlled patients under second-line regimens. MOBIDIP was interrupted because of a significant number of patients with virological failure (VF) at week 48 (W48) in PI/r (33/133, ∼25%) versus in PI/r + 3TC (4/132, ∼3%). At the time of first-line VF, 96 per cent of patients harbored the M184V mutation. The presence of the M184V mutation was related to a protective effect against VF in the PI/r + 3TC arm. We developed a methodology that allows to determine the frequency of M184V/I mutations in the HIV reverse transcriptase (RT) gene in peripheral blood mononuclear cells (PBMC) obtained before MOBIDIP simplification. Paired-end sequences were obtained from 252 PBMC samples covering the first 855 bp of the RT gene (HXB2: 2485–3405) by MiSeq technology. These sequences were subjected to an in-house Bioinformatics pipeline. The results of our pipeline were compared to the output of PASeq (https://www.paseq.org), an open web-tool for the identification of drug resistance mutations. The M184V mutation was identified at a frequency greater than 1 per cent in 178 individuals (∼71%). The M184I mutation was observed in 34 patients (∼13%), always in the presence of stop codons, and is in agreement with expectations, as this mutation is a known APOBEC-targeted site. Sixty-seven patients (∼27%) had a frequency of the M184V mutation with values greater than 75 per cent. PASeq confirmed the presence of M184V mutation in 173 patients. The frequencies estimated by the PASeq tool and in-house pipeline were correlated up to 99.5 per cent. We found a significant loss of the M184V mutation archived in PBMC between the first-line regimen treatment failure and the beginning of the MOBIDIP trial. In patients under long-term antiretroviral therapy, as in our case, viral sub-populations could be lost, reducing the presence, and frequency of a mutation. In the next step, we will evaluate the association between the presence and frequency of M184V mutation and MOBIDIP results.

Lung volumes after an increase in lung distension in pneumonectomized ferrets

1989 ◽  
Vol 67 (4) ◽  
pp. 1418-1421 ◽  
Author(s):  
J. T. McBride
Keyword(s):  
Lung Resection ◽  
Transpulmonary Pressure ◽  
Tissue Growth ◽  
Lung Growth ◽  
Lung Volumes ◽  
Compensatory Lung Growth ◽  
Rubber Balloon ◽  
Residual Capacity ◽  
The Right

To investigate the role of lung distension in compensatory lung growth, the right lung of each of 21 adult male ferrets was replaced with a silicone rubber balloon filled with mineral oil. Three to thirteen weeks after surgery, the oil was removed through a subcutaneous port. Lung volumes were measured serially until 3–6 wk after balloon deflation. With pneumonectomy the total lung capacity (TLC) decreased to less than 50% of the preoperative value and remained essentially unchanged while the balloon was inflated. At balloon deflation, TLC and vital capacity did not change immediately, whereas functional residual capacity increased by 44%, indicating a change of 2–3 cmH2O in end-expiratory transpulmonary pressure. TLC increased by 10% within 3 days and continued to increase over the subsequent 3–5 wk by a total of 25% over TLC at balloon deflation. There was little difference in this response between animals whose balloons were deflated 3 wk after surgery and those in which deflation was delayed up to 13 wk. After pneumonectomy in the adult ferret, the remaining lung increases in volume in response to an increase in lung distension even weeks or months after surgery. The extent to which this volume increase involves lung tissue growth or depends on previous lung resection is at present unknown. This model may be useful for studies of the mechanisms by which lung distension influences lung volume and compensatory lung growth.

Drug-Induced Kidney Disease Associated With Selected Antibiotics

2020 ◽  
Vol 35 (5) ◽  
pp. 225-229
Author(s):  
Alexia S. Alvarez ◽  
Oluseyi Oyerinde ◽  
Justin P. Reinert
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Older People ◽  
Hospital Costs ◽  
Kidney Injury ◽  
Clear Understanding ◽  
First Line ◽  
Drug Induced ◽  
Improved Outcomes ◽  
Hospital Stays

Structural and functional degeneration of the kidneys occur as the human body ages, making oler people especially susceptible to the consequences of acute kidney injury. Furthermore, the use of nephrotoxic agents, combined with the increased incidence of acute kidney injury and likelihood of an intensive-care unit admission, makes geriatric patients prone to develop drug-induced kidney disease. Vancomycin is routinely used as the first-line treatment for methicillin-resistant Staphylococcus aureus, but is known to be nephrotoxic; studies have shown that an early switch from vancomycin to alternatives does not necessarily prevent renal insult. Therefore, we aim to discuss the mechanisms of drug-induced kidney disease with regard to vancomycin, daptomycin, and ceftaroline and to provide insight as to their safety profiles with regard to older people. A clear understanding of this topic will aid clinicians in selecting drug therapy and may lead to shortened hospital stays, lower hospital costs, and improved outcomes of critically ill older people.

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