scholarly journals Small Airway Susceptibility to Chemical and Particle Injury

Respiration ◽  
2021 ◽  
pp. 1-13
Author(s):  
Leonie Francina Hendrina Fransen ◽  
Martin Oliver Leonard
Keyword(s):  
Animal Studies ◽  
Toxicity Testing ◽  
Airway Disease ◽  
Structural Features ◽  
Tracheobronchial Tree ◽  
Cell Phenotype ◽  
Small Airways ◽  
Disease Aetiology ◽  
Human Airways ◽  
Conducting Airways

Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.

scholarly journals Anatomical variability in the upper tracheobronchial tree: sex-based differences and implications for personalized inhalation therapies

2020 ◽  
Author(s):  
Simoni Christou ◽  
Thanasis Chatziathanasiou ◽  
Stelios Angeli ◽  
Pantelis Koullapis ◽  
Fotos Stylianou ◽  
...  
Keyword(s):  
Airway Disease ◽  
Tracheobronchial Tree ◽  
Bifurcation Angle ◽  
Regional Deposition ◽  
Luminal Area ◽  
Subject Variability ◽  
Chronic Airway Disease ◽  
The Right ◽  
Conducting Airways ◽  
Age Range

The morphometry of the large conducting airways is presumed to have a strong effect on the regional deposition of inhaled aerosol particles. Nevertheless, sex-based differences have not been fully quantified and are still largely ignored in designing inhalation therapies. To this end, we retrospectively analyzed high-resolution computer-tomography scans for 185 individuals (90 women, 95 men) in the age range of 12−89 years to determine airway luminal areas, airway lengths and bifurcation angles. Only subjects free of chronic airway disease were considered. In men, luminal areas of the upper conducting airways were on the average ~ 30-50% larger when compared to those in women, with the largest differences found in the trachea (289.72±54.25mm2 vs. 193.50±42.37mm2 for men/women respectively). The ratio of the largest luminal area in men to the smallest luminal area in women (in any given segment) ranged between 4.5 and 8.6, the largest differences being found in the lobar bronchi. Sex-based differences were minor in the case of bifurcation angles (e.g. average main bifurcation angle: 93.04±9.58o vs. 91.03±9.81o for men/women respectively), but large inter-subject variability was found irrespective of sex (e.g. range of main bifurcation angle: 65.04−122.01o vs. 69.46−113.94o for men/women respectively). Bronchial segments were shorter by ~ 5-20% in women relative to men, the largest differences being located in the upper lobes. False discovery rate (FDR) analysis revealed statistically significant associations among morphometric measures of the right lung in women (but not in men) suggesting two phenotypes among women that we attribute to the smaller female thoracic volume.

scholarly journals Biophysical characterization of melanoma cell phenotype markers during metastatic progression

2021 ◽  
Author(s):  
Anna Sobiepanek ◽  
Alessio Paone ◽  
Francesca Cutruzzolà ◽  
Tomasz Kobiela
Keyword(s):  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Structural Features ◽  
Protein Glycosylation ◽  
Cell Phenotype ◽  
Metastatic Progression ◽  
Label Free ◽  
Serine Threonine Kinase ◽  
Biophysical Characterization ◽  
Viscoelastic Parameters

AbstractMelanoma is the most fatal form of skin cancer, with increasing prevalence worldwide. The most common melanoma genetic driver is mutation of the proto-oncogene serine/threonine kinase BRAF; thus, the inhibition of its MAP kinase pathway by specific inhibitors is a commonly applied therapy. However, many patients are resistant, or develop resistance to this type of monotherapy, and therefore combined therapies which target other signaling pathways through various molecular mechanisms are required. A possible strategy may involve targeting cellular energy metabolism, which has been recognized as crucial for cancer development and progression and which connects through glycolysis to cell surface glycan biosynthetic pathways. Protein glycosylation is a hallmark of more than 50% of the human proteome and it has been recognized that altered glycosylation occurs during the metastatic progression of melanoma cells which, in turn facilitates their migration. This review provides a description of recent advances in the search for factors able to remodel cell metabolism between glycolysis and oxidative phosphorylation, and of changes in specific markers and in the biophysical properties of cells during melanoma development from a nevus to metastasis. This development is accompanied by changes in the expression of surface glycans, with corresponding changes in ligand-receptor affinity, giving rise to structural features and viscoelastic parameters particularly well suited to study by label-free biophysical methods.

Aerosol penetrance: a sensitive index of peripheral airways obstruction

1976 ◽  
Vol 40 (3) ◽  
pp. 468-471 ◽  
Author(s):  
M. B. Dolovich ◽  
J. Sanchis ◽  
C. Rossman ◽  
M. T. Newhouse
Keyword(s):  
Chronic Obstructive Lung Disease ◽  
Outer Zone ◽  
Normal Subjects ◽  
Airway Disease ◽  
Chronic Obstructive ◽  
Closing Volume ◽  
Small Airways ◽  
Peripheral Airways ◽  
Sensitive Index ◽  
Airways Obstruction

Early injury of the small airways has been demonstrated in asymptomatic smokers. Ventilatory tests including the maximum midexpiratory flow rate and closing volume have been useful in clinical detection of small airways disease in symptomatic subjects. In the present study, airway “obstruction” was assessed aerodynamically by gamma camera measurements of chest radioactivity following the inhalation of 131I-labeled aerosol (aerodynamic mass median diameter 3 mum). Studies were performed in normal subjects, asymptomatic smokers, and patients with chronic obstructive lung disease. An aerosol penetrance index (AeP) was devised from determinations which involved 1) an analysis of central (inner zone) and peripheral (outer zone) deposition of aerosol in the lung and 2) a ratio of initial counts to 24-h counts in the periphery (outer zone) of the lung. AeP values were 41.5 +/- 11.5 for the normal group, 20.9 +/- 7.6 for the smoker group, and 10.6 +/- 5.2 for the subjects with chronic obstructive airway disease. AeP was significantly reduced in the smokers indicating that the AeP is a sensitive index of early peripheral airways obstruction.

The Implications of Microarray Technology for Animal Use in Scientific Research

2002 ◽  
Vol 30 (4) ◽  
pp. 459-465 ◽  
Author(s):  
Elizabeth S. Jenkins ◽  
Caren Broadhead ◽  
Robert D. Combes
Keyword(s):  
Animal Studies ◽  
Animal Experiments ◽  
Scientific Research ◽  
Toxicity Testing ◽  
Laboratory Animals ◽  
Biological Research ◽  
Microarray Technology ◽  
Single Experiment ◽  
Technical Problems ◽  
Animal Use

Microarray technology has the potential to affect the number of laboratory animals used, the severity of animal experiments, and the development of non-animal alternatives in several areas of scientific research. Microarrays can contain hundreds or thousands of microscopic spots of DNA, immobilised on a solid support, and their use enables global patterns of gene expression to be determined in a single experiment. This technology is being used to improve our understanding of the operation of biological systems during health and disease, and their responses to chemical insults. Although it is impossible to predict with certainty any future trends regarding animal use, microarray technology might not initially reduce animal use, as is often claimed to be the case. The accelerated pace of research as a result of the use of microarrays could increase overall animal use in basic and applied biological research, by increasing the numbers of interesting genes identified for further analysis, and the number of potential targets for drug development. Each new lead will require further evaluation in studies that could involve animals. In toxicity testing, microarray studies could lead to increases in animal studies, if further confirmatory and other studies are performed. However, before such technology can be used more extensively, several technical problems need to be overcome, and the relevance of the data to biological processes needs to be assessed. Were microarray technology to be used in the manner envisaged by its protagonists, there need to be efforts to increase the likelihood that its application will create new opportunities for reducing, refining and replacing animal use. This comment is a critical assessment of the possible implications of the application of microarray technology on animal experimentation in various research areas, and makes some recommendations for maximising the application of the Three Rs.

scholarly journals Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans

1999 ◽  
Vol 87 (4) ◽  
pp. 1532-1542 ◽  
Author(s):  
Anthony P. Pietropaoli ◽  
Irene B. Perillo ◽  
Alfonso Torres ◽  
Peter T. Perkins ◽  
Lauren M. Frasier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Normal Subjects ◽  
Breath Holding ◽  
No Production ◽  
Large Contribution ◽  
Flow Rates ◽  
Expiratory Flow ◽  
Human Airways ◽  
Conducting Airways ◽  
Expiratory Flow Rates

Human airways produce nitric oxide (NO), and exhaled NO increases as expiratory flow rates fall. We show that mixing during exhalation between the NO produced by the lower, alveolar airways (V˙l NO) and the upper conducting airways (V˙u NO) explains this phenomenon and permits measurement ofV˙l NO,V˙u NO, and the NO diffusing capacity of the conducting airways (Du NO). After breath holding for 10–15 s the partial pressure of alveolar NO (Pa) becomes constant, and during a subsequent exhalation at a constant expiratory flow rate the alveoli will deliver a stable amount of NO to the conducting airways. The conducting airways secrete NO into the lumen (V˙u NO), which mixes with Pa during exhalation, resulting in the observed expiratory concentration of NO (Pe). At fast exhalations, Pa makes a large contribution to Pe, and, at slow exhalations, NO from the conducting airways predominates. Simple equations describing this mixing, combined with measurements of Pe at several different expiratory flow rates, permit calculation of Pa,V˙u NO, and Du NO.V˙l NOis the product of Pa and the alveolar airway diffusion capacity for NO. In seven normal subjects, Pa = 1.6 ± 0.7 × 10−6 (SD) Torr,V˙l NO= 0.19 ± 0.07 μl/min,V˙u NO= 0.08 ± 0.05 μl/min, and Du NO = 0.4 ± 0.4 ml ⋅ min−1 ⋅ Torr−1. These quantitative measurements ofV˙l NOandV˙u NOare suitable for exploring alterations in NO production at these sites by diseases and physiological stresses.

Does the disease state influence the responsiveness of human airways studied in vitro?

1996 ◽  
Vol 80 (6) ◽  
pp. 2211-2216 ◽  
Author(s):  
C. L. Armour ◽  
K. O. McKay ◽  
P. R. Johnson ◽  
A. R. Glanville ◽  
J. L. Black
Keyword(s):  
Electrical Field Stimulation ◽  
Airway Disease ◽  
Human Airway ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Human Airways ◽  
Deficiency Group ◽  
Comprehensive Study

Human airway tissue has been used in vitro to study mechanisms of airway disease. However, there has never been a comprehensive study that has looked at the influence of disease on the subsequent in vitro responsiveness of human airways. In this study, we obtained airway tissue from patients who were undergoing resection of the lung for carcinoma. We then compared the airway responsiveness in these tissues and in tissues from patients who had undergone lung transplantation for alpha-1-antitrypsin deficiency, emphysema, or cystic fibrosis with the responsiveness in tissues obtained from donor lungs, i.e., nondiseased. When the relationships between concentration and response were compared, we found that for histamine, electrical field stimulation, levcromakalim, and isoproterenol similar responses could be expected in tissues obtained from all the sources studied. This was not true for acetylcholine in that there were significantly lower responses in tissues from patients with alpha-1-antitrypsin deficiency (P = 0.02; n = 9) or from patients having a lung resected for carcinoma (P = 0.01; n = 6) compared with that of the nondiseased group (n = 6). Similarly, for carbachol, the responses were significantly lower in the alpha-1-antitrypsin deficiency group (P = 0.001; n = 10) and in specimens resected for carcinoma (P = 0.001; n = 6) than in the nondiseased group (n = 9). We conclude that, apart from acetylcholine and carbachol, contractile and relaxant agonists give similar responses when used in human airway tissues from various sources. Our results highlight the importance of stating the source of tissue when human airways are to be studied.

Reproductive toxicity testing of pharmaceutical compounds to support the inclusion of women in clinical trials

1997 ◽  
Vol 16 (5) ◽  
pp. 239-246 ◽  
Author(s):  
Chris Parkinson ◽  
Kate E Thomas ◽  
Cyndy E Lumley
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Animal Studies ◽  
Clinical Investigation ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Toxicity Tests ◽  
Toxicity Studies ◽  
Important Concern ◽  
The Usa

1 The potential for toxicity to reproduction and the developing fetus is an important concern requiring attention during the development of new medicines. However, there are differences in the opinions of the regulatory authorities in Europe, Japan and the USA regarding the nature and amount of data from reproductive toxicity tests that should be available at the various stages of clinical development. 2 Forty-one companies or their subsidiaries from Eur ope, Japan and the USA provided data for a ques tionnaire-based study, carried out in 1994, to ascertain the practices of pharmaceutical companies and their views on an ideal approach to the timing of reproduc tion and development toxicity studies in relation to clinical investigation. 3 Differences were identified in the stage of drug development at which animal studies were completed, the sequence of completion of specific studies, and the extent of reproduction testing completed to support the inclusion of women in clinical trials. 4 A harmonised, but flexible, guideline, encompassing the timing of reproductive toxicity studies in relation to clinical trials, would permit better integration between clinical and non-clinical studies in an international drug development programme.

SPECIAL REQUIREMENTS FOR TOXICITY TESTING OF ORAL COMPOUNDS ADMINISTERED CONTINUOUSLY OR CYCLICALLY

1974 ◽  
Vol 77 (1_Suppla) ◽  
pp. S387-S408 ◽  
Author(s):  
G. A. Overbeek ◽  
H. W. Hornstra ◽  
E. B. van Julsingha ◽  
J. P. Mumford ◽  
I. Zayed
Keyword(s):  
Side Effects ◽  
Oral Contraceptives ◽  
Predictive Value ◽  
Animal Studies ◽  
Toxicity Testing ◽  
Prolonged Treatment ◽  
Safety Studies ◽  
Short And Long Term ◽  
Dose Levels

ABSTRACT The authors feel that several reasons exist for considering contraceptives as a special class of drugs, which therefore require special safety studies. Apart from the usual short and long term studies, particular attention should be paid to the reversibility of the induced infertility, and to its possible consequences for subsequent offspring. A possible risk of damage to the foetus is partially outweighed by the low risk of pregnancy during the treatment periods with oral contraceptives. The procedures used in the Organon laboratories are briefly described. Principles on which we base the choice of dose levels and the duration of the various studies are discussed. The paucity of available data from toxicity studies in animals has prevented the presentation of a summary allowing an appraisal of the predictive value of the current methods in toxicology. Nevertheless, a few examples are given which demonstrate the need for more predictive methods. The present lack of knowledge on side effects in humans after prolonged treatment with oral contraceptives has created a feeling of uneasiness. This in its turn has resulted in some excessive regulatory requirements for very long term animal studies. In our opinion, the predictive value of these studies is extremely low because of the inadequacy of the available animal models. More value can be attached to the monitoring of side effects in humans and efforts in this direction should be increased. The Organon system of monitoring the side effects of its marketed preparations is briefly described. It is not considered feasible to standardize regulatory toxicity requirements for the time being, which should not prevent us from aiming at reasonable, more generally accepted methods of study.

scholarly journals Phenotypic Clusters On Computed Tomography Reflects Asthma Heterogeneity And Severity

2021 ◽  
Author(s):  
Sujeong Kim ◽  
Sanghun Choi ◽  
Taewoo Kim ◽  
Kwang Nam Jin ◽  
Sang-Heon Cho ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Severe Asthma ◽  
Visual Analysis ◽  
Quantitative Computed Tomography ◽  
Airway Disease ◽  
Small Airways ◽  
Functional Changes ◽  
Severe Allergic Asthma ◽  
Emphysematous Lung ◽  
Severity Of The Disease

Abstract Background: Asthma comprises heterogeneous inflammatory airway disorders whose classification has not been established. Quantitative computed tomography (QCT) methods can differentiate lung disease using accurate assessment of location, extent, and severity of the disease. This study aimed to identify heterogeneous asthmatic groups by QCT metrics of airway and parenchymal structure, which is associated with radiologists’ visual analysis and bronchodilator responses in a prospective design.Methods: Using the input from QCT-based metrics, including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph), a cluster analysis was performed and compared with grouping based on site of airway involvement and remodeling evaluated by radiologists.Results: 61 asthmatics were grouped into four clusters with different clinical severities. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbation in 5-year follow-up were observed. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthma, which had reserved bronchodilator responses of proximal airways. C3 and C4 presented severe asthmatics that exhibited reduced Dh of proximal airway and its bronchodilator responsiveness; C3 was severe allergic asthma without fSAD, while C4 was ex-smokers with significantly high fSAD% and Emph%. These clusters were correlated with the grouping by radiologists and their clinical outcomes.Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and may serve as complementary tools for predicting future asthma outcomes.

scholarly journals Bronchiolitis obliterans

Mediscope ◽  
2017 ◽  
Vol 4 (2) ◽  
pp. 39-43
Author(s):  
MA Kabir ◽  
SS Hossain ◽  
BR Dutta
Keyword(s):  
Male Patient ◽  
Teaching Hospital ◽  
Bronchiolitis Obliterans ◽  
Airway Disease ◽  
Small Airways ◽  
Organizing Pneumonia ◽  
Proper Treatment ◽  
Cryptogenic Organizing Pneumonia ◽  
Small Airway Disease ◽  
Progressive Dyspnea

The term ‘bronchiolitis obliterans’ was historically used by pathologists to refer to two distinct patterns of small-airway disease. The first was characterized by intraluminal polyps in the small airways. It was subsequently named bronchiolitis obliterans with organizing pneumonia and, more recently, cryptogenic organizing pneumonia. The second pattern was characterized by sub-epithelial inflammatory and fibrotic narrowing of the bronchioles, which is now recognized as obliterative bronchiolitis or constrictive bronchiolitis. In this study we reported a case of a male patient of 55 years who got admitted to a teaching hospital with progressive dyspnea and nonproductive cough over a period of 12 months and was released after proper treatment and management.Mediscope Vol. 4, No. 2: Jul 2017, Page 39-43

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