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Advances in Pharmacology (San Diego,... 2023Current therapies to mitigate inflammatory responses involved in airway remodeling and associated pathological features of asthma and chronic obstructive pulmonary... (Review)
Review
Current therapies to mitigate inflammatory responses involved in airway remodeling and associated pathological features of asthma and chronic obstructive pulmonary disease (COPD) are limited and largely ineffective. Inflammation and the release of cytokines and growth factors activate kinase signaling pathways that mediate changes in airway mesenchymal cells such as airway smooth muscle cells and lung fibroblasts. Proliferative and secretory changes in mesenchymal cells exacerbate the inflammatory response and promote airway remodeling, which is often characterized by increased airway smooth muscle mass, airway hyperreactivity, increased mucus secretion, and lung fibrosis. Thus, inhibition of relevant kinases has been viewed as a potential therapeutic approach to mitigate the debilitating and, thus far, irreversible airway remodeling that occurs in asthma and COPD. Despite FDA approval of several kinase inhibitors for the treatment of proliferative disorders, such as cancer and inflammation associated with rheumatoid arthritis and ulcerative colitis, none of these drugs have been approved to treat asthma or COPD. This review will provide a brief overview of the role kinases play in the pathology of asthma and COPD and an update on the status of kinase inhibitors currently in clinical trials for the treatment of obstructive pulmonary disease. In addition, potential issues associated with the current kinase inhibitors, which have limited their success as therapeutic agents in treating asthma or COPD, and alternative approaches to target kinase functions will be discussed.
Topics: Humans; Airway Remodeling; Pulmonary Disease, Chronic Obstructive; Asthma; Lung; Inflammation
PubMed: 37524486
DOI: 10.1016/bs.apha.2023.04.004 -
Clinica Chimica Acta; International... Jan 2022We present a hypersensitivity immune response to inhalation of antigens from fossil soils frequently used in tile manufacture. We found that the soil polished by a...
AIMS
We present a hypersensitivity immune response to inhalation of antigens from fossil soils frequently used in tile manufacture. We found that the soil polished by a worker affected by pneumonitis was a paleosol containing bivalves from the cretaceous period called Hippurites.
METHODS
We made a diagnostic study for pneumonitis (analysis, microbiology, radiology, high-resolution CT, bronchoalveolar lavage, pulmonary biopsy. A biochemical study of the polishing materials used (magnesium hexafluorosilicate crystallizer), steel spoilage, washing liquid and Bilbao red limestone) after scraping of the same. Allergy study included skin tests with extracts from fossil soils, determination of IgG and IgE to mollusks, IgE-immunodetection with soil extracts with the patient's serum and non-atopic controls. Histology was made using scanning electron microscopy of the lung biopsy and the fossil soil to determine the presence of remains of mollusks, fungi, pollen or other fossil elements.
RESULTS
SDS-PAGE IgE Immunoblotting assay detecting IgE binding in soil extract between 66 and 35 kDa. Likewise, IgE-Immunblotting assay with extracts from bivalve mollusks (razor shell, mussel and scallop) and gastropod (sea snail), detecting IgE binding between 100 kDa - 30 kDa, as well as in some bands with molecular mass between 20 and 14 kDa, proving sensitization to mollusks.
CONCLUSIONS
Bivalve proteins preserved in fossil soils may produce an immune hypersensitivity response. This may impact on the precautions exposed workers, in this case fossil soil cutters and polishers, should take.
Topics: Alveolitis, Extrinsic Allergic; Fossils; Humans; Hypersensitivity; Molecular Weight; Skin Tests
PubMed: 34774826
DOI: 10.1016/j.cca.2021.11.008 -
Pediatric Research Jun 2023Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation,...
BACKGROUND
Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG).
METHODS
Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined.
RESULTS
UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls.
CONCLUSIONS
UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia.
IMPACT
Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.
Topics: Animals; Mice; Heparin; Heparin, Low-Molecular-Weight; Vascular Endothelial Growth Factor A; Endothelial Cells; Disease Models, Animal; Anticoagulants; Lung; Hernias, Diaphragmatic, Congenital
PubMed: 36195630
DOI: 10.1038/s41390-022-02323-1 -
Progress in Medicinal Chemistry 2022Inhalation of small molecule drugs has proven very efficacious for the treatment of respiratory diseases due to enhanced efficacy and a favourable therapeutic index... (Review)
Review
Inhalation of small molecule drugs has proven very efficacious for the treatment of respiratory diseases due to enhanced efficacy and a favourable therapeutic index compared with other dosing routes. It enables targeted delivery to the lung with rapid onset of therapeutic action, low systemic drug exposure, and thereby reduced systemic side effects. An increasing number of pharmaceutical companies and biotechs are investing in new modalities-for this review defined as therapeutic molecules with a molecular weight >800Da and therefore beyond usual inhaled small molecule drug-like space. However, our experience with inhaled administration of PROTACs, peptides, oligonucleotides (antisense oligonucleotides, siRNAs, miRs and antagomirs), diverse protein scaffolds, antibodies and antibody fragments is still limited. Investigating the retention and metabolism of these types of molecules in lung tissue and fluid will contribute to understanding which are best suited for inhalation. Nonetheless, the first such therapeutic molecules have already reached the clinic. This review will provide information on the physiology of healthy and diseased lungs and their capacity for drug metabolism. It will outline the stability, aggregation and immunogenicity aspects of new modalities, as well as recap on formulation and delivery aspects. It concludes by summarising clinical trial outcomes with inhaled new modalities based on information available at the end of 2021.
Topics: Administration, Inhalation; Lung; Peptides; Pharmaceutical Preparations; Proteins
PubMed: 35753716
DOI: 10.1016/bs.pmch.2022.04.001 -
Physics in Medicine and Biology Feb 2019We previously reported that apparent lung mass varies across the phases of 4D computed tomography (4DCT) images. We hypothesize that these variations correspond to the...
We previously reported that apparent lung mass varies across the phases of 4D computed tomography (4DCT) images. We hypothesize that these variations correspond to the physiologic changes in pulmonary perfusion induced during normal tidal breathing, and should therefore be present in every breathing patient. In this study, we characterize and quantify the respiratory induced variation in pulmonary blood mass (▵PBM) on 89 patients treated with stereotactic body radiotherapy. ▵PBM was computed from the treatment planning helical 4DCT images of each patient. Conversion from Hounsfield Units (HU) to density and mass per voxel was made using the density calibration curve, applied to the lung parenchyma volume within each phase. A difference in the lung mass with breathing was found for all cases, as was a substantial individual variation in lung volume. We found that the ▵PBM increased during inhalation, and decreased during exhalation. A significant correlation between the individual ▵PBM and tidal volume was observed; ▵PBM increased with tidal volume. We further evaluated the anatomic distribution of ▵PBM variation comparing the central versus peripheral lung, cranial versus caudal, dependent versus non-dependent lung. Our observations regarding spatial distribution of the ▵PBM agree with previously reported differences among similar regions for the supine patient. These results show that a variation in pulmonary mass during respiration is apparent on 4DCT and suggest that these variations reflect respiratory induced changes in the pulmonary perfusion. Therefore, the 4DCT derived respiratory induced ▵PBM signal can provide further insight into the pulmonary circulation and advance the overall understanding and diagnosis of human health and disease.
Topics: Aged; Aged, 80 and over; Female; Four-Dimensional Computed Tomography; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Radiosurgery; Radiotherapy Planning, Computer-Assisted; Respiration; Tidal Volume
PubMed: 30654352
DOI: 10.1088/1361-6560/aaff7b -
Computational and Mathematical Methods... 2022This study retrospectively analyzed the clinical diagnosis, treatment process, and laboratory test data of patients with pulmonary cryptococcosis to improve the...
OBJECTIVE
This study retrospectively analyzed the clinical diagnosis, treatment process, and laboratory test data of patients with pulmonary cryptococcosis to improve the understanding and diagnosis and treatment ability of the disease.
METHODS
Patients with pulmonary cryptococcosis diagnosed in the First Affiliated Hospital of Dalian Medical University from October 2003 to July 2021 were selected, and their medical records were consulted. The general data, clinical manifestations, laboratory examinations, imaging characteristics, diagnosis, and treatment methods were studied. The software SPSS 22 was used for statistical analysis.
RESULTS
A total of 50 patients with pulmonary cryptococcosis were included in the study. The ratio of male to female was 1 : 1. The average age was 53.56 ± 11.99 years with a range of 27-82 years. Grouping the patients by age, with 10 years as an age group, we found that 40-60 years was the high-incidence age group. Two patients (4%) had a history of bird contact, and 18 patients (36%) had at least one underlying conditions. Hypertension and cough were the most common underlying condition and clinical manifestation, respectively. The main admission diagnoses were lung shadow (19/50, 38%) and chest/lung mass (15/50, 30%). In the imaging findings, the most common type of lesions was nodule/nodule shadow (29/69, 42.03%). Lesion distribution in the lower lobe, single lobe, and right lung was more frequent than that in the upper lobe, multilobes, and left lung, respectively. Burr sign (12/43, 27.91%) was the most common concomitant sign. Pulmonary ventilatory defect was found in 7 cases. Laboratory test results were largely nonspecific. The pathological examination showed granuloma, with 47 cases (94%) confirmed by postoperative biopsy. Two cases (4%) were confirmed by serology. One case (2%) was diagnosed with smear. 43 cases (86%) were treated with simple surgical resection, 6 cases (12%) were treated with antifungal drugs, and 1 case (2%) was transferred to another hospital for suspicion of pulmonary tuberculosis.
CONCLUSIONS
Pulmonary cryptococcosis is more common in the middle-aged and elderly, and the clinical specificity is low. It can occur in people with normal or impaired immune function. The main clinical and imaging manifestation is cough and pulmonary nodules, which are very easy 5to be misdiagnosed. Surgical resection is the primary treatment.
Topics: Adult; Aged; Aged, 80 and over; Child; Cough; Cryptococcosis; Female; Humans; Lung; Lung Diseases, Fungal; Male; Middle Aged; Retrospective Studies
PubMed: 35924106
DOI: 10.1155/2022/7981472 -
Journal of Thoracic Imaging Nov 2017The aim was to evaluate computed tomography (CT)-measured pulmonary artery diameter (PAD) and lung density as predictors of pulmonary hypertension (PH) in subjects with...
PURPOSE
The aim was to evaluate computed tomography (CT)-measured pulmonary artery diameter (PAD) and lung density as predictors of pulmonary hypertension (PH) in subjects with systemic sclerosis (SSc). We compared these PAD values with normal values and between SSc subgroups with PH and/or interstitial lung disease (ILD). We investigated whether PAD predicts PH and whether lung densitometry, by using the 85th percentile density value (Perc85) as a measure for ILD, can predict PH.
MATERIALS AND METHODS
PAD and Perc85 were measured in axial CT scans and compared between 54 SSc and 76 control subjects. Four SSc subgroups were defined on the basis of PH (systolic PA pressure ≥35 mm Hg) and/or ILD (fibrosis score ≥7): PH-/ILD-, PH-/ILD+, PH+/ILD-, and PH+/ILD+. The association of PAD with age, body mass index, Perc85, lung function, and hemodynamic measures was investigated using univariate correlation along with the predictive value of these measures with respect to PH.
RESULTS
PAD in SSc was larger than that in controls (30.1±4.9 vs. 26.9±2.7 mm, P<0.001). PH+ patients showed increased PAD compared with PH- patients (34.2±4.2 vs. 28.6±4.3 mm, P<0.001), where PH+/ILD+ subjects showed the widest diameter (34.6±4.1 mm). In SSc patients, hemodynamic measures, age, body mass index, Perc85, and lung function correlated with PAD. PAD was best explained by Perc85, together with age (R=0.358). PAD best predicted PH (AUC, 0.877; P<0.001), and PAD≥30.7 mm showed 80% sensitivity and 87% specificity. Perc85 also predicted PH (AUC, 0.733; P=0.024).
CONCLUSIONS
In subjects with SSc, lung density and PAD are CT markers, each with predictive value for PH.
Topics: Adult; Aged; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Organ Size; Pulmonary Artery; Scleroderma, Systemic; Sensitivity and Specificity; Tomography, X-Ray Computed; Young Adult
PubMed: 28549020
DOI: 10.1097/RTI.0000000000000279 -
BMJ Case Reports Mar 2021Bronchopulmonary sequestration is a rare congenital pulmonary abnormality of the lower airways, which includes an abnormal and non-functioning lung tissue not...
Bronchopulmonary sequestration is a rare congenital pulmonary abnormality of the lower airways, which includes an abnormal and non-functioning lung tissue not communicating with the tracheobronchial tree and having aberrant blood supply from systemic circulation with variable venous drainage. The incidence of sequestration is around 0.15%-6.4% of all congenital lung malformations.Common presenting features are cough and expectoration. Misdiagnosed cases may present with recurrent infections and haemoptysis. CT of the chest with contrast is the imaging modality of choice.This is a case report of a 32-year-old woman who presented with cough and haemoptysis. CT of the chest showed a multiloculated mass-like lesion in the left lower lobe with a feeding artery from coeliac plexus and venous drainage via the normal left pulmonary vein.Based on CT chest findings, diagnosis of intralobar pulmonary sequestration was made. The patient was reviewed by cardiothoracic surgeons and underwent surgical resection of the sequestrated lung.Common presenting features are cough and expectoration. Misdiagnosed cases may present with recurrent infections and haemoptysis. CT of the chest with contrast is the imaging modality of choice.
Topics: Adult; Bronchopulmonary Sequestration; Cough; Female; Hemoptysis; Humans; Lung; Tomography, X-Ray Computed
PubMed: 33653840
DOI: 10.1136/bcr-2020-239140 -
Clinical Imaging Oct 2021Limited diagnostic options exist for patients with suspected pulmonary embolism (PE) who cannot undergo CT-angiogram (CTA). CT-ventilation methods recover respiratory...
PURPOSE
Limited diagnostic options exist for patients with suspected pulmonary embolism (PE) who cannot undergo CT-angiogram (CTA). CT-ventilation methods recover respiratory motion-induced lung volume changes as a surrogate for ventilation. We recently demonstrated that pulmonary blood mass change, induced by tidal respiratory motion, is a potential surrogate for pulmonary perfusion. In this study, we examine blood mass and volume change in patients with PE and parenchymal lung abnormalities (PLA).
METHODS
A cross-sectional analysis was conducted on a prospective, cohort-study with 129 consecutive PE suspected patients. Patients received 4DCT within 48 h of CTA and were classified as having PLA and/or PE. Global volume change (VC) and percent global pulmonary blood mass change (PBM) were calculated for each patient. Associations with disease type were evaluated using quantile regression.
RESULTS
68 of 129 patients were PE positive on CTA. Median change in PBM for PE-positive patients (0.056; 95% CI: 0.045, 0.068; IQR: 0.051) was smaller than that of PE-negative patients (0.077; 95% CI: 0.064, 0.089; IQR: 0.056), with an estimated difference of 0.021 (95% CI: 0.003, 0.038; p = 0.0190). PLA was detected in 57 (44.2%) patients. Median VC for PLA-positive patients (1.26; 95% CI: 1.22, 1.30; IQR: 0.15) showed no significant difference from PLA-negative VC (1.25; 95% CI: 1.21, 1.28; IQR: 0.15).
CONCLUSIONS
We demonstrate that pulmonary blood mass change is significantly lower in PE-positive patients compared to PE-negative patients, indicating that PBM derived from dynamic non-contrast CT is a potentially useful surrogate for pulmonary perfusion.
Topics: Angiography; Cross-Sectional Studies; Humans; Lung; Prospective Studies; Pulmonary Embolism
PubMed: 33839544
DOI: 10.1016/j.clinimag.2021.02.023 -
Organic Letters Jun 2020The clinically approved Fondaparinux (Arixtra) has been used for the treatment of deep vein thrombosis and acute pulmonary embolism since 2002 and is considered to be...
The clinically approved Fondaparinux (Arixtra) has been used for the treatment of deep vein thrombosis and acute pulmonary embolism since 2002 and is considered to be better than the low-molecular weight heparin in terms of anticoagulation response, duration of action, and biosafety. However, the synthetic methods previously developed for its manufacture are relatively complicated, thus restricting its extensive use. We report here a potentially scalable and programmable one-pot synthesis of Fondaparinux using the [1,2,2] strategy and designed thioglycosides with well-defined reactivity as building blocks.
Topics: Anticoagulants; Chemistry Techniques, Synthetic; Fondaparinux; Heparin; Molecular Weight
PubMed: 32496799
DOI: 10.1021/acs.orglett.0c01386