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Molecular Imaging and Biology Feb 2022Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease...
PURPOSE
Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection.
PROCEDURES
Pulmonary I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues.
RESULTS
Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02).
CONCLUSION
I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19.
Topics: Acetamides; Animals; COVID-19; Chlorocebus aethiops; Cricetinae; Disease Models, Animal; Iodine Radioisotopes; Lung; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Pyrazoles; Pyrimidines; SARS-CoV-2; Vero Cells
PubMed: 34424479
DOI: 10.1007/s11307-021-01638-5 -
The Clinical Respiratory Journal Mar 2018Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease limited to the lungs. The course of disease varies widely, with some patients... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease limited to the lungs. The course of disease varies widely, with some patients experiencing acute respiratory deterioration, a condition called acute exacerbations of IPF (AE-IPF). The risk factors contributing to AE-IPF are unclear. This systematic review and meta-analysis investigated the risk factors for AE-IPF.
METHODS
Studies of risk factors for AE-IPF were identified in Medline, EMBASE and Cochrane databases. Fixed effects models were used to calculate pooled relative risks and weighted mean differences (WMD).The meta-analysis included seven articles involving 14 risk factors for AE-IPF.
RESULTS
Risk factors for AE included reductions in vital capacity (VC; WMD - 10.58, 95% confidence interval (CI) -17.17 to - 3.99), forced vital capacity (FVC; WMD -6.02, 95%CI - 8.58 to - 3.47), total lung capacity (TLC; WMD -4.88, 95%CI -7.59 to - 2.17), and PaO (WMD -4.19, 95%CI -7.66 to -0.71) and a higher alveolar-arterial oxygen difference (AaDO ; WMD 4.4, 95%CI 0.24 to 8.57). Mechanical procedures, higher serum KL-6 concentration and secondary pulmonary hypertension, might be risk factors for AE-IPF. In contrast, age, sex, body mass index (BMI), differences in diffusing lung capacity for carbon monoxide (DLCO), exposure to seasonal variations and air pollution, and virus infection might be unrelated to AE-IPF.
CONCLUSIONS
Poor pulmonary function, mechanical procedures, higher serum KL-6 and secondary pulmonary hypertension were associated with increased risks of AE-IPF.
Topics: Acute Disease; Blood Gas Analysis; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Lung; Prognosis; Pulmonary Diffusing Capacity; Risk Factors; Vital Capacity
PubMed: 28332341
DOI: 10.1111/crj.12631 -
Respiratory Research Apr 2023Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with...
Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.
Topics: Humans; Proteome; Proteomics; Idiopathic Pulmonary Fibrosis; Lung
PubMed: 37005656
DOI: 10.1186/s12931-023-02400-x -
Laboratory Investigation; a Journal of... Jan 2018Animal models can reproduce some model-specific aspects of human diseases, but some animal models translate poorly or fail to translate to the corresponding human... (Comparative Study)
Comparative Study
Animal models can reproduce some model-specific aspects of human diseases, but some animal models translate poorly or fail to translate to the corresponding human disease. Here, we develop a strategy to systematically compare human and mouse tissues, and conduct a proof-of-concept experiment to identify molecular similarities and differences using patients with idiopathic pulmonary fibrosis and a bleomycin-induced fibrosis mouse model. Our novel approach employs high-throughput tissue microarrays (TMAs) of humans and mice, high-resolution matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance-mass spectrometry imaging (MALDI-FT-ICR-MSI) to spatially resolve mass spectra at the level of specific metabolites, and hierarchical clustering and pathway enrichment analysis to identify functionally similar/different molecular patterns and pathways in pathological lesions of humans and mice. We identified a large number of common molecules (n=1366) and fewer exclusive molecules in humans (n=83) and mice (n=54). Among the common molecules, the 'ascorbate and aldarate metabolism' pathway had the highest similarity in human and mouse lesions. This proof-of-concept study demonstrates that our novel strategy employing a reliable and easy-to-perform experimental design accurately identifies pathways and factors that can be directly compared between animal models and human diseases.
Topics: Administration, Inhalation; Animals; Antibiotics, Antineoplastic; Bleomycin; Cluster Analysis; Cyclotrons; Disease Models, Animal; Humans; Immunohistochemistry; Lung; Metabolomics; Mice; Physiology, Comparative; Proof of Concept Study; Pulmonary Fibrosis; Secondary Metabolism; Species Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectroscopy, Fourier Transform Infrared; Tissue Array Analysis
PubMed: 29035378
DOI: 10.1038/labinvest.2017.110 -
Biomolecules Apr 2022Hyaluronic acid (HA) is a major component of the extracellular matrix. It is synthesized by hyaluronan synthases (HAS) into high-molecular-weight chains (HMW-HA) that... (Review)
Review
Hyaluronic acid (HA) is a major component of the extracellular matrix. It is synthesized by hyaluronan synthases (HAS) into high-molecular-weight chains (HMW-HA) that exhibit anti-inflammatory and immunomodulatory functions. In damaged, infected, and/or inflamed tissues, HMW-HA are degraded by hyaluronidases (HYAL) or reactive oxygen species (ROS) to give rise to low-molecular-weight HAs (LMW-HAs) that are potent pro-inflammatory molecules. Therefore, the size of HA regulates the balance of anti- or pro-inflammatory functions. The activities of HA depend also on its interactions with hyaladherins. HA synthesis, degradation, and activities through HA/receptors interactions define the hyaluronasome. In this review, a short overview of the role of high and low-molecular-weight HA polymers in the lungs is provided. The involvement of LMW-HA in pulmonary innate immunity via the activation of neutrophils, macrophages, dendritic cells, and epithelial cells is described to highlight LMW-HA as a therapeutic target in inflammatory respiratory diseases. Finally, the possibilities to counter LMW-HA's deleterious effects in the lungs are discussed.
Topics: Hyaluronan Receptors; Hyaluronic Acid; Immunity, Innate; Lung; Molecular Weight
PubMed: 35625586
DOI: 10.3390/biom12050658 -
The Journal of the Acoustical Society... Feb 2021The objective of this study is to predict in vivo lung mass density for patients with interstitial lung disease using different gradient boosting decision tree (GBDT)...
OBJECTIVE
The objective of this study is to predict in vivo lung mass density for patients with interstitial lung disease using different gradient boosting decision tree (GBDT) algorithms based on measurements from lung ultrasound surface wave elastography (LUSWE) and pulmonary function testing (PFT).
METHODS
Age and weight of study subjects (57 patients with interstitial lung disease and 20 healthy subjects), surface wave speeds at three vibration frequencies (100, 150, and 200 Hz) from LUSWE, and predicted forced expiratory volume (FEV1% pre) and ratio of forced expiratory volume to forced vital capacity (FEV1%/FVC%) from PFT were used as inputs while lung mass densities based on the Hounsfield Unit from high resolution computed tomography (HRCT) were used as labels to train the regressor in three GBDT algorithms, XGBoost, CatBoost, and LightGBM. 80% (20%) of the dataset was used for training (testing).
RESULTS
The results showed that predictions using XGBoost regressor obtained an accuracy of 0.98 in the test dataset.
CONCLUSION
The obtained results suggest that XGBoost regressor based on the measurements from LUSWE and PFT may be able to noninvasively assess lung mass density in vivo for patients with pulmonary disease.
Topics: Elasticity Imaging Techniques; Humans; Lung; Lung Diseases; Machine Learning; Respiratory Function Tests
PubMed: 33639787
DOI: 10.1121/10.0003575 -
The Yale Journal of Biology and Medicine Mar 2023: We aim to comprehensively describe the transcriptional activity and signaling of pulmonary parenchymal and immune cells before and after cardiopulmonary bypass (CPB)...
Integrated Analysis of Tracheobronchial Fluid from Before and After Cardiopulmonary Bypass Reveals Activation of the Integrated Stress Response and Altered Pulmonary Microvascular Permeability.
: We aim to comprehensively describe the transcriptional activity and signaling of pulmonary parenchymal and immune cells before and after cardiopulmonary bypass (CPB) by using a multi-omic approach coupled with functional cellular assays. We hypothesize that key signaling pathways from specific cells within the lung alter pulmonary endothelial cell function resulting in worsening or improving disease. : We collected serial tracheobronchial lavage samples from intubated patients less than 2-years-old undergoing surgery with CPB. Samples were immediately processed for single cell RNA sequencing (10x Genomics). Cell clustering, cell-type annotation, and visualization were performed, and differentially expressed genes (DEG) between serial samples were identified. Metabolomic and proteomic analyses were performed on the supernatant using mass spectrometry and a multiplex assay (SomaScan) respectively. Functional assays were done using electric cell-substrate impedance sensing to measure resistance across human pulmonary microvascular endothelial cells (HPMECs). : Analysis of eight patients showed a heterogeneous mixture of pulmonary parenchymal and immune cells. Cell clustering demonstrated time-dependent changes in the transcriptomic signature indicating altered cellular phenotypes after CPB. DEG analysis was represented by genes involved in host defense, innate immunity, and the mitochondrial respiratory transport chain. Ingenuity pathway analysis showed upregulation of the integrated stress response across all cell types after CPB. Metabolomic analysis demonstrated upregulation of ascorbate and aldarate metabolism. Unbiased proteomic analysis revealed upregulation of proteins involved in cytokine and chemokine pathways. Post-CPB patient supernatant improved HMPEC barrier function, suggesting a protective cellular response to CPB. : Children who undergo CPB for cardiac surgery have distinct cell populations, transcriptional activity, and metabolism that change over time. The response to ischemia-reperfusion injury in the lower airway of children appears to be protective, with the need to identify potential targets through future investigations.
Topics: Child; Humans; Child, Preschool; Cardiopulmonary Bypass; Endothelial Cells; Capillary Permeability; Proteomics; Lung
PubMed: 37009190
DOI: 10.59249/KFYZ8002 -
Clinical Imaging Sep 2022To describe quantitative CT parameters of children with a typical pattern for NEHI and compare them to controls.
OBJECTIVE
To describe quantitative CT parameters of children with a typical pattern for NEHI and compare them to controls.
MATERIALS AND METHODS
Eleven patients (7 boys) with NEHI and an available chest CT concordant NEHI were identified. Eleven age-, sex-, height-matched, with CT technique-matching were identified for comparison. An open-source software was used to segment the lung parenchyma into lobes using the fissures. Quantitative parameters such as low attenuation areas, mean lung density, kurtosis, skewness, ventilation heterogeneity, lung mass, and volume were calculated for both controls and cases.
RESULTS
Analysis of the lung parenchyma showed that patients with NEHI had a lower mean lung density (-615 HU vs -556 HU, p = 0.03) with higher ventilation heterogeneity (0.23 vs 0.19, p = 0.04), lung mass (232 g vs 146 g, p = 0.01) and volume (595 mL vs 339 mL, p = 0.008) compared to controls. Most lobes followed this trend, except the middle lobe that showed only a higher lung mass (32.9 g vs 19.6 g, p = 0.02) and volume (77.4 vs 46.9, p = 0.005) in patients with NEHI compared to controls.
CONCLUSION
Quantitative CT is a feasible technique in children with a typical pattern for NEHI and is associated with differences in attenuation, ventilation heterogeneity, and lung volume.
Topics: Child; Feasibility Studies; Humans; Hyperplasia; Lung; Lung Diseases, Interstitial; Male; Neuroendocrine Cells; Tomography, X-Ray Computed
PubMed: 35700553
DOI: 10.1016/j.clinimag.2022.06.004 -
The International Journal of... Jan 2018Pulmonary hypertension (PH) frequently occurs in infants with bronchopulmonary dysplasia (BPD), causing increased mortality and right ventricular (RV) dysfunction that...
Pulmonary hypertension (PH) frequently occurs in infants with bronchopulmonary dysplasia (BPD), causing increased mortality and right ventricular (RV) dysfunction that persists into adulthood. A first step in developing better therapeutic options is identifying and characterizing an appropriate animal model. Previously, we characterized the short-term morbidities of a model in which C57BL/6J wild-type (WT) mice were exposed to 70% O (hyperoxia) during the neonatal period. Here, we aimed to determine the long-term morbidities using lung morphometry, echocardiography (Echo), and cardiac magnetic resonance imaging (cMRI). The major highlight of this study is the use of the state-of-the art imaging technique, cMRI, in mice to characterize the long-term cardiac effects of neonatal hyperoxia exposure. To this end, WT mice were exposed to 21% O (normoxia) or hyperoxia for two weeks of life, followed by recovery in normoxia for six weeks. Alveolarization, pulmonary vascularization, pulmonary hypertension, and RV function were quantified at eight weeks. We found that hyperoxia exposure resulted in persistent alveolar and pulmonary vascular simplification. Furthermore, the Echo and cMRI studies demonstrated that hyperoxia-exposed mice had signs of PH and RV dysfunction as indicated by increased RV pressure, mass, and end-systolic and -diastolic volumes, and decreased RV stroke volume and ejection fractions. Taken together, our results demonstrate that neonatal hyperoxia exposure in mice cause cardiopulmonary morbidities that persists into adulthood and provides evidence for the use of this model to develop novel therapies for BPD infants with PH.
Topics: Animals; Animals, Newborn; Atmosphere Exposure Chambers; Bronchopulmonary Dysplasia; Disease Models, Animal; Echocardiography; Feasibility Studies; Female; Heart; Hyperoxia; Hypertension, Pulmonary; Lung; Magnetic Resonance Imaging; Male; Mice, Inbred C57BL; Myocardium; Organ Size; Pulmonary Circulation; Stroke Volume; Time Factors; Ultrasonography, Doppler, Pulsed; Ventricular Dysfunction, Right
PubMed: 29223466
DOI: 10.1016/j.biocel.2017.12.001 -
International Journal of Molecular... Feb 2023Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the...
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (-value ≤ 0.05 and Fold change ≤-1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy.
Topics: Mice; Animals; Bleomycin; Proteomics; Lung; Idiopathic Pulmonary Fibrosis; Fibrosis
PubMed: 36901840
DOI: 10.3390/ijms24054410