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Medical Physics Apr 2021Computed tomography (CT)-derived ventilation methods compute respiratory induced volume changes as a surrogate for pulmonary ventilation. Currently, there are no known...
PURPOSE
Computed tomography (CT)-derived ventilation methods compute respiratory induced volume changes as a surrogate for pulmonary ventilation. Currently, there are no known methods to derive perfusion information from noncontrast CT. We introduce a novel CT-Perfusion (CT-P) method for computing the magnitude mass changes apparent on dynamic noncontrast CT as a surrogate for pulmonary perfusion.
METHODS
CT-Perfusion is based on a mass conservation model which describes the unknown mass change as a linear combination of spatially corresponding inhale and exhale HU estimated voxel densities. CT-P requires a deformable image registration (DIR) between the inhale/exhale lung CT pair, a preprocessing lung volume segmentation, and an estimate for the Jacobian of the DIR transformation. Given this information, the CT-P image, which provides the magnitude mass change for each voxel within the lung volume, is formulated as the solution to a constrained linear least squares problem defined by a series of subregional mean magnitude mass change measurements. Similar to previous robust CT-ventilation methods, the amount of uncertainty in a subregional sample mean measurement is related to measurement resolution and can be characterized with respect to a tolerance parameter . Spatial Spearman correlation between single photon emission CT perfusion (SPECT-P) and the proposed CT-P method was assessed in two patient cohorts via a parameter sweep of . The first cohort was comprised of 15 patients diagnosed with pulmonary embolism (PE) who had SPECT-P and 4DCT imaging acquired within 24 h of PE diagnosis. The second cohort was comprised of 15 nonsmall cell lung cancer patients who had SPECT-P and 4DCT images acquired prior to radiotherapy. For each test case, CT-P images were computed for 30 different uncertainty parameter values, uniformly sampled from the range [0.01, 0.125], and the Spearman correlation between the SPECT-P and the resulting CT-P images were computed.
RESULTS
The median correlations between CT-P and SPECT-P taken over all 30 test cases ranged between 0.49 and 0.57 across the parameter sweep. For the optimal tolerance τ = 0.0385, the CT-P and SPECT-P correlations across all 30 test cases ranged between 0.02 and 0.82. A one-sample sign test was applied separately to the PE and lung cancer cohorts. A low Spearmen correlation of 15% was set as the null median value and two-sided alternative was tested. The PE patients showed a median correlation of 0.57 (IQR = 0.305). One-sample sign test was statistically significant with 96.5 % confidence interval: 0.20-0.63, P < 0.00001. Lung cancer patients had a median correlation of 0.57(IQR = 0.230). Again, a one-sample sign test for median was statistically significant with 96.5 percent confidence interval: 0.45-0.71, P < 0.00001.
CONCLUSION
CT-Perfusion is the first mechanistic model designed to quantify magnitude blood mass changes on noncontrast dynamic CT as a surrogate for pulmonary perfusion. While the reported correlations with SPECT-P are promising, further investigation is required to determine the optimal CT acquisition protocol and numerical method implementation for CT-P imaging.
Topics: Carcinoma, Non-Small-Cell Lung; Four-Dimensional Computed Tomography; Humans; Lung; Lung Neoplasms; Perfusion; Pulmonary Ventilation; Tomography, Emission-Computed, Single-Photon
PubMed: 33608933
DOI: 10.1002/mp.14792 -
Toxicology Mechanisms and Methods May 2021Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial... (Review)
Review
Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial applications; however, it is a toxic inhalation hazard agent. Inhalation of chlorine gas, based on the concentration and duration of the exposure, causes a spectrum of symptoms, including but not limited to lacrimation, rhinorrhea, bronchospasm, cough, dyspnea, acute lung injury, death, and survivors develop signs of pulmonary fibrosis and reactive airway disease. Despite the use of chlorine gas as a chemical warfare agent since World War I and its known potential as an industrial hazard, there is no specific antidote. The resurgence of the use of chlorine gas as a chemical warfare agent in recent years has brought speculation of its use as weapons of mass destruction. Therefore, developing antidotes for chlorine gas-induced lung injuries remains the need of the hour. While some of the pre-clinical studies have made substantial progress in the understanding of chlorine gas-induced pulmonary pathophysiology and identifying potential medical countermeasure(s), yet none of the drug candidates are approved by the U.S. Food and Drug Administration (FDA). In this review, we summarized pathophysiology of chlorine gas-induced pulmonary injuries, pre-clinical animal models, development of a pipeline of potential medical countermeasures under FDA animal rule, and future directions for the development of antidotes for chlorine gas-induced lung injuries.
Topics: Acute Lung Injury; Animals; Antidotes; Chemical Warfare Agents; Chlorine; Lung
PubMed: 31532270
DOI: 10.1080/15376516.2019.1669244 -
Journal of Advanced Research Feb 2023Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation...
INTRODUCTION
Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-fibrotic macrophages.
OBJECTIVES
To identify the alteration of immunometabolism in the pulmonary macrophages and investigate the feasibility of specific inhibition of M2 activation of macrophages as an effective anti-PF strategy in vivo.
METHODS
The high-content screening system was used to select lung-specific homing compounds that can modulate macrophage polarization. Imaging mass spectrometry (IMS) conjugated with chemical proteomics approach was conducted to explore the cells and proteins targeted by diphenyleneiodonium chloride (DPI). A bleomycin-induced fibrotic mouse model was established to examine the in vivo effect of DPI.
RESULTS
Pulmonary macrophages of PF at late stage exhibited predominantly the M2 phenotype with decreased glycolysis metabolism. DPI was demonstrated to inhibit profibrotic activation of macrophages in the preliminary screening. Notably, IMS conjugated with chemical proteomics approach revealed DPI specifically targeted pulmonary macrophages, leading to the efficient protection from bleomycin-induced pulmonary fibrosis in mice. Mechanistically, DPI upregulated glycolysis and suppressed M2 programming in fibrosis mice, thus resulting in pro-fibrotic cytokine inhibition, hydroxyproline biosynthesis, and collagen deposition, with a concomitant increase in alveolar airspaces.
CONCLUSIONS
DPI mediated glycolysis in lung and accordingly suppressed M2 programming, resulting in improved lung fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Lung; Macrophages; Fibrosis; Bleomycin
PubMed: 36725191
DOI: 10.1016/j.jare.2022.04.012 -
International Journal of Molecular... Mar 2021Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function... (Review)
Review
Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function that can be attributed to mechanical dysfunctions. Moreover, the alterations of adipocyte-derived signal mediators strongly influence the regulation of inflammation, resulting in chronic low-grade inflammation. Our review summarizes the known effects regarding pulmonary bacterial and viral infections. For this, we discuss model systems that allow mechanistic investigation of the interplay between obesity and lung infections. Overall, obesity gives rise to a higher susceptibility to infectious pathogens, but the pathogenetic process is not clearly defined. Whereas, viral infections often show a more severe course in obese patients, the same patients seem to have a survival benefit during bacterial infections. In particular, we summarize the main mechanical impairments in the pulmonary tract caused by obesity. Moreover, we outline the main secretory changes within the expanded adipose tissue mass, resulting in chronic low-grade inflammation. Finally, we connect these altered host factors to the influence of obesity on the development of lung infection by summarizing observations from clinical and experimental data.
Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Anti-Inflammatory Agents; Bacterial Infections; Cells, Cultured; Comorbidity; Female; Humans; Inflammation; Leptin; Lung; Macrophages; Male; Mice; Obesity; Risk Factors; Virus Diseases
PubMed: 33810619
DOI: 10.3390/ijms22073456 -
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 -
Saudi Medical Journal Oct 2022To present an unusual and a rare pulmonary affection by coronavirus disease-19 (COVID-19), in which only one lung is affected. Coronavirus disease-19 attacks the lungs... (Review)
Review
To present an unusual and a rare pulmonary affection by coronavirus disease-19 (COVID-19), in which only one lung is affected. Coronavirus disease-19 attacks the lungs and interferes seriously with their functions. The attack is usually bilaterally, while a uni lateral pulmonary affection is unusual. The presentation, both clinical and radiological findings, bronchoscopy appearance, the strange operative findings of the resected mass, the uneventful post-operative course, in addition to the histopathological report, will be presented.In conclusion, unilateral lung affection is unusual and post-viral pneumonia COVID-19 should be considered as a possible aftermath, which may not be uncommon in Iraq.
Topics: Humans; COVID-19; Pneumonia, Viral; Lung; Bronchoscopy; Iraq
PubMed: 36261211
DOI: 10.15537/smj.2022.43.10.20220294 -
Pathologica Aug 2022The thoracic district is the most frequent visceral location of synovial sarcoma, generally involving lung and pleura as a large solid mass. We present herein a...
The thoracic district is the most frequent visceral location of synovial sarcoma, generally involving lung and pleura as a large solid mass. We present herein a 57-year-old man with recurrent pneumothorax and a localized bulla at the lingula. The lesion was excised by a Video-Assisted-Thoracoscopic-Surgery (VATS) wedge resection and surprisingly consisted of a unilocular cyst with fibrous wall intermingled by a longitudinal proliferation of bland-looking, dense, monomorphic spindle cells diffusely expressing EMA, CD99, CD56 and focally staining with cytokeratins. Fluorescent in situ hybridization demonstrated the presence of SYT rearrangement and a diagnosis of pulmonary cystic monophasic synovial sarcoma was made. Only few similar cases have been reported in literature, mainly occurring in young male adults. A meticulous examination of all resected tissue from pneumothorax is the prerequisite to suspect this extremely challenging condition, while immuno-molecular studies are mandatory to achieve the correct diagnosis.
Topics: Adult; Humans; In Situ Hybridization, Fluorescence; Lung; Male; Middle Aged; Pneumothorax; Sarcoma, Synovial; Thoracic Surgery, Video-Assisted
PubMed: 36136899
DOI: 10.32074/1591-951X-377 -
American Journal of Physiology. Lung... Jun 2023Radiation-induced lung injury (RILI) is a consequence of therapeutic thoracic irradiation (TR) for many cancers, and there are no FDA-approved curative strategies....
Radiation-induced lung injury (RILI) is a consequence of therapeutic thoracic irradiation (TR) for many cancers, and there are no FDA-approved curative strategies. Studies report that 80% of patients who undergo TR will have CT-detectable interstitial lung abnormalities, and strategies to limit the risk of RILI may make radiotherapy less effective at treating cancer. Our lab and others have reported that lung tissue from patients with idiopathic pulmonary fibrosis (IPF) exhibits metabolic defects including increased glycolysis and lactate production. In this pilot study, we hypothesized that patients with radiation-induced lung damage will exhibit distinct changes in lung metabolism that may be associated with the incidence of fibrosis. Using liquid chromatography/tandem mass spectrometry to identify metabolic compounds, we analyzed exhaled breath condensate (EBC) in subjects with CT-confirmed lung lesions after TR for lung cancer, compared with healthy subjects, smokers, and cancer patients who had not yet received TR. The lung metabolomic profile of the irradiated group was significantly different from the three nonirradiated control groups, highlighted by increased levels of lactate. Pathway enrichment analysis revealed that EBC from the case patients exhibited concurrent alterations in lipid, amino acid, and carbohydrate energy metabolism associated with the energy-producing tricarboxylic acid (TCA) cycle. Radiation-induced glycolysis and diversion of lactate to the extracellular space suggests that pyruvate, a precursor metabolite, converts to lactate rather than acetyl-CoA, which contributes to the TCA cycle. This TCA cycle deficiency may be compensated by these alternate energy sources to meet the metabolic demands of chronic wound repair. Using an "omics" approach to probe lung disease in a noninvasive manner could inform future mechanistic investigations and the development of novel therapeutic targets. We report that exhaled breath condensate (EBC) identifies cellular metabolic dysregulation in patients with radiation-induced lung injury. In this pilot study, untargeted metabolomics revealed a striking metabolic signature in EBC from patients with radiation-induced lung fibrosis compared to patients with lung cancer, at-risk smokers, and healthy volunteers. Patients with radiation-induced fibrosis exhibit specific changes in tricarboxylic acid (TCA) cycle energy metabolism that may be required to support the increased energy demands of fibroproliferation.
Topics: Humans; Lung Injury; Pilot Projects; Idiopathic Pulmonary Fibrosis; Lactic Acid; Lung Neoplasms; Breath Tests; Lung; Biomarkers
PubMed: 37039378
DOI: 10.1152/ajplung.00439.2022 -
The International Journal of... Apr 2021Patients with eosinophilic granulomatosis with polyangiitis (EGPA) most commonly die from cardiac causes, however, cardiac involvement remains poorly characterised and...
Patients with eosinophilic granulomatosis with polyangiitis (EGPA) most commonly die from cardiac causes, however, cardiac involvement remains poorly characterised and the relationship between cardiac and pulmonary disease is not known. This study aimed to characterise myocardial and pulmonary manifestations of EGPA, and their relationship. Prospective comprehensive cardiopulmonary investigation, including a novel combined cardiopulmonary magnetic resonance imaging (MRI) technology, was performed in 13 patients with stable EGPA. Comparison was made with 11 prospectively recruited matched healthy volunteers. Stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis (myocardial extracellular volume 26.9% vs. 24.7%; p = 0.034), which drove a borderline increase in left ventricular mass (56 ± 9 g/m2 vs. 49 ± 8 g/m2; p = 0.065). Corrected QT interval was significantly prolonged and was associated with the severity of myocardial fibrosis (r = 0.582, p = 0.037). Stable EGPA was not associated with increased myocardial capillary permeability or myocardial oedema. Pulmonary tissue perfusion and capillary permeability were normal and there was no evidence of pulmonary tissue oedema or fibrosis. Forced expiratory volume in one second showed a strong inverse relationship with myocardial fibrosis (r = -0.783, p = 0.038). In this exploratory study, stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis, but no evidence of myocardial or pulmonary inflammation or pulmonary fibrosis. Myocardial fibrosis was strongly associated with airway obstruction and abnormal cardiac repolarisation. Further investigation is required to determine the mechanisms underlying the association between heart and lung disease in EGPA and whether an immediate immunosuppressive strategy could prevent myocardial fibrosis formation.
Topics: Airway Obstruction; Cardiomyopathies; Case-Control Studies; Churg-Strauss Syndrome; Female; Fibrosis; Humans; Lung; Lung Diseases; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardium; Predictive Value of Tests; Prognosis; Prospective Studies
PubMed: 33211241
DOI: 10.1007/s10554-020-02091-1 -
BMC Veterinary Research May 2020Constitutive and inducible defenses protect the respiratory tract from bacterial infection. The objective of this study was to characterize the response to an...
BACKGROUND
Constitutive and inducible defenses protect the respiratory tract from bacterial infection. The objective of this study was to characterize the response to an aerosolized lysate of killed bacteria, as a basis for studying the regulation and in vivo effects of these inducible innate immune responses.
RESULTS
Bacterial lysate consisting of heat-killed and sonicated Staphylococcus aureus and Escherichia coli was aerosolized to 6 calves and systemic and pulmonary innate immune and inflammatory responses were measured in the first 24 h relative to baseline. Evaluated parameters included clinical parameters (body temperature and heart and respiratory rates), blood acute phase proteins and leukocyte counts, and leukocytes and proteins in bronchoalveolar lavage fluid. Mild clinical signs with increased heart rates and rectal temperatures developed following administration of the lysate, with resolution by 24 h. Serum haptoglobin and plasma fibrinogen concentrations were elevated at 24 h relative to baseline. Bronchoalveolar lavage fluid (BALF) had increased cellularity and increased proportion of neutrophils, as well as higher concentrations of interleukin (IL)-8, IL-10 and total protein at 24 h relative to baseline. Mass spectrometry identified 965 unique proteins in BALF: 19 proteins were increased and 26 proteins were decreased relative to baseline. The upregulated proteins included those involved in innate immunity including activation of complement, neutrophils and platelets. At postmortem examination, calves receiving higher doses of lysate had areas of lobular consolidation and interlobular edema. Histologically, neutrophils were present within bronchioles and to a lesser extent within alveoli. Calves receiving highest doses of lysate had patchy areas of neutrophils, hemorrhage and hyaline membranes within alveoli.
CONCLUSIONS
Aerosolization of bacterial lysate stimulated an innate immune response in lungs and airways, with alveolar damage observed at higher doses. Such a stimulus could be of value for investigating the effects of inducible innate immune responses on occurrence of disease, or for evaluating how stress, drugs or genetics affect these dynamic responses of the respiratory tract.
Topics: Acute-Phase Proteins; Aerosols; Animals; Body Temperature; Bronchoalveolar Lavage Fluid; Cattle; Escherichia coli; Heart Rate; Immunity, Innate; Leukocyte Count; Lung; Male; Respiratory Rate; Staphylococcus aureus
PubMed: 32471444
DOI: 10.1186/s12917-020-02383-7