Changes In Lung Structure Research Articles

Computed tomography radiomics-based prognosis prediction of patients with chronic obstructive pulmonary disease

Objectivethe objective of this study was to develop a predictive model for pulmonary ventilation function in patients with chronic obstructive pulmonary disease (COPD) utilizing computed tomography (CT) and pulmonary function parameters. Material and methoda retrospective analysis was conducted on 90 patients with COPD from our hospital, who were divided into Group I (AG, normal pulmonary function), Group II (BG, mild ventilation dysfunction), Group III (CG, moderate ventilation dysfunction), Group IV (DG, severe ventilation dysfunction), Group V (EG, very severe restrictive ventilation dysfunction), and Group VI (FG, very severe mixed ventilation dysfunction) according to pulmonary function. The imaging and pulmonary function indicators of the subjects were analyzed. Resultas lung dysfunction worsened, structural changes in the lungs on CT images also progressively worsened, manifesting as an enlargement of emphysematous areas, a decrease in lung field homogeneity, changes in lung tissue density and structure, and a reduction in lung field volume. Maximal expiratory flow (MEF) when 75%, 50% of the forced vital capacity (FVC) remained in the lung, i.e. MEF75%, MEF50%, and maximum mid-expiratory flow (MMEF75%-25%) were most highly correlated with ventilation dysfunction. Conclusionthe severity of pulmonary ventilation dysfunction in patients with COPD can be better predicted by CT imaging and pulmonary function examination indicators.

Insights into Leptospira spp. Infection in Pet Cats in Croatia: Clinical, Serological and Molecular Findings with Emphasis on the Potential Important Role of Serogroup Pomona.

Leptospirosis, a globally re-emerging zoonosis caused by pathogenic Leptospira spp., poses a significant threat to public health. Leptospirosis in cats is often neglected due to its high underdiagnosis. Therefore, the role of cats in disease transmission and bacterial maintenance in the environment remains unclear. For this study, 54 serum samples, 54 urine samples and 27 EDTA-anticoagulated blood samples from pet cats presenting to the Veterinary Teaching Hospital due to health problems were used. The serum samples were tested for antibodies against 12 pathogenic serovars of Leptospira spp. using the microscopic agglutination test (MAT). EDTA-anticoagulated blood and urine samples were tested for the lipL32 gene of pathogenic Leptospira spp. by conventional (PCR) and real-time (qPCR) polymerase chain reaction. Agglutinating antibodies were detected in 18.52% (10/54) of the sera with a titre range of 1:50 to 1:12800. The most common serogroup was Pomona, followed by Sejroe, Icterohaemorrhagiae, Australis and Javanica. Leptospira spp. DNA was found in 1.85% (1/54) of the urine samples, while all EDTA-anticoagulated blood samples were negative. A statistically significant difference in seropositivity regarding lifestyle was found between outdoor/indoor and indoor-only cats, while the presence of another cat in the household significantly increased the likelihood of seropositivity. Cats with immunocompromising conditions showed a significantly increased risk of seropositivity, especially those undergoing immunosuppressive treatment. In addition, respiratory signs and changes in lung structure associated with the presence of leptospiral antibodies, and these cats were more likely to be infected with the Pomona serogroup. Moreover, cats with anaemia, leucocytosis, and thrombocytopenia were significantly more likely to have antibodies against Leptospira spp., while seropositive cats had significantly lower urine-specific gravity compared to seronegative cats. The results underline the importance of raising awareness of feline leptospirosis in veterinary care and recognising pet cats as potential carriers of leptospires. Further research is needed to clarify the specific role of the Pomona serogroup as a potentially highly evolutionary drifting serogroup in terms of pathogenicity and to clarify the zoonotic potential of infected cats, which is crucial for the implementation of effective public health measures and veterinary interventions.

Decreased Liver Kinase B1 Expression and Impaired Angiogenesis in a Murine Model of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is characterized by impaired lung alveolar and vascular growth. We investigated the hypothesis that neonatal exposure to hyperoxia leads to persistent BPD phenotype caused by decreased expression of liver kinase B1 (LKB1), a key regulator of mitochondrial function. We exposed mouse pups from Postnatal Day (P)1 through P10 to 21% or 75% oxygen. Half of the pups in each group received metformin or saline intraperitoneally from P1 to P10. Pups were killed at P4 or P10 or recovered in 21% O2 until euthanasia at P21. Lung histology and morphometry, immunofluorescence, and immunoblots were performed to detect changes in lung structure and expression of LKB1; downstream targets AMPK, PGC-1α, and electron transport chain (ETC) complexes; and Notch ligands Jagged 1 and delta-like 4. LKB1 signaling and invitro angiogenesis were assessed in human pulmonary artery endothelial cells (exposed to 21% or 95% O2 for 36 hours. Levels of LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes were decreased in lungs at P10 and P21 in hyperoxia. Metformin increased LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes at P10 and P21 in pups exposed to hyperoxia. Radial alveolar count was decreased, and mean linear intercept increased in pups exposed to hyperoxia at P10 and P21; these were improved by metformin. Lung capillary density was decreased in hyperoxia at P10 and P21 and was increased by metformin. In vitro angiogenesis was decreased in human pulmonary artery endothelial cells by 95% O2 and was improved by metformin. Decreased LKB1 signaling may contribute to decreased alveolar and vascular growth in a mouse model of BPD.

The Possible Role of Hesperidin on Triolein Induced Lung Structural Changes in Adult Male Albino Rats (Histological and Immunohistochemical Study)

The Possible Role of Hesperidin on Triolein Induced Lung Structural Changes in Adult Male Albino Rats (Histological and Immunohistochemical Study)

Aerobic exercise training engages the canonical wnt pathway to improve pulmonary function and inflammation in COPD

BackgroundWe studied whether the exercise improves cigarette smoke (CS) induced chronic obstructive pulmonary disease (COPD) in mice through inhibition of inflammation mediated by Wnt/β-catenin-peroxisome proliferator-activated receptor (PPAR) γ signaling.MethodsFirstly, we observed the effect of exercise on pulmonary inflammation, lung function, and Wnt/β-catenin-PPARγ. A total of 30 male C57BL/6J mice were divided into the control group (CG), smoke group (SG), low-intensity exercise group (LEG), moderate-intensity exercise group (MEG), and high-intensity exercise group (HEG). All the groups, except for CG, underwent whole-body progressive exposure to CS for 25 weeks. Then, we assessed the maximal exercise capacity of mice from the LEG, MEG, and HEG, and performed an 8-week treadmill exercise intervention. Then, we used LiCl (Wnt/β-catenin agonist) and XAV939 (Wnt/β-catenin antagonist) to investigate whether Wnt/β-catenin-PPARγ pathway played a role in the improvement of COPD via exercise. Male C57BL/6J mice were randomly divided into six groups (n = 6 per group): CG, SG, LiCl group, LiCl and exercise group, XAV939 group, and XAV939 and exercise group. Mice except those in the CG were exposed to CS, and those in the exercise groups were subjected to moderate-intensity exercise training. All the mice were subjected to lung function test, lung histological assessment, and analysis of inflammatory markers in the bronchoalveolar lavage fluid, as well as detection of Wnt1, β-catenin and PPARγ proteins in the lung tissue.ResultsExercise of various intensities alleviated lung structural changes, pulmonary function and inflammation in COPD, with moderate-intensity exercise exhibiting significant and comprehensive effects on the alleviation of pulmonary inflammation and improvement of lung function. Low-, moderate-, and high-intensity exercise decreased β-catenin levels and increased those of PPARγ significantly, and only moderate-intensity exercise reduced the level of Wnt1 protein. Moderate-intensity exercise relieved the inflammation aggravated by Wnt agonist. Wnt antagonist combined with moderate-intensity exercise increased the levels of PPARγ, which may explain the highest improvement of pulmonary function observed in this group.ConclusionsExercise effectively decreases COPD pulmonary inflammation and improves pulmonary function. The beneficial role of exercise may be exerted through Wnt/β-catenin-PPARγ pathway.

The Role of Pericytes in Lipopolysaccharide-Induced Murine Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome that is most commonly triggered by infection-related inflammation. Lung pericytes can respond to infection and act as immune and proangiogenic cells; moreover, these cells can differentiate into myofibroblasts in nonresolving ARDS and contribute to the development of pulmonary fibrosis. Here, we aimed to characterize the role of lung cells, which present characteristics of pericytes, such as peri-endothelial location and expression of a panel of specific markers. A murine model of lipopolysaccharide (LPS)-induced resolving ARDS was used to study their role in ARDS. The development of ARDS was confirmed after LPS instillation, which was resolved 14 days after onset. Immunofluorescence and flow cytometry showed early expansion of neural-glial antigen 2+ β-type platelet-derived growth factor receptor+ pericytes in murine lungs with loss of CD31+ β-type platelet-derived growth factor receptor+ endothelial cells. These changes were accompanied by specific changes in lung structure and loss of vascular integrity. On day 14 after ARDS onset, the composition of pericytes and endothelial cells returned to baseline values. LPS-induced ARDS activated NOTCH signaling in lung pericytes, the inhibition of which during LPS stimulation reduced the expression of its downstream target genes, pericyte markers, and angiogenic factors. Together, these data indicate that lung pericytes in response to inflammatory injury activate NOTCH signaling that supports their maintenance and in turn can contribute to recovery of the microvascular endothelium.

Assessment of Left Lung Remodeling With Magnetic Resonance Imaging in a Murine Model Following Exposure to Douglas Fir Smoke.

Wildland firefighters (WLFFs) experience lung function decline due to occupational exposure to fire smoke. WLFFs typically do not wear respiratory personal protective equipment, and if they do, it is a simple bandana, which is not effective at filtering smoke. To pinpoint the biological underpinnings of abnormal respiratory function following 3-7 years of WLFF service, we exposed mice to Douglas fir smoke (DFS) over 8 weeks. Following exposure, we assessed changes in lung structure through Magnetic Resonance Imaging (MRI) and histological analysis, which was supported by immunohistochemistry staining. With MRI, we found that the signal decay time, T2*, from ultrashort echo time (UTE) images was significantly shorter in mice exposed to DFS compared to air controls. In addition, the variation in T2* was more heterogeneously distributed throughout the left lung in DFS-exposed mice, compared to air controls. As confirmed by histological analysis, shorter T2* was caused by larger parenchyma airspace sizes and not fibrotic remodeling. Destruction of the alveolar spaces was likely due to inflammation, as measured by an influx of CD68+ macrophages and destruction due to enhanced neutrophil elastase. In addition, measurements of airspace dimensions from histology were more heterogeneously distributed throughout the lung, corroborating the enhanced relative dispersion of T2*. Findings from this study suggest that the decline in lung function observed in WLFFs may be due to emphysema-like changes in the lung, which can be quantified with MRI.

Aspergillus-associated diseases from an infectious diseases and allergological perspective

AbstractAspergillus-associated diseases are rare and pose challenges for practitioners. Diagnosis is complex and requires rational, targeted, and multidisciplinary collaboration, as well as a high degree of expertise and an individualized approach. For the infectious diseases physician, the focus is on the question of infection or colonization. In severely immunocompromised patients, invasive aspergillosis occurs, which most frequently affects the lungs (IPA) and is characterized by invasive, destructive growth. This acute clinical picture is associated with a high mortality rate. Chronic pulmonary aspergillosis (CPA) develops on the basis of pre-existing changes in lung structure caused by other pulmonary diseases and often requires surgical treatment. Another chronic form is allergic bronchopulmonary aspergillosis (ABPA). It is often associated with bronchiectasis in patients with bronchial asthma or cystic fibrosis. Sinus mycoses are divided into non-invasive and invasive forms, which can occur in immunocompromised patients and most commonly affect the maxillary sinus. Here, local surgical measures are an obligatory part of treatment, whereas the non-invasive form usually has an allergic component. In addition, drug-based antifungal and/or anti-inflammatory therapy is used for all entities.

Landscape fire smoke airway exposure impairs respiratory and cardiac function and worsens experimental asthma

Millions of people are exposed to landscape fire smoke (LFS) globally, and inhalation of LFS particulate matter (PM) is associated with poor respiratory and cardiovascular outcomes. However, how LFS affects respiratory and cardiovascular function is less well understood. We aimed to characterize the pathophysiologic effects of representative LFS airway exposure on respiratory and cardiac function and on asthma outcomes. LFS was generated using a customized combustion chamber. In 8-week-old female BALB/c mice, low (25 μg/m3, 24-hour equivalent) or moderate (100 μg/m3, 24-hour equivalent) concentrations of LFS PM (10 μm and below [PM10]) were administered daily for 3 (short-term) and 14 (long-term) days in the presence and absence of experimental asthma. Lung inflammation, gene expression, structural changes, and lung function were assessed. In 8-week-old male C57BL/6 mice, low concentrations of LFS PM10 were administered for 3 days. Cardiac function and gene expression were assessed. Short- and long-term LFS PM10 airway exposure increased airway hyperresponsiveness and induced steroid insensitivity in experimental asthma, independent of significant changes in airway inflammation. Long-term LFS PM10 airway exposure also decreased gas diffusion. Short-term LFS PM10 airway exposure decreased cardiac function and expression of gene changes relating to oxidative stress and cardiovascular pathologies. We characterized significant detrimental effects of physiologically relevant concentrations and durations of LFS PM10 airway exposure on lung and heart function. Our study provides a platform for assessment of mechanisms that underpin LFS PM10 airway exposure on respiratory and cardiovascular disease outcomes.

Mucopolysaccharidosis (MPS IIIA) mice have increased lung compliance and airway resistance, decreased diaphragm strength, and no change in alveolar structure.

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.

CT whole lung radiomic nomogram: a potential biomarker for lung function evaluation and identification of COPD

BackgroundComputed tomography (CT) plays a great role in characterizing and quantifying changes in lung structure and function of chronic obstructive pulmonary disease (COPD). This study aimed to explore the performance of CT-based whole lung radiomic in discriminating COPD patients and non-COPD patients.MethodsThis retrospective study was performed on 2785 patients who underwent pulmonary function examination in 5 hospitals and were divided into non-COPD group and COPD group. The radiomic features of the whole lung volume were extracted. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied for feature selection and radiomic signature construction. A radiomic nomogram was established by combining the radiomic score and clinical factors. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were used to evaluate the predictive performance of the radiomic nomogram in the training, internal validation, and independent external validation cohorts.ResultsEighteen radiomic features were collected from the whole lung volume to construct a radiomic model. The area under the curve (AUC) of the radiomic model in the training, internal, and independent external validation cohorts were 0.888 [95% confidence interval (CI) 0.869–0.906], 0.874 (95%CI 0.844–0.904) and 0.846 (95%CI 0.822–0.870), respectively. All were higher than the clinical model (AUC were 0.732, 0.714, and 0.777, respectively, P < 0.001). DCA demonstrated that the nomogram constructed by combining radiomic score, age, sex, height, and smoking status was superior to the clinical factor model.ConclusionsThe intuitive nomogram constructed by CT-based whole-lung radiomic has shown good performance and high accuracy in identifying COPD in this multicenter study.

Tuberculosis in the elderly population

ABSTRACT Tuberculosis (TB) is a significant public health challenge, with the elderly population being particularly affected in certain regions. Around 17.5% of TB cases in France, in 2019, occurred in individuals over 65 years old. Aging leads to decreased lung function and structural changes that predispose the elderly to TB infection. Immunosenescence, comorbidities, malnutrition, and communal living situations increase TB risk in the elderly. TB symptoms in the elderly are often nonspecific and overlap with other conditions, complicating diagnosis. Radiological presentations may differ from younger patients, and the elderly may struggle to produce sputum for testing. Elderly patients may experience varying tolerances to TB medications, and age-related physiological changes and comorbidities influence treatment tolerance and outcomes. Careful management of drug interactions is crucial. Elderly TB patients, especially those who are frail or dependent, are at higher risk for infection and complications. Adherence to treatment is critical, often necessitating directly observed therapy and nutritional support.

Anti-Allergic Inflammatory Effect of Agarum cribrosum and Its Phlorotannin Component, Trifuhalol A, against the Ovalbumin-Induced Allergic Asthma Model.

Asthma is a chronic inflammatory disease involving structural changes to the respiratory system and severe immune responses mediated by allergic cytokines and pro-inflammatory mediators. Agarum cribrosum (AC) is a kind of seaweed which contains a phlorotannin, trifuhalol A. To evaluate its anti-allergic inflammatory effect against asthma, an ovalbumin inhalation-induced mouse asthma model was used. Histologic observations proved that trifuhalol A is minimizing the lung and tracheal structure changes as well as the infiltration of eosinophils and mast cells against ovalbumin inhalation challenge. From the serum and bronchoalveolar lavage fluid, ovalbumin-specific IgE and Th2-specific cytokines, IL-4, -5, and -13, were reduced with trifuhalol A treatment. In addition, IL-1β, IL-6, and TNF-α concentrations in lung homogenate were also significantly reduced via trifuhalol A treatment. Taken together, trifuhalol A, isolated from AC, was able to protect lung and airways from Th2-specific cytokine release, and IgE mediated allergic inflammation as well as the attenuation of IL-1β, IL-6, and TNF-α in lung, which results in the suppression of eosinophils and the mast cells involved asthmatic pathology.

The SPEC score-Aquantifiable CT scoring system for primary ciliary dyskinesia.

Structural lung changes seen on computed tomography (CT) scans in persons with primary ciliary dyskinesia (pwPCD) are currently described using cystic fibrosis (CF) derived scoring systems. Recent work has shown structural changes and frequencies that are unique to PCD, indicating the need for a unique PCD-derivedscoring system. Chest CT scans from 30 pwPCD, were described for structural changes including bronchiectasis, bronchial wall thickening, mucous plugging, atelectasis, air trapping, and interlobar septal thickening and, additionally, changes previously described as being frequent in pwPCD including extensive tree-in-bud pattern of mucous plugging, bronchoceles or nodules, thickening of interlobar and interlobular septa and whole lobe atelectasis. Based on these findings a novel and unique scoring system, the Specific PCD Evaluation by CT (SPEC) score was constructed. Scans were then re-scored using the SPEC score and results compared to corresponding measurements of lung function to assess structure-function correlation. Total SPEC scores ranged from 0 to 60 (max possible score 90). There was a strong negative correlation between the SPEC score (SPEC) and forced vital capacity (FVC), forced expiratory volume over 1 s(FEV1 ) and FEV1 /FVC ratio (-r = .784, -.865, -.872 respectively). Using PCD-deriveddata we describe the construct of a PCD-specificscore for assessing lung structural damage on CT scans, the SPEC score. A strong correlation between the SPEC score and PFT variables was identified. The SPEC score holds the potential for describing longitudinal changes in CT scans and assessing the efficacy of interventive therapies in patients with PCD.

MRI and Pulmonary Function Tests' Results as Ventilation Inhomogeneity Markers in Children and Adolescents with Cystic Fibrosis.

Magnetic resonance imaging (MRI) of the chest is becoming more available in the detection and monitoring of early changes in lung function and structure in patients with cystic fibrosis (CF). The aim of this study was to assess the relationship between pulmonary function tests (PFT) and perfusion deficits in CF children measured by MRI. We performed a retrospective analysis of the perfusion lung MRI scans and the results of spirometry, oscillometry, body plethysmography, single-breath carbon monoxide uptake, and multiple-breath washout technique (MBW). There were statistically significant correlations between the MRI perfusion scores and MBW parameters (2.5% LCI, M1/M0, M2/M0), spirometry parameters (FEV1, FVC, FEF25/75), reactance indices in impulse oscillometry (X5Hz, X10Hz), total lung capacity (TLC) measured in single breath carbon monoxide uptake, markers of air-trapping in body plethysmography (RV, RV/TLC), and the diffusing capacity of the lungs for carbon monoxide. We also observed significant differences in the aforementioned PFT variables between the patient groups divided based on perfusion scores. We noted a correlation between markers of functional lung deficits measured by the MRI and PFTs in CF children. MRI perfusion abnormalities were reflected sooner in the course of the disease than PFT abnormalities.

Differential effects of two-hit models of acute and ventilator-induced lung injury on lung structure, function, and inflammation.

Acute respiratory distress syndrome (ARDS) and acute lung injury have a diverse spectrum of causative factors including sepsis, aspiration of gastric contents, and near drowning. Clinical management of severe lung injury typically includes mechanical ventilation to maintain gas exchange which can lead to ventilator-induced lung injury (VILI). The cause of respiratory failure is acknowledged to affect the degree of lung inflammation, changes in lung structure, and the mechanical function of the injured lung. However, these differential effects of injury and the role of etiology in the structure-function relationship are not fully understood. To address this knowledge gap we caused lung injury with intratracheal hydrochloric acid (HCL) or endotoxin (LPS) 2days prior to ventilation or with an injurious lavage (LAV) immediately prior to ventilation. These injury groups were then ventilated with high inspiratory pressures and positive end expiratory pressure (PEEP) = 0cmH2O to cause VILI and model the clinical course of ARDS followed by supportive ventilation. The effects of injury were quantified using invasive lung function measurements recorded during PEEP ladders where the end-expiratory pressure was increased from 0 to 15cm H2O and decreased back to 0cmH2O in steps of 3cmH2O. Design-based stereology was used to quantify the parenchymal structure of lungs air-inflated to 2, 5, and 10cmH2O. Pro-inflammatory gene expression was measured with real-time quantitative polymerase chain reaction and alveolocapillary leak was estimated by measuring bronchoalveolar lavage protein content. The LAV group had small, stiff lungs that were recruitable at higher pressures, but did not demonstrate substantial inflammation. The LPS group showed septal swelling and high pro-inflammatory gene expression that was exacerbated by VILI. Despite widespread alveolar collapse, elastance in LPS was only modestly elevated above healthy mice (CTL) and there was no evidence of recruitability. The HCL group showed increased elastance and some recruitability, although to a lesser degree than LAV. Pro-inflammatory gene expression was elevated, but less than LPS, and the airspace dimensions were reduced. Taken together, those data highlight how different modes of injury, in combination with a 2nd hit of VILI, yield markedly different effects.

Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.

Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown. Objectives: To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV. Methods: We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA in situ hybridization to identify cell types and molecular networks influenced by FOXF1 in ACDMPV lungs. Measurements and Main Results: Pathogenic single-nucleotide variants and copy-number variant deletions involving the FOXF1 gene locus in all subjects with ACDMPV (n = 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles for FOXF1 in capillary ECs and pericytes were identified. Pathogenic variants involving the FOXF1 gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV α 1 chain). Conclusions: Distinct FOXF1 gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.

Metabolic characterization of structural lung changes in patients with findings suggestive of incidental COVID-19 pneumonia on 18F-FDG PET/CT. Pathophysiological insights from multimodal images obtained during the pandemic

PurposeTo evaluate the metabolic uptake of different tomographic signs observed in patients with incidental structural findings suggestive of COVID-19 pneumonia through 18F-FDG PET/CT. Materials and Methods: We retrospectively analyzed 596 PET/CT studies performed from February 21, 2020 to April 17, 2020. After excluding 37 scans (non-18F-FDG PET tracers and brain studies), we analyzed the metabolic activity of several structural changes integrated in the CO-RADS score using the SUVmax of multimodal studies with 18F-FDG. ResultsForty-three patients with 18F-FDG PET/CT findings suggestive of COVID-19 pneumonia were included (mean age: 68±12.3 years, 22 male). SUVmax values were higher in patients with CO-RADS categories 5−6 than in those with lower CO-RADS categories (6.1±3.0 vs. 3.6±2.1, p=0.004). In patients with CO-RADS 5−6, ground-glass opacities, bilaterality and consolidations exhibited higher SUVmax values (p-values of 0.01, 0.02 and 0.01, respectively). Patchy distribution and crazy paving pattern were also associated with higher SUVmax (p-values of 0.002 and 0.01). After multivariate analysis, SUVmax was significantly associated with a positive structural diagnosis of COVID-19 pneumonia (odds ratio=0.63, 95% confidence interval=0.41−0.90; p=0.02). The ROC curve of the regression model intended to confirm or rule out the structural diagnosis of COVID-19 pneumonia showed an AUC of 0.77 (standard error=0.072, p=0.003). ConclusionsIn those patients referred for standard oncologic and non-oncologic indications (43/559; 7.7%) during pandemic, imaging with 18F-FDG PET/CT is a useful tool during incidental detection of COVID-19 pneumonia. Several CT findings characteristic of COVID-19 pneumonia, specifically those included in diagnostic CO-RADS scores (5−6), were associated with higher SUVmax values.

Achalasia Subtype Differences Based on Respiratory Symptoms and Radiographic Findings.

Three subtypes of achalasia have been defined using esophageal manometry. Several studies have reported that symptoms are experienced differently among men and women, regardless of subtype. All subtypes could have some impact on the appearance of respiratory symptoms and lung complications due to compression of the trachea or aspiration of undigested food. The aim of this research was to analyze the differences in respiratory symptoms and radiographic presentation of lung pathology depending on the diameter and achalasia types. One or more respiratory symptoms were reported in 48% of 114 patients, and all of them had two or more gastrointestinal symptoms. The symptom score (SS) is statistically significant for the prediction of subtype 1 (area under the curve = 0.318; p < 0.001, cut-off score of 6.5 had 95.2% sensitivity) and subtype 2 (area under the curve = 0.626; p = 0.020, cut-off score of 7.5 had 93.1% sensitivity). The most common type was subtype 2 (50.8%), and although only 14 patients had subtype 3, they had the largest esophageal diameter (mean 5.8 cm). The difference in esophageal diameter was significant between subtype 1 and 3 (p = 0.011), subtype 2 and subtype 3 (p = 0.011). Nine patients (6%) had mega-esophagus (four patients in type 1, three in type 2 and two in type 3). More than half of all patients (51.7%) had at least one parenchymal lung change on CT scan. Recurrent micro-aspirations led to changes in the structure of the airways and lung parenchyma such as ground glass (GGO) and nodular changes (12%) and fibrosis (14.5%), and they had higher esophageal diameters (p < 0.001). Patients with chronic lung CT changes had significantly higher esophageal diameter than with acute changes (p < 0.001). Awareness of the association of achalasia and lung disorders is important in early diagnosis and treatment. More than half (57.5%) of patients with achalasia had some clinical and/or structural pulmonary abnormalities. All three subtypes had similar respiratory symptoms, meaning they cannot be used to predict the subtype of achalasia; on the contrary, SS can predict the first two subtypes. A higher diameter of the esophagus is associated with chronic structural lung changes. Although unexpected, the pathological radiological findings and diameter were significantly different in subtype 3 patients, but those parameters cannot lead us to a specified subtype.

Pressure-volume mechanics of inflating and deflating intact whole organ porcine lungs

Pressure-volume curves of the lung are classical measurements of lung function and are impacted by changes in lung structure due to disease or shifts in air-delivery volume or cycling rate. Diseased and preterm infant lungs have been found to show heterogeneous behavior which is highly frequency dependent. This breathing rate dependency has motivated the exploration of multi-frequency oscillatory ventilators to deliver volume oscillation with optimal frequencies for various portions of the lung to provide more uniform air distribution. The design of these advanced ventilators requires the examination of lung function and mechanics, and an improved understanding of the pressure–volume response of the lung. Therefore, to comprehensively analyze whole lung organ mechanics, we investigate six combinations of varying applied volumes and frequencies using ex-vivo porcine specimens and our custom-designed electromechanical breathing apparatus. Lung responses were evaluated through measurements of inflation and deflation slopes, static compliance, peak pressure and volume, as well as hysteresis, energy loss, and pressure relaxation. Generally, we observed that the lungs were stiffer when subjected to faster breathing rates and lower inflation volumes. The lungs exhibited greater inflation volume dependencies compared to frequency dependencies. This study’s reported response of the lung to variations of inflation volume and breathing rate can help the optimization of conventional mechanical ventilators and inform the design of advanced ventilators. Although frequency dependency is found to be minimal in normal porcine lungs, this preliminary study lays a foundation for comparison with pathological lungs, which are known to demonstrate marked rate dependency.