Lung Emphysema Research Articles

Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model

COPD is a chronic lung disease that affects millions of people, declining their lung function and impairing their life quality. Despite years of research and drug approvals, we are still not capable of halting progression or restoring normal lung function. Mesenchymal stem cells (MSC) are cells with extraordinary repair capacity, and MSC-based therapy brings future hope for COPD treatment, although the best source and route of administration are unclear. MSC from adipose tissue (AD-MSC) represents an option for autologous treatment; however, they could be less effective than donor MSC. We compared in vitro behavior of AD-MSC from COPD and non-COPD individuals by migration/proliferation assay, and tested their therapeutic potential in an elastase mouse model. In addition, we tested intravenous versus intratracheal routes, inoculating umbilical cord (UC) MSC and analyzed molecular changes by protein array. Although COPD AD-MSC have impaired migratory response to VEGF and cigarette smoke, they were as efficient as non-COPD in reducing elastase-induced lung emphysema. UC-MSC reduced lung emphysema regardless of the administration route and modified the inflammatory profile in elastase-treated mice. Our data demonstrate equal therapeutic potential of AD-MSC from COPD and non-COPD subjects in the pre-clinical model, thus supporting their autologous use in disease.

Intratracheally injected human-induced pluripotent stem cell-derived pneumocytes and endothelial cells engraft in the distal lung and ameliorate emphysema in a rat model

ObjectivesPulmonary emphysema is characterized by the destruction of alveolar units and reduced gas exchange capacity. In the present study, we aimed to deliver induced pluripotent stem cell-derived endothelial cells and pneumocytes to repair and regenerate distal lung tissue in an elastase-induced emphysema model. MethodsWe induced emphysema in athymic rats via intratracheal injection of elastase as previously reported. At 21 and 35 days after elastase treatment, we suspended 80 million induced pluripotent stem cell-derived endothelial cells and 20 million induced pluripotent stem cell-derived pneumocytes in hydrogel and injected the mixture intratracheally. On day 49 after elastase treatment, we performed imaging, functional analysis, and collected lungs for histology. ResultsUsing immunofluorescence detection of human-specific human leukocyte antigen 1, human-specific CD31, and anti--green fluorescent protein for the reporter labeled pneumocytes, we found that transplanted cells engrafted in 14.69% ± 0.95% of the host alveoli and fully integrated to form vascularized alveoli together with host cells. Transmission electron microscopy confirmed the incorporation of the transplanted human cells and the formation of a blood–air barrier. Human endothelial cells formed perfused vasculature. Computed tomography scans revealed improved vascular density and decelerated emphysema progression in cell-treated lungs. Proliferation of both human and rat cell was higher in cell-treated versus nontreated controls. Cell treatment reduced alveolar enlargement, improved dynamic compliance and residual volume, and improved diffusion capacity. ConclusionsOur findings suggest that human induced pluripotent stem cell-derived distal lung cells can engraft in emphysematous lungs and participate in the formation of functional distal lung units to ameliorate the progression of emphysema.

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome.

Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.

A case report of subconjunctival emphysema as a rare complication of pulmonary resections.

Lung volume reduction surgery (LVRS) is performed to the selected patients with lung emphysema who have higher residual volume, restricted pulmonary functions and limited diaphragmatic movement. Post-operative prolonged air leak is not uncommon following LVRS due to pulmonary emphysema. In some patients with prolonged air leak, pneumoderma may develop. Subconjunctival emphysema is a bizarre and very rarely seen complication. We report a patient suffering from subconjunctival emphysema after an LVRS along with a diagnostic wedge resection for a suspected pulmonary nodule which was revealed to be a large cell neuroendocrine carcinoma. The condition was resolved with conservative management with no visual impairment. He has been doing well and tumour free for 38 months.

NCR negative group 3 innate lymphoid cell (NCR- ILC3) participates in abnormal pathology of lung in cigarette smoking-induced COPD mice.

Natural cytotoxicity receptor negative innate lymphoid cell (NCR- ILC3) involves into mucosal homeostasis, inflammation regulation and tissue remodeling. The proportion of NCR- ILC3 is increased in the lung of smokers with chronic obstructive pulmonary disease (COPD). However, there's still few understandings on the role of NCR- ILC3 in COPD pathogenesis. COPD mice were induced by cigarette smoking. The pathology in lung was detected in histology. The frequency of NCR- ILC3 (CD3-CD45+RORγt+NkP46-) from murine lung was detected using flow cytometry. IL-17+RORγt+ double positive cells in lung were assessed by double immunofluorescence staining. The protein expressions of epithelial-to-mesenchymal transition (EMT) markers, namely E-cadherin and Vimentin, were assessed using immunohistochemistry staining and western blotting. The frequency of NCR- ILC3 in lung was higher in COPD group than controls. The IL-17+RORγt+ cells in lung from COPD mice were more than controls. E-cadherin expression was decreased but Vimentin expression was increased in lung of COPD mice, when compared with controls. The frequency of NCR- ILC3 in lung tissues were positively correlated with mean linear intercept in lung, destructive index in lung and EMT, respectively. NCR- ILC3 could contribute to emphysema and EMT in lung of cigarette smoking-induced COPD, which will provide further understanding on COPD pathogenesis of immune response.

Associations and relative risks of pulmonary hypertension and lung diseases in individuals with methamphetamine use disorder

ObjectiveMethamphetamine causes considerable short- and long-term adverse health effects. Our aim was to assess the effects of methamphetamine use on pulmonary hypertension and lung diseases at the population level. MethodsThis population-based retrospective study used data from the Taiwan National Health Insurance Research Database between 2000 and 2018 that included 18,118 individuals with methamphetamine use disorder (MUD) and 90,590 matched participants of the same age and sex without substance use disorder as the non-exposed group. A conditional logistic regression model was used to estimate associations of methamphetamine use with pulmonary hypertension and lung diseases such as lung abscess, empyema, pneumonia, emphysema, pleurisy, pneumothorax, or pulmonary hemorrhage. Incidence rate ratios (IRRs) of pulmonary hypertension and hospitalization due to lung diseases were determined between the methamphetamine group and non-methamphetamine group using negative binomial regression models. ResultsDuring an 8-year observation period, 32 (0.2%) individuals with MUD and 66 (0.1%) non-methamphetamine participants suffered from pulmonary hypertension, and 2652 (14.6%) individuals with MUD and 6157 (6.8%) non-methamphetamine participants suffered from lung diseases. After adjusting for demographic characteristics and comorbidities, individuals with MUD were 1.78 times (95% confidence interval (CI) = 1.07–2.95) more likely to have pulmonary hypertension and 1.98 times (95% CI = 1.88–2.08) more likely to have a lung disease, especially emphysema, lung abscess, and pneumonia in descending order. Furthermore, compared to the non-methamphetamine group, the methamphetamine group was associated with higher risks of hospitalization caused by pulmonary hypertension and lung diseases. The respective IRRs were 2.79 and 1.67. Individuals with polysubstance use disorder were associated with higher risks of empyema, lung abscess, and pneumonia compared to individuals with MUD alone, with respective adjusted odds ratios of 2.96, 2.21, and 1.67. However, pulmonary hypertension and emphysema did not differ significantly between MUD individuals with or without polysubstance use disorder. ConclusionsIndividuals with MUD were associated with higher risks of pulmonary hypertension and lung diseases. Clinicians need to ensure that a methamphetamine exposure history is obtained as part of the workup for these pulmonary diseases and provide timely management for this contributing factor.

Pulmonary emphysema and coronary artery calcifications at baseline LDCT and long-term mortality in smokers and former smokers of the ITALUNG screening trial

ObjectivesCardiovascular disease (CVD), lung cancer (LC), and respiratory diseases are main causes of death in smokers and former smokers undergoing low-dose computed tomography (LDCT) for LC screening. We assessed whether quantification of pulmonary emphysematous changes at baseline LDCT has a predictive value concerning long-term mortality.MethodsIn this longitudinal study, we assessed pulmonary emphysematous changes with densitometry (volume corrected relative area below − 950 Hounsfield units) and coronary artery calcifications (CAC) with a 0–3 visual scale in baseline LDCT of 524 participants in the ITALUNG trial and analyzed their association with mortality after 13.6 years of follow-up using conventional statistics and a machine learning approach.ResultsPulmonary emphysematous changes were present in 32.3% of subjects and were mild (6% ≤ RA950 ≤ 9%) in 14.9% and moderate-severe (RA950 > 9%) in 17.4%. CAC were present in 67% of subjects (mild in 34.7%, moderate-severe in 32.2%). In the follow-up, 81 (15.4%) subjects died (20 of LC, 28 of other cancers, 15 of CVD, 4 of respiratory disease, and 14 of other conditions). After adjusting for age, sex, smoking history, and CAC, moderate-severe emphysema was significantly associated with overall (OR 2.22; 95CI 1.34–3.70) and CVD (OR 3.66; 95CI 1.21–11.04) mortality. Machine learning showed that RA950 was the best single feature predictive of overall and CVD mortality.ConclusionsModerate-severe pulmonary emphysematous changes are an independent predictor of long-term overall and CVD mortality in subjects participating in LC screening and should be incorporated in the post-test calculation of the individual mortality risk profile.Key Points• Densitometry allows quantification of pulmonary emphysematous changes in low-dose CT examinations for lung cancer screening.• Emphysematous lung density changes are an independent predictor of long-term overall and cardio-vascular disease mortality in smokers and former smokers undergoing screening.• Emphysematous changes quantification should be included in the post-test calculation of the individual mortality risk profile.

Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.

Surgical Etiology of Respiratory Distress in Infant and Short Term Outcome at Benghazi Children Hospital (2017-2018)

Background: Respiratory distress (RD) is a common problem in newborns immediately following birth. It is often seen during the transition from fetal to neonatal life. Aims: This study was conducted to demonstrate the surgical causes of respiratory distress in infants admitted to paediatric surgical department of Benghazi Children Hospital and to describe the short term outcome of the sample. Methodology: A retrospective observational descriptive cross section study was done to achieve the aims of this study. Results: A sample of (50) children admitted with respiratory distress due to congenital anomalies, the age range of the sample was from one day to one year, male were (70%) and females and (30%). Residency (20%) from Benghazi and (80%) from outside Benghazi. Normal delivery was reported in52% of the cases and (48%) C/S, (86%) were born at term and (14%) preterm. The mean weight of the cases was (3.38) (±1.91) kg with minimum of (2) kg and maximum (10) kg. TOF in (52%), diaphragmatic hernia in (40%) and lung emphysema in (8%). Clinical presentation of the cases was mainly with respiratory distress in (84%), while (16%) presented with frothy secretion, ultrasound scan was done to (88%) and was normal. Echocardiogram was normal, atrial septal defect in (16%), ventricular septal defect in (14%), patent ductus arteriosus in (8%). (80%) were operated. Death was recorded in half of the cases. Cases with TOF were in total (26) cases of them (17) died and (9) survived, diaphragmatic hernia cases were (20), of them (12) discharged and (8) died, all cases of congenital lobar emphysema discharged. This association was highly significant Fisher`s (exact=6.9 P=0.005). all preterm neonate died (seven cases) and those who were term were in total (43) of them (25) survived and (18) died, Fisher`s (exact=10.85 P=0.005). Cases who were presented with respiratory distress were in total (42) of them (18) died and (25) discharged, while cases who presented with frothy secretions ....

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study

BackgroundThe association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations.MethodsUsing X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case–control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses.ResultsAmong 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC (beta 0.020, SE 0.004, p 4.97 × 10–08), with suggestive evidence of association with FEV1 (beta 0.092, SE 0.018, p 3.40 × 10–07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions.ConclusionsThis investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology.Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.

Endotyping COPD: hypoxia-inducible factor-2 as a molecular "switch" between the vascular and airway phenotypes?

COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelial Hif-2α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular "switch" between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidases via iron- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets.

Impact of Coronavirus Disease 2019 on Hospital Admissions, Health Status, and Behavioral Changes of Patients with COPD.

Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of acquiring severe coronavirus disease 2019 (COVID-19), which is why self-isolation was recommended. However, long periods of social isolation, accompanied by limited access to health care systems, might influence the outcome of patients with severe COPD negatively. Data from COPD and pneumonia patients at Charité-Universitätsmedizin Berlin and the volume of endoscopic lung volume reduction (ELVR) surgeries from the German Lung Emphysema Registry (Lungenemphysem Register e.V.) were analyzed from pre-pandemic (2012 to 2019) to the pandemic period (2020 and 2021). In addition, 52 patients with COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stage 4 status included in the lung emphysema registry received questionnaires during lockdowns from June 2020 to April 2021. Admissions and ventilation therapies administered to COPD patients significantly decreased during the COVID-19 pandemic. Likewise, there was a reduction in ELVR treatments and follow-ups registered in German emphysema centers. Mortality was slightly higher among patients hospitalized with COPD during the pandemic. Increasing proportions of COPD patients with GOLD stage 3 and GOLD stage 4 status reported behavioral changes and subjective feelings of increasing COPD symptoms the longer the lockdown lasted. However, COPD symptom questionnaires revealed stable COPD symptoms over the pandemic time period. This study reveals reduced COPD admissions and elective treatment procedures of COPD patients during the pandemic, but a slight increase in mortality among patients hospitalized with COPD, irrespective of COVID-19. Correspondingly, patients with severe COPD reported subjective deterioration of their health status, probably caused by their very strict compliance with lockdown measures.

Development of Inhalable Spray Dried Nitrofurantoin Formulations for the Treatment of Emphysema

A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm; FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production.

INOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.

Lung Cancer Screening Using Clinical Photon-Counting Detector Computed Tomography and Energy-Integrating-Detector Computed Tomography: A Prospective Patient Study.

To evaluate the diagnostic quality of photon-counting detector (PCD) computed tomography (CT) in patients undergoing lung cancer screening compared with conventional energy-integrating detector (EID) CT in a prospective multireader study. Patients undergoing lung cancer screening with conventional EID-CT were prospectively enrolled and scanned on a PCD-CT system using similar automatic exposure control settings and reconstruction kernels. Three thoracic radiologists blinded to CT system compared PCD-CT and EID-CT images and scored examinations using a 5-point Likert comparison score (-2 [left image is worse] to +2 [left image is better]) for artifacts, sharpness, image noise, diagnostic image quality, emphysema visualization, and lung nodule evaluation focusing on the border. Post hoc correction of Likert scores was performed such that they reflected PCD-CT performance in comparison to EID-CT. A nonreader radiologist measured objective image noise. Thirty-three patients (mean, 66.9 ± 5.6 years; 11 female; body mass index; 30.1 ± 5.1 kg/m 2 ) were enrolled. Mean volume CT dose index for PCD-CT was lower (0.61 ± 0.21 vs 0.73 ± 0.22; P < 0.001). Pooled reader results showed significant differences between imaging modalities for all comparative rankings ( P < 0.001), with PCD-CT favored for sharpness, image noise, image quality, and emphysema visualization and lung nodule border, but not artifacts. Photon-counting detector CT had significantly lower image noise (74.4 ± 10.5 HU vs 80.1 ± 8.6 HU; P = 0.048). Photon-counting detector CT with similar acquisition and reconstruction settings demonstrated improved image quality and less noise despite lower radiation dose, with improved ability to depict pulmonary emphysema and lung nodule borders compared with EID-CT at low-dose lung cancer CT screening.

The importance of volumetric CT assessment of lung emphysema in COPD patients

The importance of volumetric CT assessment of lung emphysema in COPD patients

Whole-body analysis of TRPML3 (MCOLN3) expression using a GFP-reporter mouse model reveals widespread expression in secretory cells and endocrine glands.

TRPML3 (mucolipin 3, MCOLN3) is an endolysosomal cation channel belonging to the TRPML subfamily of transient receptor potential channels. Gain-of-function mutations in the Trpml3 gene cause deafness, circling behavior and coat color dilution in mice due to cell death of TRPML3-expressing hair cells of the inner ear or skin melanocytes, respectively. Furthermore, TRPML3 was found to play a role in the long term survival of cochlear hair cells (its absence contributing to presbycusis), in specialized giant lysosomes that neonatal (birth to weaning) enterocytes used for the uptake and digestion of maternal milk nutrients, and in the expulsion of exosome-encased bacteria such as uropathogenic E. coli, infecting bladder epithelial cells. Recently, TRPML3 was found to be expressed at high levels in alveolar macrophages and loss of TRPML3 results in a lung emphysema phenotype, confirmed in two independently engineered Trpml3 knockout lines. TRPML3 is not ubiquitously expressed like its relative TRPML1 and thus cellular expression of TRPML3 on a whole-tissue level remains, with the exceptions mentioned above, largely elusive. To overcome this problem, we generated a τGFP reporter mouse model for TRPML3 and compared expression data obtained from this model by immunofluorescence on tissue sections with immunohistochemistry using TRPML3 antibodies and in situ hybridization. We thus uncovered expression in several organs and distinct cell types. We confirmed TRPML3 expression in both neonatal and adult alveolar macrophages, in melanocytes of hair follicles and glabrous skin, in principle cells of the collecting duct of the neonatal and adult kidney, and in olfactory sensory neurons of the olfactory epithelium, including its fibres protruding to the glomeruli of the olfactory bulb. Additionally, we localized TRPML3 in several glands including parathyroid, thyroid, salivary, adrenal, and pituitary gland, testes and ovaries, suggestive of potential roles for the channel in secretion or uptake of different hormones.

Standardised Sonneratia apetala Buch.-Ham. fruit extract inhibits human neutrophil elastase and attenuates elastase-induced lung injury in mice.

Chronic obstructive pulmonary disease (COPD) along with asthma is a major and increasing global health problem. Smoking contributes to about 80%-90% of total COPD cases in the world. COPD leads to the narrowing of small airways and destruction of lung tissue leading to emphysema primarily caused by neutrophil elastase. Neutrophil elastase plays an important role in disease progression in COPD patients and has emerged as an important target for drug discovery. Sonneratia apetala Buch.-Ham. is a mangrove plant belonging to family Sonneratiaceae. It is widely found in the Sundarban regions of India. While the fruits of this plant have antibacterial, antifungal, antioxidant and astringent activities, fruit and leaf extracts have been shown to reduce the symptoms of asthma and cough. The aim of this study is to find whether hydro alcoholic fruit extracts of S. apetala inhibit neutrophil elastase and thus prevent the progression of neutrophil elastase-driven lung emphysema. The hydroalcoholic extract, ethanol: water (90:10), of the S. apetala Buch.-Ham. fresh fruits (SAM) were used for neutrophil elastase enzyme kinetic assay and IC50 of the extract was determined. The novel HPLC method has been developed and the extract was standardized with gallic acid and ellagic acid as standards. The extract was further subjected to LC-MS2 profiling to identify key phytochemicals. The standardized SAM extract contains 53μg/mg of gallic acid and 95μg/mg of ellagic acid, based on the HPLC calibration curve. SAM also reversed the elastase-induced morphological change of human epithelial cells and prevented the release of ICAM-1 in vitro and an MTT assay was conducted to assess the viability. Further, 10mg/kg SAM had reduced alveolar collapse induced by neutrophil elastase in the mice model. Thus, in this study, we reported for the first time that S. apetala fruit extract has the potential to inhibit human neutrophil elastase in vitro and in vivo.

Correlation of lung function with ultra-low-dose CT-detected lung parenchymal abnormalities: a cohort study of 1344 asbestos exposed individuals

IntroductionDeliberate exposure to medical ionising radiation should be as low as reasonably practicable but the reduction of radiation from CT should be balanced against diagnostic image quality. The ability of...

Robotic free pericardial fat pledget technique for treating pulmonary air leak.

There is no clear evidence for the ideal technique for treating intraoperative air leak. A previous study showed that the VIO soft-coagulation system (VIO 300D system; Erbe Elektromedizin) is useful for minor air leaks, as the automatically adjusted voltage output does so without causing sparks or tissue carbonization, resulting in covering the pulmonary fistula with a fibrin membrane.1 Although suturing is required to treat deeper lung injuries, simple suturing of emphysematous lungs may induce further lung injury.