Adipose-derived mesenchymal stem cells protects renal function in a rat model of emphysema.

BACKGROUND AND OBJECTIVE: The link between lung disease and kidney disorders has already been confirmed. Previous studies have documented that obstructive pulmonary disease is an independent predictor of decreased renal function, which reduces glomerular filtration rate. Recently, mesenchymal stem cells are the most important cell used in cell therapy. Accordingly, the present experiment was designed to evaluate the efficacy of adipose-derived mesenchymal stem cells (AMSCs) on improvement of renal function in elastase induced-pulmonary emphysema rats. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats divided into the 3 groups. Following intra-tracheal administration of elastase, the in vivo emphysema model established and confirmed according to the specific markers. Subsequently, systemic AMSCs injection was developed. the kidney injuries markers such as Blood urea nitrogen (BUN), creatinine, sodium and potassium as well as the kidney histopathologic parameters were assessed in all groups. Moreover, the oxidative stress markers levels including Malondialdehyde (MDA), Total antioxidant capacity (TAC), Catalase (CAT) and Glutathione peroxidase (GPx) were measured in kidney tissue and also inflammatory cytokines including IL-10, IL-6, and IFN-Ƴ were assessed in serum samples. RESULTS: The marked rise in kidney injuries markers were observed which showed by enhancement of BUN and Creatinine levels in emphysema rats compared to the control. Furthermore, the results demonstrated increases in MDA levels and decreases in antioxidant activity which was in line with increases in inflammation cytokines in renal tissue. Conversely, AMSCs treatment improved renal function as shown by the decreases BUN, Creatinine and proteinuria. Furthermore, renal histological assay demonstrate improvement in glomerular and tubular damage and inflammatory cells accumulation. CONCLUSIONS: Our results documented the promising kidney-protective properties of Adipose-Derived Mesenchymal Stem Cells in the kidney injuries induced by emphysema.

Exposure to total particulate matter obtained from combustion of diesel vehicles (EURO 3 and EURO 5): Effects on the respiratory systems of emphysematous mice.

Air pollution has association with chronic obstructive pulmonary disease (COPD) and reduced life expectancy. This study investigated the deleterious effects caused by tobacco smoke and diesel exhaust particles (DEP) from vehicles operating under EURO 3 and EURO 5 standards. Experiments were carried out on C57BL/6 mice divided into six groups: control group, group exposed to cigarette smoke (CS), two groups exposed to DEP (AAE3 and AAE5), and two groups exposed to tobacco smoke and vehicle DEP (CSE3 and CSE5). Results showed that, when compared to AA, groups AAE3 and AAE5 showed changes in respiratory mechanics, and that DEP originating from EURO 5 diesel vehicles was less harmful when compared to DEP originating from EURO 3 diesel vehicles. Analyses of groups CSE3 and CSE5 revealed increased inspiratory capacity and decreased tissue elastance, when compared to their respective controls, suggesting an exacerbation of changes in respiratory system mechanics compatible with COPD development.

In Silico Ventilation Within the Dose-Volume is Predictive of Lung Function Post-radiation Therapy in Patients with Lung Cancer.

Lung cancer is a leading cause of death worldwide. Radiation therapy (RT) is one method to treat this disease. A common side effect of RT for lung cancer is radiation-induced lung damage (RILD) which leads to loss of lung function. RILD often compounds pre-existing smoking-related regional lung function impairment. It is difficult to predict patient outcomes due to large variability in individual response to RT. In this study, the capability of image-based modelling of regional ventilation in lung cancer patients to predict lung function post-RT was investigated. Twenty-five patient-based models were created using CT images to define the airway geometry, size and location of tumour, and distribution of emphysema. Simulated ventilation within the 20 Gy isodose volume showed a statistically significant negative correlation with the change in forced expiratory volume in 1 s 12-months post-RT (p = 0.001, R = - 0.61). Patients with higher simulated ventilation within the 20 Gy isodose volume had a greater loss in lung function post-RT and vice versa. This relationship was only evident with the combined impact of tumour and emphysema, with the location of the emphysema relative to the dose-volume being important. Our results suggest that model-based ventilation measures can be used in the prediction of patient lung function post-RT.

Use of Hyaluronic Acid (HA) in Chronic Airway Diseases.

Hyaluronic acid (HA) is a key component of the extracellular matrix of the lungs. A unique attribute of HA is its water-retaining properties, so HA has a major role in the regulation of fluid balance in the lung interstitium. Hyaluronic acid has been widely used in the treatment of eyes, ears, joints and skin disorders, but in the last years, it has been also proposed in the treatment of certain lung diseases, including airway diseases, due to its anti-inflammatory and water-binding capacities. Hyaluronic acid aerosol decreases the severity of elastase-induced emphysema in murine models, prevents bronchoconstriction in asthmatics and improves some functional parameters in chronic obstructive pulmonary disease (COPD) patients. Due to the protection of HA against bronchoconstriction and its hydration properties, inhaled HA would increase the volume of airway surface liquid, resulting in mucus hydration, increased mucous transport and less mucous plugging of the airways. In addition, it has been seen in human studies that the treatment with nebulised HA improves the tolerability of nebulised hypertonic saline (even at 6% or 7% of concentration), which has been demonstrated to be an effective treatment in bronchial secretion management in patients with cystic fibrosis and bronchiectasis. Our objective is to review the role of HA treatment in the management of chronic airway diseases.

Comparative analysis of pathophysiological parameters between emphysematous smokers and emphysematous patients with COPD.

Emphysematous smokers with normal spirometry form a considerable proportion of the clinical population. However, despite presenting with respiratory symptoms and activity limitation, they cannot be diagnosed with chronic obstructive lung disease (COPD) according to current criteria. Thus, we aimed to determine whether emphysema in smokers has a different pathogenesis from that in patients with COPD. We compared 12 pairs of lung tissue samples from emphysematous patients with normal spirometry and COPD, and determined the degree of emphysema using computed tomography. With a focus on COPD-related pathogenesis, we independently assessed inflammatory response, protease-antiprotease balance, oxidative stress, and apoptosis in both groups. Both groups showed similar pathological changes at a comparable degree of emphysema; the expression of inflammatory factors was comparable, with overexpression of proteases and decreased levels of antiproteases. Moreover, there was no significant difference in the activities of glutathione and superoxide dismutase, and expression of apoptosis-related factors. In conclusion, emphysema in smokers with normal spirometry and in patients with COPD had similar pathogenesis. Forced expiratory volume in 1 second cannot be used as the sole diagnostic criterion in patients with COPD; early intervention is of great importance to such patients.

Quantitative Emphysema Measurement On Ultra-High-Resolution CT Scans.

Purpose: To evaluate the advantages of ultra-high-resolution computed tomography (U-HRCT) scans for the quantitative measurement of emphysematous lesions over conventional HRCT scans. Materials and methods: This study included 32 smokers under routine clinical care who underwent chest CT performed by a U-HRCT scanner. Chronic obstructive pulmonary disease (COPD) was diagnosed in 13 of the 32 participants. Scan data were reconstructed by 2 different protocols: i) U-HRCT mode with a 1024×1024 matrix and 0.25-mm slice thickness and ii) conventional HRCT mode with a 512×512 matrix and 0.5-mm slice thickness. On both types of scans, lesions of emphysema were quantitatively assessed as percentage of low attenuation volume (LAV%, <-950 Hounsfield units). LAV% values determined for scan data from the U-HRCT and conventional HRCT modes were compared by the Wilcoxon matched-pairs signed rank test. The association between LAV% and forced expiratory volume in 1 s per forced vital capacity (FEV1/FVC) was assessed by the Spearman rank correlation test. Results: Mean values for LAV% determined for the U-HRCT and conventional HRCT modes were 8.9 ± 8.8% and 7.3 ± 8.4%, respectively (P<0.0001). The correlation coefficients for LAV% and FEV1/FVC on the U-HRCT and conventional HRCT modes were 0.50 and 0.49, respectively (both P<0.01). Conclusion: Compared with conventional HRCT scans, U-HRCT scans reveal emphysematous lesions in greater detail, and provide slightly increased correlation with airflow limitation.

Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice.

Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16-/- mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16-/- mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.

Spirometric assessment of emphysema presence and severity as measured by quantitative CT and CT-based radiomics in COPD.

BACKGROUND: The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics. METHODS: We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below - 950 Hounsfield Units (%LAA-950insp) patients were classified as having no emphysema (NE) with %LAA-950insp < 6, moderate emphysema (ME) with %LAA-950insp ≥ 6 and < 14, and severe emphysema (SE) with %LAA-950insp ≥ 14. We also obtained stratified clusters of emphysema CT features by an automated unsupervised radiomics approach (CALIPER). An emphysema severity index (ESI), derived from mathematical modeling of the maximum expiratory flow-volume curve descending limb, was compared with pulmonary function data and the three CT classifications of emphysema presence and severity as derived from CT metrics and radiomics. RESULTS: ESI mean values and pulmonary function data differed significantly in the subgroups with different emphysema degree classified by VIDA, ImbioLDA and CALIPER (p < 0.001 by ANOVA). ESI differentiated NE from ME/SE CT-classified patients (sensitivity 0.80, specificity 0.85, AUC 0.86) and SE from ME CT-classified patients (sensitivity 0.82, specificity 0.87, AUC 0.88). CONCLUSIONS: Presence and severity of emphysema in patients with COPD, as quantified by CT metrics and radiomics can be estimated by mathematical modeling of airway function as derived from standard spirometry.

Non-inflammatory emphysema induced by NO2 chronic exposure and intervention with demethylation 5-Azacytidine.

AIMS: A rat model of emphysema was established that mimics the features of the human emphysema subtype and explores the effects of demethylation on lung function and blood tests. MATERIALS AND METHODS: Rats were randomly assigned to NO2, NO2 + 5-Azacytidine, and normal air groups based on a emphysema rat model induced by chronic NO2 exposure. This study estimates the characteristics of emphysema by conducting an analysis for IL-6 and TNF-α levels in bronchoalveolar lavage fluids (BALF) and plasma. Furthermore, CD68 macrophage immunofluorescent staining and inflammatory cell counts in BALF were compared between rats exposed to NO2 and normal air. KEY FINDINGS: 5-Azacytidine treatment led to restored ∆weight at 14 and 75 days of intervention and NO2 + 5-Azacytidine significantly reversed the effect of NO2 exposure on ∆weight. Intervention with 5-Azacytidine alleviated the decline of pulmonary function with a significant increase in FEV100/FVC% at 75 days in NO2 + 5-Azacytidine rats compared to NO2 rats. 5-Azacytidine reduced the counts of white blood cells (WBCs), granulocytes, lymphocytes, and monocytes at 14 days, but increased WBC, granulocyte, and monocyte counts at 45 days. Red blood cell counts, hemoglobin, and hematocrit concentrations were significantly reduced in NO2 + 5-Azacytidine rats. SIGNIFICANCE: This non-inflammatory rat emphysema model (induced by chronic NO2 exposure with global DNA hypomethylation and demethylation therapy with 5-Azacytidine) effectively improved emphysema by alleviating the decline of lung function and hypoxia, and slightly reinforced immune function. These results indicate the therapeutic potential of demethylation agents for the prevention and treatment of emphysema induced by the air pollutant NO2.

RAGE is a Critical Mediator of Pulmonary Oxidative Stress, Alveolar Macrophage Activation and Emphysema in Response to Cigarette Smoke.

The receptor for advanced glycation end products (RAGE), a cell membrane receptor, recognizes ligands produced by cigarette smoke (CS) and has been implicated in the pathogenesis of COPD. We demonstrate that deletion or pharmacologic inhibition of RAGE prevents development of CS-induced emphysema. To identify molecular pathways by which RAGE mediates smoking related lung injury we performed unbiased gene expression profiling of alveolar macrophages (AM) obtained from RAGE null and C57BL/6 WT mice exposed to CS for one week or four months. Pathway analysis of RNA expression identified a number of genes integral to the pathogenesis of COPD impacted by the absence of RAGE. Altered expression of antioxidant response genes and lung protein 4-HNE immunostaining suggest attenuated oxidative stress in the RAGE null mice despite comparable CS exposure and lung leukocyte burden as the WT mice. Reduced endoplasmic reticulum stress in response to CS exposure also was observed in the AM from RAGE null mice. These findings provide novel insight into the sources of oxidative stress, macrophage activation, and the pathogenesis of lung disease due to CS exposure.

The importance of pathophysiology to the understanding of functional limitations in the bioarchaeology of care approach.

This article presents a partial bioarchaeology of care case study of a mummified adult female with chronic obstructive pulmonary disease (COPD) from late historic period United States. It examines likely clinical and functional impacts of disease and corresponding need for provision of care, stopping short of Stage 4 Interpretation/analysis. The case study illustrates and argues for the importance of an interdisciplinary research team for achieving a comprehensive understanding of disability and care. The article highlights the necessity of knowledge of pathophysiology for identifying the potential interventions (supports) dictated by the associated functional limitations. inter alia, this case is a powerful illustration of the way analysis of preserved soft tissue can provide insights into disease and likely care that are inaccessible using skeletal analysis alone. The article represents an interesting contribution to the theory and methodology of both the bioarchaeology of care approach and mummy studies.

[Favorable evolution after medical treatment in three cases of emphysematous pyelonephritis: about 3 cases]. / La pyélonéphrite emphysémateuse à évolution favorable après traitement médical: à propos de 3 observations.

Emphysematous pyelonephritis is a necrotic infection of the kidney characterized by the presence of gas within the renal parenchyma, the secretory cavities or the perirenal spaces. It is a severe condition that could be life-threatening. Patient's management remains controversial and is based either on surgery or on medical treatment. Percutaneous drainage can be also used for the treatment of these patients. We report 3 cases with EPN treated with only antibiotics. Patients' evolution was favorable. These results show that medical treatment could be sufficient.

Nrf2 attenuates inflammatory response in COPD/emphysema: Crosstalk with Wnt3a/ß-catenin and AMPK pathways.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and abnormal inflammatory response. Wnt/ß-catenin and AMP-activated protein kinase (AMPK) have been shown to modulate lung inflammatory responses and injury. However, it remains elusive whether Wnt/ß-catenin and AMPK modulate nuclear factor erythroid-2 related factor-2 (Nrf2)-mediated protective responses during the development of emphysema. Here we showed that treatment with a Wnt pathway activator (LiCl) reduced elastase-induced airspace enlargement and cigarette smoke extract (CSE)-induced lung inflammatory responses in WT mice, which was associated with increased activation of Nrf2 pathway. Interestingly, these effects of LiCl were not observed in Nrf2-/- mice exposed to elastase. In normal human bronchial epithelial (NHBE) cells, Wnt3a overexpression up-regulated, whereas Wnt3a knockdown further down-regulated the levels of Nrf2 and its target proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by CSE treatment. In contrast, Nrf2 deficiency did not have any effects on Wnt/ß-catenin pathway in mouse lungs and NHBE cells. Both elastase and CSE exposures reduced AMPK phosphorylation. A specific AMPK activator metformin increased Wnt3a, ß-catenin, Nrf2 phosphorylation and activation but reduced the levels of IL-6 and IL-8 in NHBE cells and mouse lungs exposed to CSE. Furthermore, Nrf2 deficiency abolished the protection of metformin against CSE-induced increase in IL-6 and IL-8 in NHBE cells. In conclusion, Nrf2 mediates the protective effects of both Wnt3a/ß-catenin and AMPK on lung inflammatory responses during the development of COPD/emphysema. These findings provide potential therapeutic targets for the intervention of COPD/emphysema.

Heteropolymerization of α-1-antitrypsin mutants in cell models mimicking heterozygosity.

The most common genotype associated with severe α-1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α-1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M. However, it is unknown whether Z AAT can co-polymerize with other AAT variants in vivo. We co-expressed two AAT variants, each modified by a different tag, in cell models that replicate AAT deficiency. We used pull-down assays to investigate interactions between co-expressed variants and showed that Z AAT forms heteropolymers with S and with the rare Mmalton (Phe52del) and Mwurzburg (Pro369Ser) mutants, and to a lesser extent with the wild-type protein. Heteropolymers were recognized by the 2C1 mAb that binds to Z polymers in vivo. There was increased intracellular accumulation of AAT variants when co-expressed with Z AAT, suggesting a dominant negative effect of the Z allele. The molecular interactions between S and Z AAT were confirmed by confocal microscopy showing their colocalization within dilated ER cisternae and by positivity in Proximity Ligation Assays. These results provide the first evidence of intracellular co-polymerization of AAT mutants and contribute to understanding the risk of liver disease in SZ and MZ heterozygotes.

The cytoprotective role of DJ-1 and p45 NFE2 against human primary alveolar type II cell injury and emphysema.

Emphysema is characterized by irreversibly enlarged airspaces and destruction of alveolar walls. One of the factors contributing to this disease pathogenesis is an elevation in extracellular matrix (ECM) degradation in the lung. Alveolar type II (ATII) cells produce and secrete pulmonary surfactants and proliferate to restore the epithelium after damage. We isolated ATII cells from control non-smokers, smokers and patients with emphysema to determine the role of NFE2 (nuclear factor, erythroid-derived 2). NFE2 is a heterodimer composed of two subunits, a 45 kDa (p45 NFE2) and 18 kDa (p18 NFE2) polypeptides. Low expression of p45 NFE2 in patients with emphysema correlated with a high ECM degradation. Moreover, we found that NFE2 knockdown increased cell death induced by cigarette smoke extract. We also studied the cross talk between p45 NFE2 and DJ-1. DJ-1 protein is a redox-sensitive chaperone that protects cells from oxidative stress. We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis.

Does the presence of emphysema increase the risk of radiation pneumonitis in lung cancer patients?

Introduction: Radiotherapy (rt) plays an important role in the treatment of lung cancer. One of the most common comorbidities in patients with lung cancer is pulmonary emphysema. The literature offers conflicting data about whether emphysema increases the occurrence and severity of radiation pneumonitis (rp). As a result, whether high doses of rt (with curative intent) should be avoided in patients with emphysema is still unclear. Objective: We measured the documented incidence of rp in patients with and without emphysema who received curative radiation treatment. Methods: This retrospective cohort study considered patients in the lung cancer clinical database of the Peter Brojde Lung Cancer Centre. Data from the database has been used previously for research studies, including a recent publication about emphysema grading, based on the percentage of lung occupied by emphysema on computed tomography (ct) imaging. Results: Using previously published methods, chest ct imaging for 498 patients with lung cancer was scored for the presence of emphysema. The analysis considered 114 patients who received at least 30 Gy radiation. Of those 114 patients, 64 (56%) had emphysema, with approximately 23% having severe or very severe disease. The incidence of rp was 34.4% in patients with emphysema (n = 22) and 32.0% in patients with no emphysema (n = 16, p = 0.48). No difference in the incidence of rp was evident between patients with various grades of emphysema (p = 0.96). Similarly, no difference in the incidence of rp was evident between the two treatment protocols-that is, definitive rt 17 (37%) and combined chemotherapy-rt 21 (31%, p = 0.5). Conclusions: In our cohort, the presence of emphysema on chest ct imaging was not associated with an increased risk of rp. That finding suggests that patients with lung cancer and emphysema should be offered rt when clinically indicated. However, further prospective studies will be needed for confirmation.