Treatment Of Emphysema Research Articles

Multicentre European study for the treatment of advanced emphysema with bronchial valves

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p<0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.

Abstract 313: The Nuclear Liver X Receptor as a Potential Regulator of Interleukin 18 Binding Protein in the Lung

Background and Objectives: Second hand smoke (SHS) is a major risk factor for development of chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis in non-smokers. The role of liver X receptor (LXR) in the pathogenesis of COPD/emphysema is not well understood. Both LXR and LXR were found in the lung. The alpha isoform is involved in the regulation of lipid metabolism whereas the beta isoform is involved in the regulation of inflammation. Here we investigate the effects of cigarette smoke (CS) on LXR activation as well as target gene and protein regulation in vivo and in vitro . Methods: Sprague Dawley rats were exposed to SHS for 2 months. Lung tissue and bronchoalveolar lavage fluid (BALf) cells were examined for LXR gene expression and emphysema development (measured by mean linear intercept). Rat alveolar macrophages (AM) and rat pulmonary microvascular endothelial cells (RPMVEC) were treated with cigarette smoke extract (CSE), LPS or DMHCA, a steroidal LXR agonist) in vitro and changes in LXR and its target gene and protein expression were examined. Results: LXR gene expression was impaired and the expression of the LXR target gene, ATP binding cassette transporter A1 (ABCA1), was significantly downregulated in BALf cells from SHS-exposed rat lungs and in rat AM treated with CSE. Real-time PCR revealed significant downregulation of LXR and upregulation of LXR in BALf cells after 1 month of SHS exposure. Similar changes were also observed in CSE-treated RPMVEC. There was a significant increase in the pro-inflammatory interleukin 18 (IL18) levels in BALf cells of SHS-exposed rats, whereas the levels of IL18 binding protein (IL18bp), an endogenous inhibitor of IL18, remained unchanged. Interestingly, activation of LXR led to upregulation of IL18bp in AM and peritoneal macrophages where potential LXR response element (LXRE) sites were indentified, in silico , in the promoter region of IL18bp. Additionally, emphysematous changes and foamy macrophage accumulation were observed in lungs of LXR-deficient mice. Conclusions: These findings implicate IL18bp as a new LXR target gene involved in the anti-inflammatory signaling pathway. Our data suggest that LXR agonist treatment may be beneficial in the prevention and treatment of CS-induced emphysema.

Emphysema lung lobe volume reduction: effects on the ipsilateral and contralateral lobes

To investigate volumetric and density changes in the ipsilateral and contralateral lobes following volume reduction of an emphysematous target lobe. The study included 289 subjects with heterogeneous emphysema, who underwent bronchoscopic volume reduction of the most diseased lobe with endobronchial valves and 132 untreated controls. Lobar volume and low-attenuation relative area (RA) changes post-procedure were measured from computed tomography images. Regression analysis (Spearman's rho) was performed to test the association between change in the target lobe volume and changes in volume and density variables in the other lobes. The target lobe volume at full inspiration in the treatment group had a mean reduction of -0.45 L (SE = 0.034, P < 0.0001), and was associated with volume increases in the ipsilateral lobe (rho = -0.68, P < 0.0001) and contralateral lung (rho = -0.16, P = 0.006), and overall reductions in expiratory RA (rho = 0.31, P < 0.0001) and residual volume (RV)/total lung capacity (TLC) (rho = 0.13, P = 0.03). When the volume of an emphysematous target lobe is reduced, the volume is redistributed primarily to the ipsilateral lobe, with an overall reduction. Image-based changes in lobar volumes and densities indicate that target lobe volume reduction is associated with statistically significant overall reductions in air trapping, consistent with expansion of the healthier lung. Computed tomography allows assessment of the treatment of emphysema with endobronchial valves. • Endobronchial valves can reduce the volume of an emphysematous lung lobe. • Compensatory expansion is greater in ipsilateral lobes than in the contralateral lung. • Reduced air trapping is measurable by RV/TLC and smaller low attenuation area.

Alpha-1-antitrypsin and other proteinase inhibitors

Since the end of the 1980s augmentation therapy with alpha-1 antitrypsin (AAT) from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has demonstrated to be safe and weekly infusions of AAT have demonstrated to result in plasma AAT concentration above those considered protective for the lungs. Randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy. This is the first example of an antiprotease effective in restoring the protease/antiprotease imbalance in the lungs and changing the natural history of congenital emphysema. On the basis of the results obtained with the long-term infusion of AAT, there is growing interest in the possible use of antiprotease treatment in patients with smokers COPD. However, no drugs are yet available to increase antiprotease protection of the lower airways of smokers.

Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

Respiratory Review of 2012: Bronchoscopic Innovations and Advances

Recent advances in bronchoscopy have led to changes in clinical diagnostics and therapeutics in pulmonary medicine. In diagnostic bronchoscopy, there have also been new developments in endobronchial ultrasound technology which may be incorporated into clinical practice in the near future. Functional bronchoscopy, which evaluates information such as airway pressure, airflow, or gas exchange, suggests promising clinical advances in the near future. In therapeutic bronchoscopy, bronchoscopic volume reduction is a novel approach for the treatment of severe emphysema. In this review, seven recently published articles representing current advances in bronchoscopy are summarized and discussed.

Characterization of outcomes 1 year after endoscopic thermal vapor ablation for patients with heterogeneous emphysema

IntroductionEndoscopic lung volume reduction has been developed as a therapeutic option for advanced emphysema. Six-month results following treatment with endoscopic thermal vapor ablation (InterVapor™; Uptake Medical, Tustin, CA) were described previously, and here we report observations from the 12-month assessment.MethodsTwo multicenter, international, single-arm trials of InterVapor (unilateral upper lobe treatment) in patients with upper lobe predominant emphysema were conducted. Inclusion criteria: forced expiratory volume in 1 second (FEV1) 15%–45% predicted, residual volume > 150%, total lung capacity > 100%, 6-minute walk distance (6MWD) >140 m, and diffusing capacity for carbon monoxide > 20% predicted. Efficacy endpoints: spirometry, body plethysmography, lung volumes by high-resolution computed tomography, St George’s Respiratory Questionnaire, modified Medical Research Council dyspnea scale, and 6MWD. All adverse events were collected and independently adjudicated.ResultsForty four patients were treated at a mean (standard deviation) age of 63 (5.6) years, FEV1 0.86 mL (0.25 mL) (n = 22 men and 22 women). Mean (standard deviation) changes from baseline at 12 months were: FEV1 86.2 mL (173.8 mL), St George’s Respiratory Questionnaire −11.0 (14.0) units, treated lobar volume from high-resolution computed tomography −751.8 mL (653.9 mL), residual volume −302.8 mL (775.6 mL), 6MWD 18.5 m (63.7 m), and modified Medical Research Council dyspnea scale score −0.83 (0.97) (P < 0.05 for all except 6MWD). Improvements were numerically larger at 6 versus 12 months. GOLD stage III and IV patients had similar outcomes at 6 months; however, improvements relative to baseline were numerically higher in GOLD stage IV patients. Larger improvements were observed in patients with higher heterogeneity. In total, 39 serious adverse events were reported in 23 patients with 10 events in 8 patients between 6 and 12 months.ConclusionUnilateral lobar InterVapor treatment of heterogeneous emphysema improved lung function and health outcomes 1 year following treatment. The magnitude of improvement was larger at 6 months compared to 12 months. Improvements relative to baseline continue to be exhibited at 12 months despite the expected disease related decline over time.Clinical trialsNCT 01041586 and NCT 01102712

Video-Assisted Approach Combined with the Open Brompton Technique for Intracavitary Drainage of Giant Bullae

The modified Monaldi procedure represents a nonexcisional treatment option for patients with giant bullous emphysema as an alternative to bullectomy. We want to highlight its role in the surgical treatment of emphysema and discuss changes made to the open-access Brompton approach through introduction of video-assisted thoracic surgical technique.

Effects of allogeneic mesenchymal stem cells in experimental treatment of pulmonary emphysema

The aim of the study was to asses morphologic and morphometric lung tissue changes and peritoneal macrophages activity (MA) after allogeneic mesenchymal stem cells (MSCs) systemic transplantation in acute elastase model of pulmonary emphysema(PE) in rats.&#x0D; Methods: Forty Wistar rats, 3-months old, were randomized into 4 groups. Control group (1 group) was injected intratracheally 0,4 ml of normal saline, other animals (2-4 groups) received one intratracheal injection of 20 units (U) porcine pancreatic elastase in 0,4 ml of saline. Next day (3 group) and 7 day (4 group) rats were intravenously injected 2 x 106 autologous MSCs in 0,5 ml of saline. 2 group was used as emphysema control. Before euthanizing at the 21* day rats were undergone peritoneal lavage with analysis of hemi-luminescent macrophages activity in the obtained fluid.&#x0D; Results: the lungs of 2-4 groups had various degrees of PE. The width of alveolar ducts (VAD) in group 2 experimental emphysema increased by 231% versus the control group. The transplantation of MSCs in a day after elastase decreased VAD by an average of 50.3% compared to the control of experimental emphysema. In animals MSCs injected at the 7th day of study, this sizes decreased more greater - by 64,5%, but was higher by 40.7% compared to the first control group. Another quantitative measure of PE - alveolar index - was significantly increased by 149% in group 2 compared to control. The transplantation of MSCs at 1st and 7th day of experiment leaded to alveolar index decreasing, respectively on 163.4 and 237% . The peak Index of hemi-luminescent macrophages activity (Mv/106 cells) was 28,8+1,1 (1 group), 57,3 +1,3 (2 group), 35,8+1,6 (3 group), 31,9+1,9 (4 group).&#x0D; Conclusions: our study confirmed the possibility of regenerative lung tissue effect of autologous MSCs intravenous injected in experimental rat models of PE.

The National Emphysema Treatment Trial (NETT)

Substantial information regarding the role of lung volume reduction surgery (LVRS) in severe emphysema emanates from the National Emphysema Treatment Trial (NETT). The NETT was not a crossover trial and therefore was able to examine the effects of optimal medical management and LVRS on short- and long-term survival,as well as lung function, exercise performance, and quality of life.The NETT generated multiple insights into the preoperative, perioperative,and postoperative management of patients undergoing thoracotomy; described pain control techniques that were safe and effective; and emphasized the need to address nonpulmonary issues to optimize surgical outcomes. After the NETT, newer investigation has focused on bronchoscopic endobronchial interventions and other techniques less invasive than LVRS to achieve lung reduction.In this review, we summarize what we currently know about the role of LVRS in the treatment of severe emphysema as a result of insights gained from the NETT and provide a brief review of the newer techniques of lung volume reduction.

Decreases in Bone Mineral Content by Dietary All-Trans Retinoic Acid Precede Decreases in Bone Mineral Density in a Weanling Rat Model of Cigarette Smoke - Induced Lung Injuries

Research has indicated that excessive vitamin A can have deleterious impacts on bone. Retinoic acid (RA), the most active metabolite of vitamin A, has been tested in clinical trials for treatment of lung cancer and emphysema. These trials are not measuring Bone Mineral Content (BMC) or Bone Mineral Density (BMD). In this study, we used an animal model to determine potential deleterious effects of all-trans RA on bone mass when used as a means to protect against or treat cigarette smoke-induced lung injuries, and also to evaluate BMC as a potential early indicator of osteoporosis risk. Twenty-four male weanling rats were fed either a control diet or a RA-supplemented diet. Half of each group was exposed to 40 cigarettes per day, 5 days per week, for 4 weeks. BMC and BMD were measured at weeks 2 and 4. RA supplementation in all groups significantly decreased (p < 0.05) only BMC at week 2 and both BMC and BMD (both p < 0.05) at week 4. The same results were observed when BMC was expressed relative to body weight. These data suggest that caution should be used when RA is used to treat smoke-related lung injuries.

The National Emphysema Treatment Trial (NETT)

The National Emphysema Treatment Trial (NETT) was a multicenter prospective randomized controlled trial that compared optimal medical treatment, including pulmonary rehabilitation, with optimal medical treatment plus lung volume reduction surgery (LVRS). It was the largest and most complete collection of patient demographic, clinical, physiological, and radiographic data ever compiled in severe emphysema. NETT investigated the effects of optimal medical management and LVRS on short- and long-term survival, as well as lung function, exercise performance, and quality of life. NETT also provided much information regarding the evaluation and prognosis of severe emphysema; specifically the important negative influences that hyperinflation and small airway disease have on survival. NETT emphasized the importance of addressing nonpulmonary issues such as nutrition, cardiac disease, anxiety, and depression in emphysema. NETT demonstrated that physiological, genomic, and radiographic phenotype can predict patient survival as well as response to treatment. Because the major purpose of NETT was to compare bilateral LVRS with optimal medical treatment in emphysema, patients enrolled into NETT were comprehensively characterized and selected to have a specific window of airflow obstruction and hyperinflation and to lack significant comorbidities. The NETT patient population’s restrictive features offer distinct advantages (well-characterized predominant emphysematous phenotype) and disadvantages (lack of comorbidities and significant chronic bronchitis) that must be considered when interpreting the implications of these results. Herein, we provide a summary of the major NETT findings that provide insight into the evaluation and medical treatment of emphysema.

A Review of α1-Antitrypsin Deficiency

α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.

TESRA Study Results

Results from the Treatment of Emphysema with a Selective Retinoid Agonist [TESRA; NCT00413205] study showed that emphysema patients had a mixed response to treatment with the retinoid agonist palovarotene. Treatment with palovarotene failed to meet the primary endpoint of improving lung function (FEV1) in the overall analysis.

Abstract 1746: Modulation of ABCG2 mediated multidrug resistance by xanthine derivatives

Abstract ABCG2 is an ATP-binding-cassette (ABC) transporter that confers multidrug resistance (MDR) in tumor cells by extruding a broad variety of chemotherapeutic agents, ultimately leading to failure of cancer therapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Adenosine receptors (ARs), belong to the G-protein coupled receptor superfamily, and play important roles in stimulating neuronal cells, regulating cell proliferation and controlling immune responses. Adenosine receptor antagonists, a large collection of small molecules mainly composed of methylxanthines and other xanthine derivatives, have been used or implicated in many therapeutic applications, such as treatment of asthma, chronic bronchitis, emphysema and neural degenerative diseases. Previously, we have shown that the non-selective AR antagonist 1,3,7-methyxanthine (caffeine) can dramatically downregulate ABCG2 expression levels in cancer cell lines, increasing the intracellular retention of the ABCG2 specific substrate Mitoxantrone (MX) and markedly sensitizing cells to this chemotherapeutic agent. In order to find more potent and specific modulators of ABCG2 expression, we recently tested other ARs antagonists. Among the compounds we have examined, the non-selective antagonists theophylline, theobromine, paraxanthine, and the A2R selective antagonists 8-(3-chlorostyryl), caffeine (CSC) and 3,7-dimethyl-1-propargylxanthine (DMPX), were capable of downregulating ABCG2 protein levels to varying degrees. An A1R selective antagonist, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), currently in clinical trials, also decreased the expression of ABCG2 significantly at physiologically- relevant concentrations. In addition, the natural ligand of the ARs, adenosine, completely blocked the downregulation of ABCG2 by caffeine, suggesting that adenosine receptors and their downstream signaling pathways are involved in the regulation of ABCG2 gene expression. These findings suggest that xanthine adenosine receptor antagonists could be developed as combination therapy to improve the efficacy of drugs that are ABCG2 substrates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2011-1746

Mechanical failure, stress redistribution, elastase activity and binding site availability on elastin during the progression of emphysema

Emphysema is a disease of the lung parenchyma with progressive alveolar tissue destruction that leads to peripheral airspace enlargement. In this review, we discuss how mechanical forces can contribute to disease progression at various length scales. Airspace enlargement requires mechanical failure of alveolar walls. Because the lung tissue is under a pre-existing tensile stress, called prestress, the failure of a single wall results in a redistribution of the local prestress. During this process, the prestress increases on neighboring alveolar walls which in turn increases the probability that these walls also undergo mechanical failure. There are several mechanisms that can contribute to this increased probability: exceeding the failure threshold of the ECM, triggering local mechanotransduction to release enzymes, altering enzymatic reactions on ECM molecules. Next, we specifically discuss recent findings that stretching of elastin induces an increase in the binding off rate of elastase to elastin as well as unfolds hidden binding sites along the fiber. We argue that these events can initiate a positive feedback loop which generates slow avalanches of breakdown that eventually give rise to the relentless progression of emphysema. We propose that combining modeling at various length scales with corresponding biological assays, imaging and mechanics data will provide new insight into the progressive nature of emphysema. Such approaches will have the potential to contribute to resolving many of the outstanding issues which in turn may lead to the amelioration or perhaps the treatment of emphysema in the future.

Lung Volume Reduction Surgery Using the NETT Selection Criteria

The National Emphysema Treatment Trial (NETT) proved that lung volume reduction surgery (LVRS) was safe and effective in patients with certain clinical characteristics and using defined inclusion-exclusion criteria. Based on the selection criteria developed in that trial, we performed bilateral LVRS on 49 patients during the period of February 2004 until May 2009. Forty-nine patients underwent lung volume reduction by either median sternotomy (10) or video-assisted thoracoscopic surgery (39) selected according to NETT described parameters. Preoperative characteristics were the following: mean (±SD) age 62.5±6.6 years, preoperative FEV1 (forced expiratory volume in the first second of expiration) 691 cc (±159), % of predicted FEV1 25.3 (±6.2), preoperative Dlco (diffusing capacity of lung for carbon monoxide) 7.6 (±2.7), and % of predicted DLCO 27% (±7.3). All patients had upper lobe predominant disease and either low exercise capacity (n=23) or high exercise capacity (n=26) as defined by the NETT. There was no operative or 90-day mortality. Median length of stay was 8 days (interquartile range=6 to 10). Two patients required reintubation and tracheostomy but were decannulated prior to discharge. The BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity), a multidimensional predictor of survival in chronic obstructive pulmonary disease, improved -2.3 (±1.5, p<0.0001) (missing data: 5 of 42, 11.9%) and the FEV1 improved 286 cc (±221, p<0.0001), both 1 year after surgery. Probability of survival was 0.98 (95% CI [confidence interval]=0.94 to 1) at 1 year, and 0.95 (95% CI=0.88 to 1) at 3 years. Surgical lung volume reduction for emphysema can be performed in patients using selection criteria developed by the NETT with very low surgical risk and excellent midterm results. Surgical LVRS is the standard against which other nonsurgical treatments for advanced emphysema should be judged.

육미지황환(六味地黃丸)의 elastase 활성과 DPPH, NO 소거능에 미치는 영향

Objectives : Elastic fibers are found in the skin, lungs, arteries, veins and other structures. Elastases destroy the elastic fibers and cause the emphysema and pulmonary hypertension. Oxidative stress is needed for these pathologic changes. Accordingly, present study was designed to investigate the effect of Yukmigeehwang-hwan extracts (YHE) on elastase activity and anti-oxidative effects of YHE. Methods : The inhibitory effects on elastase and DPPH and NO free radical scavenging activities of YHE were measured. Results : The elastase activity was significantly inhibited by YHE. YHE significantly scavenged DPPH and NO free radicals as well. Conclusion : YHE showed the elastase-inhibiting effects and anti-oxidative activities in vitro. These results suggest that YHE may have potential roles in the treatment of pulmonary emphysema and pul- monary hypertension.

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Subcutaneous emphysema during fracture line inspection: case report

The development of subcutaneous emphysema is a well-known complication that has been reported after dental extraction, endodontic treatment, or restorative preparation. Gaseous invasion, leading to swelling, crepitus on palpation, is commonly restricted to the connective tisssues immediately adjacent to the entry site. However, the use of compressed air- and water-cooled turbines may allow large amounts of air and water to be driven through the fascial planes into the mediastinum, pleural space, or even the retroperitoneum. This case report is about the patient who presented with subcutaneous emphysema that occurred after fracture line inspection. Possible cause, treatment, and prevention of emphysema will be discussed.