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PubMed1986

Increased left ventricular stiffness impairs filling in dogs with pulmonary emphysema in respiratory failure.

In a chronic canine model of pulmonary emphysema, we studied the interaction between left ventricular (LV) mechanics and pulmonary disease during severe hypoxemia. The hypoxemia was similar to that which may occur during a severe exacerbation of chronic obstructive lung disease. In six dogs with papain-induced emphysema and in seven dogs without emphysema, LV mechanics were examined when a hypoxic gas mixture was inspired to reduce PO2 to about 35 mmHg (hypoxic study) and during nonhypoxic conditions (room air study). In both groups, LV diastolic compliance was reduced during the hypoxic study by a similar amount. This finding could not be explained in terms of ventricular interdependence. Our analysis suggested that hypoxia decreased diastolic compliance (i.e., increased LV diastolic stiffness) by impairing LV relaxation. The primary effect of hypoxia was to decrease the extent to which LV relaxation occurred for a given end-diastolic pressure, while the rate of LV relaxation was decreased just slightly. This study indicates that severe hypoxemia because of respiratory failure may impair myocardial relaxation leading to a decrease in LV filling.

Animals↗
PubMed2005

Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema.

Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1alpha/CCL-3 (MIP-1alpha/CCL-3), MIP-1beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.

Animals↗
PubMed2006

Elastin fragments drive disease progression in a murine model of emphysema.

Mice lacking macrophage elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from macrophage elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both macrophage accumulation and airspace enlargement.

Animals↗
PubMed2006

Toll-like receptor 4 deficiency causes pulmonary emphysema.

TLRs have been studied extensively in the context of pathogen challenges, yet their role in the unchallenged lung is unknown. Given their direct interface with the external environment, TLRs in the lungs are prime candidates to respond to air constituents, namely particulates and oxygen. The mechanism whereby the lung maintains structural integrity in the face of constant ambient exposures is essential to our understanding of lung disease. Emphysema is characterized by gradual loss of lung elasticity and irreversible airspace enlargement, usually in the later decades of life and after years of insult, most commonly cigarette smoke. Here we show Tlr4(-/-) mice exhibited emphysema as they aged. Adoptive transfer experiments revealed that TLR4 expression in lung structural cells was required for maintaining normal lung architecture. TLR4 deficiency led to the upregulation of what we believe to be a novel NADPH oxidase (Nox), Nox3, in lungs and endothelial cells, resulting in increased oxidant generation and elastolytic activity. Treatment of Tlr4(-/- )mice or endothelial cells with chemical NADPH inhibitors or Nox3 siRNA reversed the observed phenotype. Our data identify a role for TLR4 in maintaining constitutive lung integrity by modulating oxidant generation and provide insights into the development of emphysema.

Animals↗
PubMed2001

Evaluation of bronchodilator responses in patients with "irreversible" emphysema.

Given the emerging physiological and clinical rationale for pharmacological lung-volume reduction, assessment of volume responses to bronchodilators is likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The authors examined the magnitude of lung-volume reduction after acute bronchodilator treatment in patients with advanced emphysema. Eighty-four stable patients with emphysema (mean+/-SEM forced expiratory volume in one second (FEV1): 32+/-1% predicted) performed spirometry and body plethysmography before and 15-30 min after 200 microg salbutamol. Only irreversible patients with a postbronchodilator change in FEV1 <10% pred were considered in this study. Postsalbutamol, the majority of subjects (83%) had significant improvements in one or more lung volumes: on average, residual volume (RV), functional residual capacity (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed by -18+/-2, -10+/-1, 8+/-1, 9+/-1 and 7+/-1% pred (p<0.0005 each). Total lung capacity (TLC) decreased 0.12+/-0.04 L (p<0.01). Change in IC reflected change in FRC (r=-0.60, p<0.0005), but more strongly in the 57% of patients with no significant change in TLC (r=-0.93, p<0.0005). The magnitude and frequency of volume responses were greatest in patients with the most severe COPD; for example, RV decreased by 0.51+/-0.09 L (23+/-4% pred) and 0.27+/-0.04 L (14+/-2% pred) in severe and moderate subgroups, respectively. Significant reductions in lung hyperinflation occurred in the absence of a change in forced expiratory volume in one second after low-dose salbutamol in a majority of patients with advanced emphysema; the greatest changes occurred in those with the most severe disease.

Aged↗
PubMed2002

Magnetic resonance analysis of abnormal diaphragmatic motion in patients with emphysema.

The purpose of this study was to quantitatively evaluate paradoxical diaphragmatic motion using magnetic resonance (MR) imaging. A total of 27 subjects were examined, including 12 normal young adults, six control individuals, and nine patients with emphysema. With subjects in the supine position, 30 sequential sagittal MR images of the entire right lung were obtained during tidal and deep slow breathing. Diaphragmatic movement between sequential images was estimated as the displacement area and the total diaphragmatic movement in a respiratory cycle was calculated. The paradoxical motion of the diaphragm, representing the inverted movement to increase or decrease lung area, since paradoxical movement ratio (Mpr=(total paradoxical diaphragmatic movement/total diaphragmatic movement)x100), was evaluated. In patients with emphysema, paradoxical diaphragmatic motion was observed on MR images during deep breathing. The mean Mpr in emphysematous patients during deep breathing was 10+/-4%, which was significantly higher than 0.5+/-0.2% in young adults (p<0.05), and 1.2+/-0.6% in aged-matched controls (p<0.05). The present results indicate that magnetic resonance images could be used to detect paradoxical diaphragmatic motion in patients with emphysema.

Adult↗
PubMed2002

Alterations in gene expression in hamster diaphragm after emphysema and lung volume reduction surgery.

UNLABELLED: The authors have demonstrated previously that emphysema and lung volume reduction surgery (LVRS) resulted in a significant shift of type IIx/b to type IIa fibres in the diaphragm of hamsters with elastase-induced emphysema. To explore the mechanisms leading to this fibre switching, the mRNA expression of the myogenic regulatory factors, the inhibitors of DNA binding proteins (Id-proteins) and insulin-like growth factor-I were examined. Ribonucleic acid was extracted from the diaphragm of control, emphysematous, emphysematous and sham operated and LVRS hamsters and subjected to reverse transcriptase polymerase chain reaction. Compared to control, the ratio MyoD to myogenin declined with emphysema, sham and even more after LVRS, due to a decrease in MyoD mRNA and an increase in myogenin mRNA. Similarly, compared to control, Id-1 protein mRNA levels decreased significantly in sham and even more in LVRS. Id-2 protein mRNA levels decreased in all groups, but reached statistical significance in LVRS only, compared to control. IN CONCLUSION: 1) the reduced MyoD/myogenin ratio may be the mechanism of the shift to a slower fibre type, 2) the decreased MyoD/myogenin ratio in lung volume reduction surgery animals suggests that lung volume reduction surgery enhances rather than decreases the load placed on the diaphragm and 3) the observed down-regulation of the inhibiting factors may facilitate the diaphragm adaptation to overload.

Animals↗
PubMed2003

Helium-3 MRI diffusion coefficient: correlation to morphometry in a model of mild emphysema.

Hyperpolarised gases have been most recently used in magnetic resonance imaging to demonstrate new image-derived pulmonary function parameters. One of these parameters is the apparent diffusion coefficient, which reflects the sizes of the structures that compartmentalise gas within the lung (i.e. alveolar space). In the present study, noninvasive parameters were compared to microscopic measurements (mean linear intercept and mean alveolar internal area). Nonselective helium-3 gas density coronal ex vivo images and apparent diffusion maps were acquired in control and elastase-induced panacinar emphysema rats. Total lung capacity was considered the reference for both imaging experiments and lung fixation. A mild degree of emphysema was found based on mean linear intercept (134 +/- 25 microm) versus control (85 +/- 14 microm). The apparent diffusion coefficients were significantly different between the two groups (0.18 +/- 0.02 and 0.15 +/- 0.01 cm2 x s(-1) for elastase and control, respectively). A significant correlation between the apparent diffusion coefficient and corresponding morphometric parameters in mild emphysema was demonstrated for the first time. This study opens the possibility of estimating absolute airspace size using noninvasive techniques.

Animals↗
PubMed2005

Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean+/-sd): total lung capacity 88%+/-17, forced vital capacity (FVC) 88%+/-18, forced expiratory volume in one second (FEV1) 80%+/-21 (% predicted), FEV1/FVC 69%+/-13, carbon monoxide diffusion capacity of the lung 37%+/-16 (% predicted), carbon monoxide transfer coefficient 46%+/-19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1+/-2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

Adult↗
PubMed2006

Ventilation inhomogeneity in alpha1-antitrypsin-deficient emphysema.

The slope of phase III of the single-breath nitrogen wash-out test (sbN2-test) measures ventilation inhomogeneity and, in smokers, is strongly associated with small airways pathology. The present authors aimed to study ventilation inhomogeneity in emphysema related to type Z alpha1-antitrypsin (AAT) and to assess its relationship with indices of parenchymal damage and airways obstruction. A total of 18 subjects, consisting of ex-smokers with type Z AAT and emphysema (confirmed by computed tomography scan), were studied in a cross-sectional design. Post-bronchodilation flow-volume curves and gas transfer parameters were measured; sbN2-test curves were obtained and the slope of phase III was determined. The mean value of the slope (4.6+/-1.3% N2 x L(-1)) was higher than reference values +2sd; it was significantly correlated with the transfer factor of the lung for carbon monoxide (R = -0.75) and the transfer coefficient of the lung for carbon monoxide (R = -0.58), but not with airways obstruction. There was no correlation between phase III slope values and cumulative smoking. In patients with type Z alpha1-antitrypsin emphysema, the increased ventilation inhomogeneity predominantly reflects parenchymal abnormalities, demonstrating that measurement of airways obstruction is not sufficient to characterise the disease. Determination of the sensitivity of the single-breath nitrogen wash-out test slope in detecting disease progression may give complementary information to spirometry.

Adult↗
PubMed1995

Digestion of proteoglycans in porcine pancreatic elastase-induced emphysema in rats.

Pulmonary emphysema was induced in rats by a single intratracheal instillation of pancreatic elastase. The short-term effects of elastase instillation on basement membrane components were evaluated using immunohistochemical and biochemical methods. Lung alveoli showed a decrease in heparan sulphate proteoglycan content (especially of its heparan sulphate chains) 3 h to 7 days after induction. Type IV collagen, laminin and fibronectin were not affected. The glycosaminoglycan content of the lung was decreased during the first 3 days after induction, while the glycosaminoglycan concentration in urine was increased during the first 4 days by an increase of heparan sulphate and dermatan sulphate. The increase in urinary glycosaminoglycan content was positively correlated with the extent of emphysema developed after 40 days. We conclude that proteoglycans are target molecules for elastase, and may be involved in the pathogenesis of emphysema.

Animals↗
PubMed1998

Two-year results after lung volume reduction surgery in alpha1-antitrypsin deficiency versus smoker's emphysema.

Lung volume reduction surgery (LVRS) improves exercise capacity and relieves dyspnoea in patients with smoker's emphysema (SE). It is unclear, however, whether LVRS similarly improves lung function in alpha1-antitrypsin-deficiency emphysema (alpha1 E). To address this question, this study prospectively compared the intermediate-term functional outcome in 12 consecutive patients with advanced alpha1E and 18 patients with SE who underwent bilateral LVRS. Before surgery there were no statistically significant differences between the two groups in the six-minute walking distance, dyspnoea score, respiratory mechanics or lung function data, except for the forced expiratory volume in one second, which was lower in the deficient group (24 versus 31% of the predicted value; p<0.05). In both groups, bilateral LRVS produced significant improvements in dyspnoea, the six-minute walking distance, lung function and respiratory mechanics. In the alpha1E group, the functional data, with the exception of the six-minute walking distance, returned to baseline at 6-12 months postoperation and showed further deterioration at 24 months. The functional status of the SE group remained significantly improved over this period. In conclusion, the functional improvements resulting from bilateral lung volume reduction surgery are sustained for at least 2 yrs in most patients with smoker's emphysema, but this type of surgery offers only short-term benefits for most patients with alpha1E.

Dyspnea↗
PubMed2006

Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Several mechanisms are involved in the development of the disease: influx of inflammatory cells into the lung (leading to chronic inflammation of the airways), imbalance between proteolytic and anti-proteolytic activity (resulting in the destruction of healthy lung tissue) and oxidative stress. Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD. There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema. Data from animal models suggest a role for Vascular Endothelial Growth Factor (VEGF) in the induction of apoptosis of structural cells in the lung. Other mediators of apoptosis, such as caspase-3 and ceramide, could be interesting targets to prevent apoptosis and the development of emphysema. In this review, recent data on the role of apoptosis in COPD from both animal models as well as from studies on human subjects will be discussed. The aim is to provide an up to date summary on the increasing knowledge on the role of apoptosis in COPD and pulmonary emphysema.

Animals↗
PubMed2005

PKC translocation and ERK1/2 activation in compensated right ventricular hypertrophy secondary to chronic emphysema.

BACKGROUND: Right ventricular hypertrophy (RVH) is an important complication of chronic lung disease. However, the signal transduction pathways involved as well as the physiological changes to the right ventricle have not been investigated. Emphysema was produced in male, Syrian Golden hamsters by intra-tracheal instillation of 250 IU/kg elastase (Emp, n = 17). Saline treated animals served as controls (Con, n = 15). RESULTS: Nine months later, Emp hamsters had 75% greater lung volume, and evidence of RVH at the gross and myocyte level (RV:tibia length Emp 6.84 +/- 1.18 vs. Con 5.14 +/- 1.11 mg/mm; myocyte cross sectional area Emp 3737 vs. Con 2695 microm2), but not left ventricular hypertrophy. Serial echocardiographic analysis from baseline to nine months after induction of emphysema revealed increasing right ventricular internal dimension and decreased pulmonary artery acceleration time only in Emp hamsters. There was an increase in translocation of PKC betaI and PKC epsilon from cytosolic to membranous cell fractions in RV of Emp hamsters. Phosphorylation of PKC epsilon was unchanged. Translocation of PKC alpha and betaII were unchanged. Emp animals had a 22% increase in phospho-ERK 1/2, but no change in levels of total ERK 1/2 compared to Con. CONCLUSION: These data suggest that PKC betaI, epsilon and ERK 1/2 may play a role in mediating compensated RVH secondary to emphysema and may have clinical relevance in the pathogenesis of RVH.

Animals↗
PubMed1992

Lung density and lung mass in emphysema.

Mean lung density (dm) and radiologic (VLx) lung volume can be calculated using CT scan data. As many emphysematous patients are overdistended, the analysis of dm alone could be meaningless. However, lung mass (m) can be calculated as the product of dm and VLx. Twenty-four patients suspected of mild or severe emphysema as judged by roentgenographic and physiologic examinations as well as 16 healthy subjects were included in the protocol. They all underwent both a CT scan of the whole lung and functional tests from which the following were derived: airway resistance, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC), CO transfer capacity, quasi-static compliance at functional residual capacity (FRC), and blood gases. All CT scans were performed at the FRC of each patient. The dm was lower in emphysema patients than in healthy subjects, as m was greater in patients than in healthy subjects; 1,303 +/- 398 g and 997 +/- 133 g, respectively. Although dm values were significantly correlated to FEV1, FEV1/FVC, and TLC, m values were not correlated to any of these functional indices. Unexpectedly, these results show that most patients (22/24) with emphysema have a normal or increased lung mass. Normal or above normal m values might be due to oversecretion in some patients. Nevertheless, the synthesis of new tissue due to chronic inflammation is the most likely explanation that could account for this finding.

Adult↗
PubMed1996

Lung volume reduction surgery for emphysema.

There has been dramatic resurgence of interest in surgical treatment of emphysema, particularly "lung volume reduction" procedures. Recent studies have demonstrated improvements in pulmonary function, lung mechanics, exercise tolerance, and quality of life in selected patients following volume reduction procedures. However, considerable uncertainty remains regarding overall benefit, optimal patient selection, operative techniques, and duration of response. This summarizes current approaches to lung volume reduction surgery, available clinical outcome information, selection criteria, and physiologic mechanisms of response, and discusses the potential role for surgical volume reduction in treatment of emphysema. Recent data appear to support the efficacy of bilateral staple lung volume reduction surgery in patients with severe symptomatic heterogeneously distributed emphysema. Further studies will be needed to determine relative value of different operative techniques and benefit in patients with other clinical presentations.

Algorithms↗
PubMed1998

Effects of lung volume reduction surgery on exercise pulmonary hemodynamics in severe emphysema.

STUDY OBJECTIVES: To clarify the effects of lung volume reduction surgery (LVRS) on pulmonary hemodynamics in severe emphysema and to evaluate the role of pulmonary circulation in the increased exercise performance after LVRS. DESIGN: In eight male patients with severe emphysema, we measured pulmonary artery (Ppa) and occlusion (Pop) pressures and cardiac output through a Swan-Ganz thermodilution catheter, and we calculated cardiac index (CI), pulmonary vascular resistance index, and driving pressure. The study was performed at rest and during exercise using a supine bicycle ergometer at 25 W, under room air and O2 inhalation. Exercise performance was expressed as endurance time in minutes. Pulmonary function tests were performed. The patients underwent an identical study before and 6 months after LVRS. RESULTS: The patients' exercise performance was significantly increased after LVRS (5.9+/-1.8 min) compared with that before LVRS (3.6+/-0.9 min). LVRS resulted in a significant increase in FEV1 and a significant decrease in residual volume. Before LVRS, Ppa was increased both at rest and during exercise. LVRS did not change rest or exercise Ppa. LVRS significantly decreased Pop during exercise from 24+/-10 mm Hg to 18+/-7 mm Hg. CI at rest and during exercise were significantly increased after LVRS. O2 administration significantly decreased Ppa during exercise both before and after LVRS. CONCLUSIONS: These findings suggest that LVRS does not improve pulmonary hypertension at rest or during exercise in patients with severe emphysema and that elevated Pop during exercise before LVRS is probably related to lung mechanic abnormalities.

Aged↗
PubMed1999

Survival following bilateral staple lung volume reduction surgery for emphysema.

STUDY OBJECTIVES: Despite numerous reports of short-term response to lung volume reduction surgery (LVRS) for treatment of emphysema, to our knowledge, longer-term survival has not been reported. We describe survival following LVRS in a large cohort of 256 patients treated with bilateral staple LVRS (n = 236 video-assisted thoracic surgery [VATS] approaches, n = 20 median sternotomy) by a single group of physicians over a 3 1/2-year period from April 1994 to November 1997. DESIGN: Prospective survival study. Overall survival, survival stratified by preoperative presentation, and acute postoperative response were investigated using Kaplan-Meier methods. The simultaneous effects of preoperative predictors and postoperative response variables on survival were examined using a Cox proportional hazards model. SETTING: Community hospital and university medical center. PATIENTS: We studied 256 consecutive patients with severe emphysema treated with LVRS. INTERVENTIONS: Bilateral staple LVRS by VATS. MEASUREMENTS AND RESULTS: Overall survival information was known with certainty for 246 of 256 patients as of February 1, 1998. Median follow-up time was 623 days (range, 0 to 1,545 days). Mean FEV1 was 0.635L+/-0.015 L preoperatively and rose to 1.068L+/-0.029 L postoperatively. By standard analysis methods (missing patients censored at the time of last contact), 1-year survival was 85+/-2.3% compared with 83+/-2.4% 1-year survival with "worst case" analytic methods (assuming all missing patients died). Two-year survival averaged 81+/-2.7% by standard analysis vs 76+/-2.9% by worst case evaluation. Survival was significantly better for patients who were younger (< or = 70 years old, p = 0.02) and with higher baseline FEV1 (> 0.5, p < 0.03) and PO2 (> 54, p < 0.001). Patients who had greatest short-term improvement in FEV1 following surgery (> 0.56 L increase) also had significantly better longer-term survival following LVRS. CONCLUSIONS: To our knowledge, this is the first longer-term survival analysis of a large series of patients who underwent bilateral staple LVRS for emphysema. Substantial long-term mortality is seen, particularly within identifiable high-risk subgroups. Careful comparison to comparably matched control patients will be needed to definitively assess the benefits and risks of LVRS. This study suggests that prospective, controlled trials may need to stratify patient randomization based on preoperative risk factors to obtain meaningful results.

Aged↗