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1.  Associated inflammation or increased flow-mediated shear stress, but not pressure alone, disrupts endothelial caveolin-1 in infants with pulmonary hypertension 
Pulmonary Circulation  2012;2(4):492-500.
Endothelial caveolin-1 loss is an important feature of pulmonary hypertension (PH); the rescue of caveolin-1 abrogates experimental PH. Recent studies in human PH suggest that the endothelial caveolin-1 loss is followed by an enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation. In order to evaluate caveolin-1 expression in infants with PH, we examined the available clinical histories, hemodynamic data, and the expression of caveolin-1, PECAM-1, vWF, and smooth muscle α-actin in the lung biopsy/autopsy specimens obtained from infants with congenital heart disease (CHD, n = 8) and lung disease (n = 9). In CHD group, PH associated with increased pulmonary blood flow exhibited loss of endothelial caveolin-1 and PECAM-1 in pulmonary arteries; additional vWF loss was associated with enhanced expression of caveolin-1 in SMC. In the absence of PH, increased or decreased pulmonary blood flow did not disrupt endothelial caveolin-1, PECAM-1, or vWF; nor was there any enhanced expression of caveolin-1 in SMC. In Lung Disease + PH group, caveolin-1, PECAM-1, and vWF were well preserved in seven infants, and importantly, SMC in these arteries did not exhibit enhanced caveolin-1 expression. Two infants with associated inflammatory disease exhibited loss of endothelial caveolin-1 and PECAM-1; additional loss of vWF was accompanied by enhanced expression of caveolin-1 in SMC. Thus, associated flow-induced shear stress or inflammation, but not elevated pulmonary artery pressure alone, disrupts endothelial caveolin-1. Subsequent vWF loss, indicative of extensive endothelial damage is associated with enhanced expression of caveolin-1 in SMC, which may worsen the disease.
doi:10.4103/2045-8932.105038
PMCID: PMC3555420  PMID: 23372934
congenital heart defect; endothelial cells; lung disease; smooth muscle cells
2.  Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD 
Respiratory Research  2013;14(1):65.
Background
De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking.
Methods
Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6.
Results
The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar parenchyma (p < 0.001) in patients with advanced COPD compared with never-smoking controls. A similar increase in lymphatic D6 immunoreactivity was observed in bronchioles (p < 0.05) and alveolar parenchyma (p < 0.01).
Conclusions
This study shows that severe stages of COPD is associated with increased numbers of alveolar lymphatic vessels and a change in lymphatic vessel phenotype in major peripheral lung compartments. This novel histopathological feature is suggested to have important implications for distal lung immune cell traffic in advanced COPD.
doi:10.1186/1465-9921-14-65
PMCID: PMC3728038  PMID: 23758732
Chronic obstructive pulmonary disease; Alveolar; Lymphatic vessel; CCL21; D6; Immunohistochemistry; Inflammation
3.  Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease 
Circulation Research  2011;109(5):543-553.
Rationale
Senescence of pulmonary artery-smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension (PH) associated with chronic lung diseases.
Objective
To investigate whether cell senescence contributes to pulmonary vessel remodeling and PH in chronic obstructive pulmonary disease (COPD).
Methods and results
In 124 patients with COPD, investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and PH severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16- and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age- and sex-matched control smokers. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell-population doublings, an increased percentage of beta-galactosidase-positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage, compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors.
Conclusion
PA-SMC senescence is an important contributor to the process of pulmonary vascular remodeling that underlies PH in chronic lung disease.
doi:10.1161/CIRCRESAHA.111.241299
PMCID: PMC3375237  PMID: 21719760
Aged; Cell Aging; physiology; Cells, Cultured; Female; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; pathology; physiopathology; Myocytes, Smooth Muscle; pathology; physiology; Pulmonary Artery; pathology; physiopathology; Pulmonary Disease, Chronic Obstructive; etiology; pathology; physiopathology; pulmonary hypertension; senescence; smooth muscle cells; remodeling
4.  Impact of Caveolin-1 Expression on the Prognosis of Transitional Cell Carcinoma of the Upper Urinary Tract 
Journal of Korean Medical Science  2008;23(2):296-301.
This study aimed to investigate the relationship of caveolin-1 expression with prognosis in patients with transitional cell carcinoma of the upper urinary tract (TCC-UUT). Formalin-fixed, paraffin-embedded tissue sections of TCC-UUT from 98 patients, who had undergone radical nephroureterectomy, were stained immunohistochemically using antibodies against caveolin-1. The expression pattern of caveolin-1 was compared with the clinicopathological variables. The caveolin-1 expression was significantly correlated with T stage (p<0.001) and grade (p=0.036). The survival rate of patients with caveolin-1 positive tumors was significantly lower than that of patients with caveolin-1 negative tumors (p<0.0001). The univariate analyses identified T stage, grade, and caveolin-1 expression as significant prognostic factors for cancer-specific survival, whereas the multivariate analyses indicated that T stage and caveolin-1 expression were independent prognostic factors. These results show that the increased expression of caveolin-1 is associated with tumor progression and poor prognosis in TCC-UUT, suggesting that caveolin-1 may play an important role in the progression of TCC-UUT.
doi:10.3346/jkms.2008.23.2.296
PMCID: PMC2526442  PMID: 18437015
Caveolin 1; Prognosis; Carcinoma, Transitional Cell; Upper Urinary Tract
5.  Prevalence and Characteristics of Pulmonary Hypertension Associated with COPD - A Pilot Study in Patients Referred to a Pulmonary Rehabilitation Program Clinic 
Mædica  2013;8(3):243-248.
ABSTRACT
Objectives: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmo­nary disease (COPD); its prevalence is currently unknown. The objectives of the study were: (a) to provide data on the prevalence of PH among the COPD patients referred to a pulmonary rehabilitation program; (b) to evaluate possible correlations of PH with the severity of COPD, the presence of hypoxemia and polycythemia.
Material and methods: We retrospectively studied 31 consecutive patients with the diagnosis of COPD hospitalised in our clinic in which echocardiography was performed. Spirometry, peripheral oxygen saturation, haematocrit, echocardiography data, history of exacerbations and cardiac comorbidities were obtained from patients records. PH was defined as systolic pulmonary arterial pressure (sPAP) greater than 35 mmHg or by the presence of right ventricle (RV) abnormalities.
Outcomes: The prevalence of PH was 38.7%. Resting hypoxemia was significantly more frequent in the PH group than in the non PH patients (p=0.019). Other differences were not statistically significant (severity of bronchial obstruction and polycythemia, cardiac comorbidities). The impact of PH on RV was found in only 5 patients with RV enlargement; no patient had RV hypertrophy or RV systolic dysfunction. Suspected "out of proportion" PH (sPAP greater than 50 mmHg) was encountered in 2 out of 12 patients with PH.
Conclusions: The prevalence of PH in patients with COPD was 38.7%. Resting hypoxemia was significantly more frequent in PH patients. As PH has an important role in the prognosis of COPD patients, it should be evaluated in as many COPD patients as possible.
PMCID: PMC3869112  PMID: 24371492
pulmonary hypertension; chronic obstructive pulmonary disease; echocardiography
6.  Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment 
Thorax  2005;60(7):605-609.
The development of pulmonary hypertension is a poor prognostic sign in patients with chronic obstructive pulmonary disease (COPD), affecting both mortality and quality of life. Although pulmonary hypertension in COPD is traditionally viewed as a result of emphysematous destruction of the vascular bed and/or hypoxia, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressures. New human and animal experimental data are beginning to show that pulmonary hypertension in this setting is probably a result of the direct effect of tobacco smoke on the intrapulmonary vessels with abnormal production of mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, ultimately leading to aberrant vascular remodelling and aberrant vascular physiology. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest that the treatments used for primary pulmonary hypertension may be beneficial in patients with COPD.
doi:10.1136/thx.2005.042994
PMCID: PMC1747459  PMID: 15994270
7.  Activation of RhoA/Rho-kinase pathway accounts for pulmonary endothelial dysfunction in patients with chronic obstructive pulmonary disease 
Physiological Reports  2013;1(5):e00105.
Recent evidence suggests that activation of RhoA/Rho-kinase accounts for systemic and pulmonary endothelial dysfunction in smokers with normal lung function. However, its role in patients with chronic obstructive pulmonary disease (COPD) has not yet been investigated. The aim of this study was to evaluate the regulation of RhoA/Rho-kinase pathway and pulmonary endothelial dysfunction in patients with COPD. Pulmonary arteries were obtained from nonsmokers (control subjects) and patients with nonhypoxemic and hypoxemic COPD (n = 6–7/group). Endothelium-dependent and -independent relaxations were evaluated by acetylcholine and sodium nitroprusside, respectively. Gene and protein expressions of endothelial nitric oxide synthase (eNOS) were measured by RT-PCR, Western blot, and immunohistochemistry. Nitrate, cGMP, and endothelin-1 (ET-1) concentrations, as well as Rho-kinase activity were measured by ELISA. Protein expressions of total RhoA and GTP-RhoA were measured by Western blot and pull-down assay, respectively. Endothelium-dependent relaxation, and nitrate and cGMP levels were significantly reduced in pulmonary arteries of COPD patients as compared with control subjects. Conversely, activity of RhoA/Rho-kinase was increased in pulmonary arteries of COPD patients as compared with control subjects. In patients with COPD, pulmonary endothelial dysfunction was related to the downregulation of eNOS activity and upregulation of RhoA/Rho-kinase activity.
doi:10.1002/phy2.105
PMCID: PMC3841041  PMID: 24303177
COPD; endothelial dysfunction; eNOS; RhoA; Rho-kinases
8.  Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1 
Cardiovascular Research  2012;93(4):682-693.
Aims
Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by pulmonary vasoconstriction and vascular remodelling, leading to increased pulmonary vascular resistance and right heart failure. Loss of nitric oxide (NO) signalling and increased endothelial nitric oxide synthase (eNOS)-derived oxidative stress are central to the pathogenesis of PAH, yet the mechanisms involved remain incompletely determined. In this study, we investigated the role activated CD47 plays in promoting PAH.
Methods and results
We report high-level expression of thrombospondin-1 (TSP1) and CD47 in the lungs of human subjects with PAH and increased expression of TSP1 and activated CD47 in experimental models of PAH, a finding matched in hypoxic human and murine pulmonary endothelial cells. In pulmonary endothelial cells CD47 constitutively associates with caveolin-1 (Cav-1). Conversely, in hypoxic animals and cell cultures activation of CD47 by TSP1 disrupts this constitutive interaction, promoting eNOS-dependent superoxide production, oxidative stress, and PAH. Hypoxic TSP1 null mice developed less right ventricular pressure and hypertrophy and markedly less arteriole muscularization compared with wild-type animals. Further, therapeutic blockade of CD47 activation in hypoxic pulmonary artery endothelial cells upregulated Cav-1, increased Cav-1CD47 co-association, decreased eNOS-derived superoxide, and protected animals from developing PAH.
Conclusion
Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS.
doi:10.1093/cvr/cvr356
PMCID: PMC3291089  PMID: 22215724
Pulmonary arterial hypertension; CD47; eNOS; Caveolin-1; Reactive oxygen species
9.  Pyrrolidine Dithiocarbamate Restores Endothelial Cell Membrane Integrity and Attenuates Monocrotaline-Induced Pulmonary Artery Hypertension 
Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1 and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF-κB have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC, starting on day 1, 3 and 14 × 2 wks) an inhibitor of inflammation and NF-κB activation. Hemodynamic data, the expression of inhibitory (I)-κBα, caveolin-1 and Tie2 (a membrane protein), activation of PY-STAT3 and NF-κB, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wks post-MCT. There were progressive reduction in the expression of caveolin-1, Tie2 and activation of PY-STAT3 in the lungs. Reduction in I-κBα expression was present at 2 and 4 wks post-MCT. Superoxide chemiluminescence and NF-κB activation were observed only at 2 wks post-MCT and both decreased by 4 wks post-MCT despite progressive PAH. PDTC (starting on day 1 and 3) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I-κBα expression and reduced superoxide chemiluminescence at 2 wks, but did not inhibit NF-κB activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-κB activation appear to be a transient phenomenon in the MCT model. Thus, the disruption of endothelial cell membrane integrity resulting in cav-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.
doi:10.1152/ajplung.00069.2007
PMCID: PMC2441448  PMID: 18390833
Caveolin-1; I-κBα; Inflammation; PY-STAT3; Tie2
10.  Clinical Utility of Echocardiography for the Diagnosis and Management of Pulmonary Vascular Disease in Young Children With Chronic Lung Disease 
Pediatrics  2008;121(2):317-325.
Objective
The goal was to determine the clinical utility of Doppler echocardiography in predicting the presence and severity of pulmonary hypertension in patients with chronic lung disease who subsequently underwent cardiac catheterization.
Methods
A retrospective review of data for all patients <2 years of age with a diagnosis of bronchopulmonary dysplasia, congenital diaphragmatic hernia, or lung hypoplasia who underwent echocardiography and subsequently underwent cardiac catheterization for evaluation of pulmonary hypertension was performed. The accuracy of echocardiography in diagnosing pulmonary hypertension, on the basis of estimated systolic pulmonary artery pressure, was compared with the detection of pulmonary hypertension with the standard method of cardiac catheterization.
Results
Thirty-one linked measurements for 25 children were analyzed. Systolic pulmonary artery pressure could be estimated in 61% of studies, but there was poor correlation between echocardiography and cardiac catheterization measures of systolic pulmonary artery pressure in these infants. Compared with cardiac catheterization measurements, echocardiographic estimates of systolic pulmonary artery pressure diagnosed correctly the presence or absence of pulmonary hypertension in 79% of the studies in which systolic pulmonary artery pressure was estimated but determined the severity of pulmonary hypertension (severe pulmonary hypertension was defined as pulmonary/systemic pressure ratio of ≥0.67) correctly in only 47% of those studies. Seven (58%) of 12 children without estimated systolic pulmonary artery pressure demonstrated pulmonary hypertension during subsequent cardiac catheterization. In the absence of estimated systolic pulmonary artery pressure, qualitative echocardiographic findings, either alone or in combination, had worse predictive value for the diagnosis of pulmonary hypertension.
Conclusion
As used in clinical practice, echocardiography often identifies pulmonary hypertension in young children with chronic lung disease; however, estimates of systolic pulmonary artery pressure were not obtained consistently and were not reliable for determining the severity of pulmonary hypertension.
doi:10.1542/peds.2007-1583
PMCID: PMC3121163  PMID: 18245423
chronic lung disease; bronchopulmonary dysplasia; pulmonary hypertension; echocardiography; cardiac catheterization
11.  COPD/emphysema: The vascular story 
Pulmonary Circulation  2011;1(3):320-326.
In this perspective, we review published data which support the concept that many or most chronic and progressive lung diseases also involve the lung vessels and that microvascular abnormalities and endothelial cell death contribute to the pathobiology of emphysema. Lung vessel maintenance depends on Vascular Endothelial Growth Factor signaling and both are compromised in the emphysematous lung tissue. Although hypoxic pulmonary vasoconstriction has been considered as an important factor contributing to the vascular remodeling in chronic obstructive pulmonary disease (COPD) (COPD/emphysema, it is now clear that inhaled cigarette smoke can damage the lung vessels independent of the lung vascular tone. We propose that a “sick lung circulation” rather than the right heart afterload may better explain the cardiac abnormalities in COPD patients which are usually summarized with the term “cor pulmonale.” The mechanisms and causes of pulmonary hypertension are likely complex and include vessel loss, in situ thrombosis, and endothelial cell dysfunction. Assessment of the functional importance of pulmonary hypertension in COPD requires hemodynamic measurements during exercise.
doi:10.4103/2045-8932.87295
PMCID: PMC3224423  PMID: 22140621
cor pulmonale; exercise; lung endothelial cells; pulmonary hypertension; pulmonary vascular remodeling
12.  C-Reactive Protein and Serum Amyloid A Overexpression in Lung Tissues of Chronic Obstructive Pulmonary Disease Patients: A Case-Control Study 
Background. Although researchers have consistently demonstrated systemic inflammation in chronic obstructive pulmonary disease (COPD), its origin is yet unknown. We aimed to compare the lung bronchial and parenchymal tissues as potential sources of major acute-phase reactants in COPD patients and resistant smokers.
Methods. Consecutive patients undergoing elective surgery for suspected primary lung cancer were considered for the study. Patients were categorized as COPD or resistant smokers according to their spirometric results. Lung parenchyma and bronchus sections distant from the primary lesion were obtained. C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) gene expressions were evaluated by RT-PCR. Protein levels were evaluated in paraffin embedded lung tissues by immunohistochemistry and in serum samples by nephelometry.
Results. Our study included 85 patients with COPD and 87 resistant smokers. In bronchial and parenchymal tissues, both CRP and SAA were overexpressed in COPD patients. In the bronchus, CRP, SAA1, SAA2, and SA4 gene expressions in COPD patients were 1.89-fold, 4.36-fold, 3.65-fold, and 3.9-fold the control values, respectively. In the parenchyma, CRP, SAA1, and SAA2 gene expressions were 2.41-, 1.97-, and 1.76-fold the control values, respectively. Immunohistochemistry showed an over-stained pattern of these markers on endovascular cells of COPD patients. There was no correlation with serum protein concentration.
Conclusions. These results indicate an overexpression of CRP and SAA in both bronchial and parenchymal tissue in COPD, which differs between both locations, indicating tissue/cell type specificity. The endothelial cells might play a role in the production of theses markers.
doi:10.7150/ijms.6152
PMCID: PMC3691791  PMID: 23801879
COPD; C-reactive protein; Serum Amyloid A; gene expression; immunohistochemistry.
13.  Echocardiographic evaluation of heart in chronic obstructive pulmonary disease patient and its co-relation with the severity of disease 
Background:
Chronic obstructive pulmonary disease (COPD) has considerable effects on cardiac functions, including those of the right ventricle, left ventricle, and pulmonary blood vessels. Most of the increased mortality associated with COPD is due to cardiac involvement. Echocardiography provides a rapid, noninvasive, portable, and accurate method to evaluate the cardiac changes.
Aims:
To assess the cardiac changes secondary to COPD by echocardiography and to find out the correlation between echocardiographic findings and severity of COPD, if there is any.
Materials and Methods:
A total 40 of patients of COPD were selected and staged by pulmonary function test (PFT) and evaluated byechocardiography.
Results:
On echocardiographic evaluation of COPD, 50% cases had normal echocardiographic parameters. Measurable tricuspid regurgitation (TR) was observed in 27/40 cases (67.5%). Pulmonary hypertension (PH), which is defined as systolic pulmonary arterial pressure (sPAP)> 30 mmHg was observed in 17/27 (63%) cases in which prevalence of mild, moderate, and severe PH were 10/17 (58.82%), 4/17 (23.53%), and 3/17 (17.65%), respectively. The frequencies of PH in mild, moderate, severe, and very severe COPD were 16.67%, 54.55%, 60.00%, and 83.33%, respectively. Right atrial pressure was 10 mmHg in 82.5% cases and 15 mmHg in 17.5% cases. Cor pulmonale was observed in 7/17 (41.17%) cases; 7.50% cases had left ventricle (LV) systolic dysfunction and 47.5% cases had evidence of LV diastolic dysfunction defined as A ≥ E (peak mitral flow velocity of the early rapid filling wave (E), peak velocity of the late filling wave caused by atrial contraction (A) on mitral valve tracing) Left ventricle hypertrophy was found in 22.5% cases.
Conclusion:
Prevalence of PH has a linear relationship with severity of COPD and severe PH is almost associated with cor pulmonale. Echocardiography helps in early detection of cardiac complications in COPD cases giving time for early interventions.
doi:10.4103/0970-2113.80321
PMCID: PMC3109831  PMID: 21712919
Chronic obstructive pulmonary disease; cor pulmonale; echocardiography; pulmonary hypertension
14.  Pulmonary Arterial Enlargement and Acute Exacerbations of COPD 
The New England journal of medicine  2012;367(10):913-921.
BACKGROUND
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations.
METHODS
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
RESULTS
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
CONCLUSIONS
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.)
doi:10.1056/NEJMoa1203830
PMCID: PMC3690810  PMID: 22938715
15.  Noninvasive Assessment of Right Heart Function and Hemodynamics during Exercise in Patients with Pulmonary Arterial Hypertension 
Southern medical journal  2013;106(2):141-146.
Objectives
Noninvasive assessment of right heart function and hemodynamics in patients with pulmonary arterial hypertension (PAH) is most often performed at rest, whereas the symptoms, in general, present with exertion. Assessment during exertion is limited to symptom assessment and the 6-minute walk distance. We investigated the feasibility of obtaining echocardiographic data that could accurately reflect pulmonary artery pressures (PAP), particularly mean PAP and right ventricular function during exercise in patients with PAH.
Methods
We investigated right ventricular function and hemodynamics using echocardiography during symptom-limited exercise in 10 consecutive patients undergoing right heart catheterization (RHC) as part of their clinical evaluation for PAH. We further assessed these measurements for correlation with known predictors of outcome in PAH in an exploratory analysis.
Results
We were able to successfully obtain complete right heart measurements by echocardiography, including mean PAP, in the majority (9 of 10) of the subjects. One patient had an incomplete tricuspid regurgitation jet at rest and with exercise. Echocardiographic pulmonary vascular resistance correlated with RHC cardiac output and brain natriuretic peptide level, whereas tricuspid annular plane systolic excursion during exercise correlated with right atrial pressure on RHC, brain natriuretic peptide, and 6-minute walk distance. Tricuspid regurgitation velocity and mean PAP with exercise correlated moderately with mean PAP and cardiac output by RHC.
Conclusions
Exercise echocardiography can provide meaningful data in patients with PAH, including measuring mean PAP. The presence of correlations in this small number of patients indicates promising targets for future investigation.
doi:10.1097/SMJ.0b013e3182805165
PMCID: PMC3626433  PMID: 23380750
pulmonary arterial hypertension; exercise echocardiography; right ventricular function
16.  Contribution of oxidative stress to pulmonary arterial hypertension 
World Journal of Cardiology  2010;2(10):316-324.
Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
doi:10.4330/wjc.v2.i10.316
PMCID: PMC2999041  PMID: 21160609
Pulmonary arterial hypertension; Rosuvastatin; Oxidative stress; Nicotinamide adenine dinucleotide phosphate oxidase; Statins
17.  Plasma C-Reactive Protein and Endothelin-1 Level in Patients with Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension 
Journal of Korean Medical Science  2010;25(10):1487-1491.
Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) ≥35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.
doi:10.3346/jkms.2010.25.10.1487
PMCID: PMC2946660  PMID: 20890431
Chronic Obstructive Pulmonary Disease; Pulmonary Hypertension; C-Reactive Protein; Endothelin-1
18.  Bronchial Secretory Immunoglobulin A Deficiency Correlates With Airway Inflammation and Progression of Chronic Obstructive Pulmonary Disease 
Rationale: Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown.
Objectives: We investigated relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD.
Methods: Lung tissue specimens and bronchoalveolar lavage were obtained from lifetime nonsmokers and former smokers with or without COPD. Epithelial structural changes were quantified by morphometric analysis. Expression of pIgR was determined by immunostaining and real-time polymerase chain reaction. Immunohistochemistry was performed for IgA, CD4 and CD8 lymphocytes, and cytomegalovirus and Epstein-Barr virus antigens. Total IgA and SIgA were measured by ELISA and IgA transcytosis was studied using cultured human bronchial epithelial cells.
Measurements and Main Results: Areas of bronchial mucosa covered by normal pseudostratified ciliated epithelium were characterized by pIgR expression with SIgA present on the mucosal surface. In contrast, areas of bronchial epithelial remodeling had reduced pIgR expression, localized SIgA deficiency, and increased CD4+ and CD8+ lymphocyte infiltration. In small airways (<2 mm), these changes were associated with presence of herpesvirus antigens, airway wall remodeling, and airflow limitation in patients with COPD. Patients with COPD had reduced SIgA in bronchoalveolar lavage. Air–liquid interface epithelial cell cultures revealed that complete epithelial differentiation was required for normal pIgR expression and IgA transcytosis.
Conclusions: Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.
doi:10.1164/rccm.201010-1629OC
PMCID: PMC3265275  PMID: 21512171
polymeric immunoglobulin receptor; bronchial epithelium; cell differentiation; epithelial remodeling; mucosal host defense
19.  Increased Nitric Oxide Production Prevents Airway Hyperresponsiveness in Caveolin-1 Deficient Mice Following Endotoxin Exposure 
Journal of allergy & therapy  2012;Suppl 1(4):2155-.
Background
Caveolin-1, the hallmark protein of caveolae, is highly expressed within the lung in the epithelium, endothelium, and in immune cells. In addition to its classical roles in cholesterol metabolism and endocytosis, caveolin-1 has also been shown to be important in inflammatory signaling pathways. In particular, caveolin-1 is known to associate with the nitric oxide synthase enzymes, downregulating their activity. Endotoxins, which are are composed mainly of lipopolysaccharide (LPS), are found ubiquitously in the environment and can lead to the development of airway inflammation and increased airway hyperresponsiveness (AHR).
Methods
We compared the acute responses of wild-type and caveolin-1 deficient mice after LPS aerosol, a well-accepted mode of endotoxin exposure, to investigate the role of caveolin-1 in the development of environmental lung injury.
Results
Although the caveolin-1 deficient mice had greater lung inflammatory indices compared to wild-type mice, they exhibited reduced AHR following LPS exposure. The uncoupling of inflammation and AHR led us to investigate the role of caveolin-1 in the production of nitric oxide, which is known to act as a bronchodilator. The absence of caveolin-1 resulted in increased nitrite levels in the lavage fluid in both sham and LPS treated mice. Additionally, inducible nitric oxide synthase expression was increased in the lung tissue of caveolin-1 deficient mice following LPS exposure and administration of the potent and specific inhibitor 1400W increased AHR to levels comparable to wild-type mice.
Conclusions
We attribute the relative airway hyporesponsiveness in the caveolin-1 deficient mice after LPS exposure to the specific role of caveolin-1 in mediating nitric oxide production.
doi:10.4172/2155-6121.S1-004
PMCID: PMC3836011  PMID: 24273688
Caveolin-1; Lipopolysaccharide; Airway hyperresponsiveness; Nitric oxide; Lung injury; Cytokines
20.  Right Heart Structural Changes Are Independently Associated with Exercise Capacity in Non-Severe COPD 
PLoS ONE  2011;6(12):e29069.
Background
Pulmonary hypertension (PH) occurs frequently and results in functional limitation in advanced COPD. Data regarding the functional consequence of PH in less severe COPD are limited. Whether echocardiographic evidence of right sided heart pathology is associated with functional outcomes in patients with non-severe COPD is unknown.
Methods
We evaluated pulmonary function, six minute walk distance, and echocardiography in 74 consecutive patients with non-severe COPD. We performed multivariable linear regression to evaluate the association between right heart echocardiographic parameters and six minute walk distance adjusting for lung function, age, sex, race, and BMI.
Main Results
The mean six minute walk distance was 324±106 meters. All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.3%±6.1%). 54.1% had evidence of some degree of diastolic dysfunction. 17.6% of subjects had evidence of right ventricular enlargement and 36.5% had right atrial enlargement. In univariate analysis RV wall thickness (β = −68.6; p = 0.002), log right atrial area (β = −297.9; p = 0.004), LV mass index (β = −1.3; p = 0.03), E/E' ratio (β = −5.5; p = 0.02), and degree of diastolic dysfunction (β = −42.8; p = 0.006) were associated with six minute walk distance. After adjustment for co-variables, the associations between right atrial area (log right atrial area β = −349.8; p = 0.003) and right ventricular wall thickness (β = −43.8; p = 0.04) with lower six minute walk distance remained significant independent of forced expiratory volume in one second (FEV1). LV mass index, E/E' ratio, and degree of diastolic dysfunction were not independent predictors of six minute walk distance.
Conclusion
In patients with non-severe COPD right sided cardiac structural changes are associated with lower six minute walk distance independent of lung function. These findings may indicate that echocardiographic evidence of pulmonary hypertension is present in patients with non-severe COPD and has important functional consequences.
doi:10.1371/journal.pone.0029069
PMCID: PMC3248404  PMID: 22220201
21.  Elastin expression in very severe human COPD 
The European respiratory journal  2009;34(2):324-331.
Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD.
Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2–3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs.
Compared with donors, non-COPD and stage 2–3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased.
The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.
doi:10.1183/09031936.00123008
PMCID: PMC3758126  PMID: 19357152
Chronic obstructive pulmonary disease; elastin; emphysema; gene expression
22.  Analysis of the Airway Microbiota of Healthy Individuals and Patients with Chronic Obstructive Pulmonary Disease by T-RFLP and Clone Sequencing 
PLoS ONE  2013;8(7):e68302.
Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory lung disease that affects a large number of patients and has significant impact. One hallmark of the disease is the presence of bacteria in the lower airways. Objective: The aim of this study was to analyze the detailed structure of microbial communities found in the lungs of healthy individuals and patients with COPD. Nine COPD patients as compared and 9 healthy individuals underwent flexible bronchoscopy and BAL was performed. Bacterial nucleic acids were subjected to terminal restriction fragment (TRF) length polymorphism and clone library analysis. Overall, we identified 326 T-RFLP band, 159 in patients and 167 in healthy controls. The results of the TRF analysis correlated partly with the data obtained from clone sequencing. Although the results of the sequencing showed high diversity, the genera Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus constituted the major part of the core microbiome found in both groups. A TRF band possibly representing Pseudomonas sp. monoinfection was associated with a reduction of the microbial diversity. Non-cultural methods reveal the complexity of the pulmonary microbiome in healthy individuals and in patients with COPD. Alterations of the microbiome in pulmonary diseases are correlated with disease.
doi:10.1371/journal.pone.0068302
PMCID: PMC3706416  PMID: 23874580
23.  CAVEOLINS AND LUNG FUNCTION 
The primary function of the mammalian lung is to facilitate diffusion of oxygen to venous blood and to ventilate carbon dioxide produced by catabolic reactions within cells. However, it is also responsible for a variety of other important functions, including host defense and production of vasoactive agents to regulate not only systemic blood pressure, but also water, electrolyte and acid-base balance. Caveolin-1 is highly expressed in the majority of cell types in the lung, including epithelial, endothelial, smooth muscle, connective tissue cells, and alveolar macrophages. Deletion of caveolin-1 in these cells results in major functional aberrations, suggesting that caveolin-1 may be crucial to lung homeostasis and development. Furthermore, generation of mutant mice that under-express caveolin-1 results in severe functional distortion with phenotypes covering practically the entire spectrum of known lung diseases, including pulmonary hypertension, fibrosis, increased endothelial permeability, and immune defects. In this Chapter, we outline the current state of knowledge regarding caveolin-1-dependent regulation of pulmonary cell functions and discuss recent research findings on the role of caveolin-1 in various pulmonary disease states, including obstructive and fibrotic pulmonary vascular and inflammatory diseases.
doi:10.1007/978-1-4614-1222-9_11
PMCID: PMC3449096  PMID: 22411320
24.  Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways 
Circulation research  2009;105(7):676-685.
Rationale
Oxidants are important signaling molecules known to increase endothelial permeability, although the mechanisms underlying permeability regulation are not clear.
Objective
To define the role of caveolin-1 in the mechanism of oxidant-induced pulmonary vascular hyperpermeability and edema formation.
Methods and Results
Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H2O2). Caveolin-1 deficient mice (cav-1-/-) were resistant to H2O2-induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H2O2 was completely rescued by expression of caveolin-1 in cav-1-/- mouse lung microvessels, but was not restored by the phosphorylation-defective caveolin-1 mutant. The increase in caveolin-1 phosphorylation induced by H2O2 was dose-dependently coupled to both increased 125I-albumin transcytosis and decreased transendothelial electrical resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H2O2 exposure resulted in the dissociation of vascular endothelial cadherin/β-catenin complexes, and resultant endothelial barrier disruption.
Conclusions
Caveolin-1 phosphorylation-dependent signaling plays a crucial role in oxidative stress-induced pulmonary vascular hyperpermeability via transcellular and paracellular pathways. Thus, caveolin-1 phosphorylation may be an important therapeutic target for limiting oxidant-mediated vascular hyperpermeability, protein-rich edema formation, and acute lung injury.
doi:10.1161/CIRCRESAHA.109.201673
PMCID: PMC2776728  PMID: 19713536
vascular endothelial barrier; transcytosis; adherens junctions; caveolin-1; lung edema
25.  Caveolin-1, TGF-β receptor internalization, and the pathogenesis of systemic sclerosis 
Current opinion in rheumatology  2008;20(6):713-719.
Purpose
To review the scientific literature supporting the participation of caveolin-1 in the pathogenesis of tissue fibrosis and that modulation of the caveolin-1 pathway may represent a novel treatment for systemic sclerosis (SSc) and other fibrotic diseases.
Recent Findings
Caveolin-1 plays an important role in the regulation of transforming growth factor β (TGF-β) signaling owing to its participation in TGF-β receptor (TβR) internalization. TβR internalized through caveolin-1 lipid rafts undergoes rapid degradation, effectively decreasing TGF-β signaling. Studies have shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts. Caveolin-1 was reduced in affected SSc lungs and skin and in idiopathic pulmonary fibrosis (IPF) lung tissues and fibroblasts. Increasing caveolin-1 expression markedly improved bleomycin-induced pulmonary fibrosis. Restoration of caveolin bioavailability employing penetratin, a cell-permeable peptide carrier for a bioactive caveolin-1 fragment abrogated TGF-β activation of cultured human dermal fibroblasts. Systemic administration of penetratin-caveolin-1 peptide to mice with bleomycin-induced lung fibrosis reduced fibrosis.
Summary
Caveolin-1 plays an important role in the regulation of TGF-β signaling and participates in the pathogenesis of SSc and IPF. Restoration of caveolin function employing active caveolin-1 fragments coupled to cell-permeable carrier peptides may represent a novel approach for their treatment.
PMCID: PMC2732362  PMID: 18949888
Caveolin-1; TGF-β; fibrosis; collagen; systemic sclerosis; idiopathic pulmonary fibrosis

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