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Norbert F Voelkel

Publications and source records attributed to Norbert F Voelkel.

At least 19 recordsLinked to original sources
PubMed2007

Gene expression profiling in pulmonary hypertension.

The application of functional genomics toward the investigation of complex medical conditions has moved from a futuristic dream to a medical reality in less then a decade. The ability to examine the expression level of thousands of genes simultaneously has opened the door for entirely new approaches toward experimental observation and discovery. The resulting data from these genomic studies is being collected at an unprecedented scale. This wealth of data can present its own obstacles in terms of analysis. However, as new and more powerful means of examining these experiments are developed, medical science is reaping significant benefit. The power of microarray gene expression analysis has been directed at a diverse and complex array of diseases. As will be discussed in this article, the investigation of pulmonary hypertension has already benefited greatly from the application of this technology.

Animals↗
PubMed2006

Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury.

Clinical studies demonstrate that acute renal failure (ARF) is associated with increased mortality, which may be due to pulmonary complications. ARF may affect the lung via increased renal production or impaired clearance of mediators of lung injury, such as proinflammatory cytokines. Bilateral nephrectomy is a method to examine directly the deleterious systemic effects of absent renal clearance in ARF without the confounding effects that are associated with ischemia-reperfusion injury (e.g., ischemic ARF) or systemic toxicity (e.g., cisplatin-induced ARF). This study contrasts the effects of ischemic ARF and bilateral nephrectomy on serum cytokines and lung injury. It demonstrates that the acute absence of kidney function after both ischemic ARF and bilateral nephrectomy is associated with an increase in multiple serum cytokines, including IL-6 and IL-1beta, and that the cytokine profiles were distinct. Lung injury after ischemic ARF and bilateral nephrectomy was similar and was characterized by pulmonary vascular congestion and neutrophil infiltration. For investigation of the role of proinflammatory cytokines in pulmonary injury after ARF, the anti-inflammatory cytokine IL-10 was administered before bilateral nephrectomy. IL-10 treatment improved pulmonary architecture and was associated with a reduction in inflammatory markers, including bronchoalveolar lavage fluid total protein, pulmonary myeloperoxidase activity (a biochemical marker of neutrophils), and the chemokine macrophage inflammatory protein 2. These data demonstrate for the first time that the acute absence of kidney function results in pulmonary injury independent of renal ischemia and highlight the critical role of the kidney in the maintenance of serum cytokine balance and pulmonary homeostasis.

Acute Kidney Injury↗
PubMed2006

HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques.

RATIONALE: HIV-infected patients with pulmonary arterial hypertension have histologic manifestations that are indistinguishable from those found in patients with idiopathic pulmonary arterial hypertension. In addition, the role of pleiotropic viral proteins in the development of plexiform lesions in HIV-related pulmonary hypertension (HRPH) has not been explored. Simian immunodeficiency virus (SIV) infection of macaques has been found to closely recapitulate many of the characteristic features of HIV infection, and thus hallmarks of pulmonary arterial hypertension should also be found in this nonhuman primate model of HIV. OBJECTIVES: To determine whether pulmonary arterial lesions were present in archived SIV-infected macaque lung tissues from Johns Hopkins University and two National Primate Research Centers. METHODS: Archived macaque and human lung sections were examined via immunohistochemistry for evidence of complex vascular lesions. RESULTS: Complex plexiform-like lesions characterized by lumenal obliteration, intimal disruption, medial hypertrophy, thrombosis, and recanalized lumena were found exclusively in animals infected with SHIV-nef (a chimeric viral construct containing the HIV nef gene in an SIV backbone), but not in animals infected with SIV. The mass of cells in the lesions were factor VIII positive, and contained cells positive for muscle-specific and smooth muscle actins. Lung mononuclear cells were positive for HIV Nef, suggesting viral replication. Endothelial cells in both the SHIV-nef macaques and patients with HRPH, but not in patients with idiopathic pulmonary arterial hypertension, were also Nef positive. CONCLUSIONS: The discovery of complex vascular lesions in SHIV-nef- but not SIV-infected animals, and the presence of Nef in the vascular cells of patients with HRPH, suggest that Nef plays a key role in the development of severe pulmonary arterial disease.

Animals↗
PubMed2006

Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension.

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.

Animals↗
PubMed2006

Sarcoidois and pulmonary hypertension--a case report.

We report a case of severe pulmonary hypertension associated with sarcoidosis with a unique histopathological presentation. This 43-year old obese patient first presented eight years ago with complaint of dyspnea on exertion for four years and was diagnosed as primary pulmonary hypertension. Six years later, a skin biopsy performed on her left cheek to rule out squamous cell carcinoma revealed sarcoidosis. The patient was then put on steroid therapy and subsequently, the oxygen saturation improved transiently, although the mean pulmonary arterial pressure did not show improvement. The patient was then started on prostacyclin infusion and was hemodynamically stable, but the pulmonary artery pressures worsened. The patient died from complications subsequent to a diagnostic procedure. An autopsy limited to the lungs was performed and routinely prepared hematoxylin and eosin stained sections were examined. Immunohistochemical stains for CD31, factor VIII-related antigen and muscle-specific actin were performed on selected sections. The diagnosis of sarcoidosis was confirmed. However, pulmonary fibrosis was not seen. The granulomas surrounded medium- and small-sized pulmonary arteries, but did not destroy the vessel wall. Plexiform lesions indicating severe pulmonary hypertension were identified in pulmonary arteries, which were not involved by granulomas.

Adult↗
PubMed2006

Severe pulmonary hypertension in postmenopausal obese women.

CONTEXT: Severe pulmonary hypertension (PH) is a rare disorder triggered by a variety of factors and disease conditions and characterized by a shared pathophysiology. Two decades ago it was widely held that "primary" (idiopathic) pulmonary hypertension (PPH) is a disease of young women. However, we noticed recently in the UCHSC Pulmonary Hypertension Center that women with severe PH are frequently postmenopausal and overweight or obese. OBJECTIVES: To determine whether severe PH is a disease not only of young women but also of postmenopausal women who are overweight or obese. DESIGN, SETTING, AND PARTICIPANTS: The medical records of 541 postmenopausal female patients at the UCHSC Pulmonary Hypertension Center were reviewed. The patients were divided into two groups based on their diagnosis of either primary or secondary PH. MAIN OUTCOME MEASURES: The medical records of postmenopausal women with severe PH were further reviewed for history of diabetes, systemic hypertension, and the use of anti-depressants, hormone replacement therapy, combination of anti-depressants and hormone replacement therapy, as well as anorexigens. Laboratory data such as elevated cholesterol, elevated uric acid, and elevated C-reactive protein (CRP) were recorded in these patients, as well as physical exam data to determine the body-mass index (BMI) of the patients. RESULTS: 56% of all pulmonary hypertensive women who were patients at the UCHSC Pulmonary Hypertension Center were postmenopausal. 39% of postmenopausal women with PPH and 48% with secondary severe PH were obese. In addition, postmenopausal obese women frequently had systemic hypertension and were on hormone replacement therapy as well as antidepressant medication. CONCLUSIONS: Obesity, hormone replacement therapy and anti-depressant therapy may contribute to the development of severe PH in genetically predisposed women. Further investigation, in the form of a prospective, case-control study, is needed to determine whether these factors exert a causative effect in postmenopausal women.

Antidepressive Agents↗
PubMed2006

Morphologic changes in explanted lungs after prostacyclin therapy for pulmonary hypertension.

Prostacyclin (PGI2) causes vasodilation and inhibition of platelet aggregation in vivo. PGI2 is also postulated to affect pulmonary vascular remodeling, at least partly through anti-proliferative effect via PGI2 receptor (PGIR). However, the mechanism(s) of action by which (PGI2) exerts its therapeutic effect is still not clear despite clear clinical benefit seen in severe pulmonary hypertension (PH) patients. We performed a histopathologic and morphometric study on the explanted lung tissues from PGI2-treated patients prior to lung transplantation (n = 9), in an attempt to elucidate morphologic changes associated with PGI2 treatment. Explanted lungs from PH patients without PGI2 treatment were examined as the control (n = 11). We also studied the possible differences in PGIR expression between the treated and untreated groups by immunohistochemical method. Seven out of 9 treated patients showed moderate to severe bronchial and perivascular inflammation, as opposed to only 1 such case in the control group. Five out of 9 treated cases showed moderate to severe alveolar edema with or without evidence of old hemorrhage, in contrast to only 1 case showing moderate alveolar edema in control patients. Morphometry did not reveal any significant difference between the two groups either in the % thickness of intima, media, or adventitia or in the density of plexiform lesions. Immunostain also failed to demonstrate any notable difference in PGIR expression. In conclusion, PGI2-treated cases revealed more pronounced pulmonary alveolar edema and inflammation, but no morphological evidence of altered vascular remodeling or PGIR expression after PGI2 therapy.

Adult↗
PubMed2006

Pulmonary flow reserve in children with idiopathic pulmonary arterial hypertension: implications for diagnosis and therapy.

AIMS: Endothelial dysfunction is likely to contribute to the pathogenesis of idiopathic Pulmonary Arterial Hypertension (iPAH). We hypothesize that there are different patterns of endothelial cell function, which we studied in 17 children with iPAH. METHODS AND RESULTS: Pulmonary flow reserve was determined by acetylcholine infusion into segmental pulmonary arteries utilizing quantitative angiography and intra-arterial Doppler flow wire. Depending on the reactivity of the pulmonary to systemic arterial pressure ratio to short-term oxygen and intravenous epoprostenol or aerosolized iloprost responders and nonresponders were classified. In 7 responders to oxygen-prostanoid administration the pressure ratio decreased from 0.9 +/- 0.2 to 0.31 +/- 0.11 (p = 0.01), the mean pulmonary flow reserve showed an excessive increase to 3.6 +/- 2.0 (p = 0.01) after infusion of acetylcholine. In 10 non-responders the pressure ratios remained unchanged during oxygen-prostanoid testing. 4 of 5 patients without any effect to acetylcholine died despite long-term epoprostenol treatment. The other 5 nonresponders to oxygen-prostanoid showed an impaired but significant increase of the pulmonary flow reserve of 1.6 +/- 1.1 (p = 0.01). 2 of these patients did not only improve clinically, but regained vascular reactivity by additional therapy with sildenafil. CONCLUSION: Endothelial reactivity in iPAH is either extensive, impaired or absent. Acetylcholine infusion casts a light on the pathogenesis and has implications for therapy.

Acetylcholine↗
PubMed2006

Importance of right ventricular end-systolic regional wall stress in idiopathic pulmonary arterial hypertension: a new method for estimation of right ventricular wall stress.

RV dysfunction in idiopathic (primary) pulmonary hypertension (IPAH) is often characterized by chamber dilation, ventricular hypertrophy, and impaired systolic function. In this study we characterize right ventricular (RV) chamber size, end-diastolic thickness, myocardial mass, and ejection fraction in patients with right ventricular heart failure from IPAH, n = 16 and compare these characteristics to a control population of cardiac transplant patients (TX, n = 4) and a group of normal subjects (N, n = 5). Subjects underwent both gated cardiac magnetic resonance imaging (MRI) of the right ventricle and right heart catheterization (RHC). Using parameters from both the MRI and RHC, an estimate of RV end-systolic relative wall stress (RWS) was calculated. RV RWS was 34.7 +/- 8.4 and 17.3 +/- 3.8 Kdynes/cm2 in the cardiac transplant and control subjects respectively and was significantly elevated 104.1 Kdynes/cm2 in IPAH patients (IPAH vs N and TX; p = 0.004 and 0.008 ). RV ejection fraction RVEF was lower in IPAH patients 0.36 +/- .10 than in N and TX 0.57 +/- .04 and 0.55 +/- .08 respectively, (p = 0.0006 N and 0.0007 TX). An inverse linear correlation was demonstrated between RWS and RVEF (y = 215- 332x; R = .80, p < or = .0001). Right ventricular RWS is significantly elevated in IPAH and may provide a useful quantitative monitoring tool in patients with IPAH to assess the benefit of different therapeutic interventions and provide prognostic information.

Cardiomegaly↗
PubMed2006

Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth.

We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension is associated with not only initial endothelial cell (EC) apoptosis followed by the emergence of apoptosis-resistant proliferating EC but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that EC death results in the selection of an apoptosis-resistant, proliferating, and phenotypically altered EC phenotype. We postulate here that the initial apoptosis of EC induces the release of mediators that cause VSMC proliferation. We cultured EC in an artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416. Flow cytometry for the proliferation marker bromodeoxyuridine showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC, whereas serum-free medium conditioned by nonapoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of transforming growth factor (TGF)-beta1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-beta1 blockade prevented the proliferation of cultured VSMC. In conclusion, EC death induced by high shear stress and VEGFR blockade leads to the production of factors, in particular TGF-beta1, that activate VSMC proliferation.

Animals↗
PubMed2006

A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema.

RATIONALE: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of alpha1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema. OBJECTIVES: We propose that, in addition to its antielastolytic effects, alpha1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. METHODS, MEASUREMENTS, AND MAIN RESULTS: Transduction of human alpha1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human alpha1-antitrypsin intravenously. CONCLUSIONS: Our findings suggest that inhibition of structural alveolar cell apoptosis by alpha1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of alpha1-antitrypsin.

Adenoviridae↗
PubMed2006

Vascular endothelial growth factor in the lung.

Vascular endothelial growth factor (VEGF) is a pluripotent growth and permeability factor that has a broad impact on endothelial cell function. The lung tissue is very rich in this protein; many different lung cells produce VEGF and also respond to VEGF. VEGF is critical for the development of the lung and serves as a maintenance factor during adult life. In addition to the physiological functions of this protein, there is increasing evidence that VEGF also plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema. Here we provide a comprehensive overview of the rapidly expanding literature.

Animals↗
PubMed2006

Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension.

Caveolae are cell plasma membrane microdomains implicated in organizing and concentrating many signaling molecules. In the lung, caveolae are in endothelium, smooth muscle, fibroblasts, and pneumocytes. Caveolin is the main structural protein of caveolae. Caveolin 1 is down-regulated in transformed cells and may be a tumor suppressor protein. Caveolin 2 is coexpressed and hetero-oligomerizes with caveolin 1. Because the cells of the plexiform lesions in severe pulmonary hypertension (PH) are phenotypically altered, we wondered whether these cells lack caveolin. We now demonstrate by immunolocalization that while caveolin is expressed in lung endothelial, smooth-muscle, and alveolar septal cells, its expression is absent or decreased in plexiform lesions and in some muscularized precapillary arterioles. In contrast, Western blot analysis of total lung extracts from patients with severe PH shows no significant reduction in caveolin. Similar to the human lung tissue, a rat model of severe PH demonstrates absent-to-decreased caveolin expression in the complex vascular lesions. Additionally, it appears that caveolin and heme oxygenase 1 (HO-1) [a heat shock protein] are co-expressed since HO-1 expression parallels caveolin expression in vascular lesions. We propose that loss of caveolin expression in the cells of the complex vascular lesions in severe PH reflects the proliferating and apoptosis-resistant nature of these cells.

Adult↗
PubMed2006

Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease?

The alveolar destruction leading to airspace enlargement in patients with end-stage chronic obstructive pulmonary disease (COPD) is frequently progressive, despite smoking cessation. Several laboratories have accumulated data demonstrating the presence of immune cells in bronchial biopsy specimens and lung tissue sections from patients with COPD. Recently, the accumulation of T and B lymphocytes, often forming follicles, in the lung parenchyma from patients with severe COPD has been reported. In addition, it has been postulated that there might be an autoimmune component to COPD. T-cell receptor analysis has provided data consistent with the concept of T-cell clones in the lung tissue from patients with COPD. Against this background, we developed a model of autoimmune emphysema in adult rats. Based on published data showing that immunization of mice with human umbilical vein endothelial cells (HUVECs) causes production of anti-vascular endothelial growth factor (VEGF) receptor II (KDR) antibodies, and our own data indicating that administration of a VEGF receptor blocker in adult rats causes emphysema, we reasoned that intraperitoneal injection of HUVECs in rats would generate both anti-VEGF receptor antibodies and emphysema. Indeed, intraperitoneal injection of HUVECs caused emphysema. We further explored the autoimmune nature of this model, identified KDR antibodies in the serum of HUVEC-immunized rats, and injected serum from the emphysematous rats into naive rats and mice, which resulted in emphysema. Presently, we are in the process of investigating whether cigarette smoke extract causes emphysema. We recently identified anti-endothelial cell antibodies in the serum of patients with end-stage emphysema.

Animals↗