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Biomedical subjects

Raed A Dweik

Publications and source records attributed to Raed A Dweik.

At least 19 recordsLinked to original sources
PubMed2007

Alterations of cellular bioenergetics in pulmonary artery endothelial cells.

Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NO). Because NO regulates cellular respiration and mitochondrial biogenesis, we hypothesized that abnormalities of bioenergetics may be present in IPAH. Evaluation of pulmonary artery endothelial cells from IPAH and control lungs in vitro revealed that oxygen consumption of IPAH cells was decreased, especially in state 3 respiration with substrates glutamate-malate or succinate, and this decrease paralleled reduction in Complex IV activity and IPAH cellular NO synthesis. IPAH pulmonary artery endothelial cells had decreased mitochondrial dehydrogenase activity and lowered mitochondrial numbers per cell and mitochondrial DNA content, all of which increased after exposure to NO donors. Although IPAH/pulmonary artery endothelial cells' ATP content was similar to control under normoxia, cellular ATP did not change significantly in IPAH cells under hypoxia, whereas ATP decreased 35% in control cells, identifying a greater dependence on cellular respiration for energy in control cells. Evidence that glucose metabolism was subserving the primary role for energy requirements of IPAH cells was provided by the approximately 3-fold greater glycolytic rate of IPAH cells. Positron emission tomography scan with [18F]fluoro-deoxy-D-glucose performed on IPAH patients and healthy controls revealed significantly higher uptake in IPAH lungs as compared with controls, confirming that the glycolytic rate was increased in vivo. Thus, there are substantial changes in bioenergetics of IPAH endothelial cells, which may have consequences for pulmonary hypertensive responses and potentially in development of novel imaging modalities for diagnosis and evaluation of treatment.

Adenosine Triphosphate↗
PubMed2006

Role of epithelial nitric oxide in airway viral infection.

The airway mucosal epithelium is the first site of virus contact with the host, and the main site of infection and inflammation. Nitric oxide (NO) produced by the airway epithelium is vital to antiviral inflammatory and immune defense in the lung. Multiple mechanisms function coordinately to support high-level basal NO synthesis in healthy airway epithelium and further induction of NO synthesis in the infected airway of normal hosts. Hosts deficient in NO synthesis, such as those patients with cystic fibrosis, have impaired antiviral defense and may benefit from therapies to augment NO levels in the airways.

Animals↗
PubMed2006

Validation study of fractional exhaled nitric oxide measurements using a handheld monitoring device.

We tested reproducibility of exhaled nitric oxide (FE(NO)) and inter-operator handling when measured with a handheld device, NIOX MINO. We enrolled 20 volunteers using a priori goals of acceptable reproducibility to be mean within-subject standard deviation less than 3 parts per billion (ppb) for FE(NO) measurements less than 30 ppb, and mean coefficient of variation less than 10% for FE(NO) measurements more than 30 ppb. Seventeen subjects with measurements less than 30 ppb displayed a mean standard deviation of 1.15, and 3 subjects with FE(NO) more than 30 ppb had a mean coefficient of variation of 2.4%. We conclude that NIOX MINO demonstrates excellent reproducibility for all ranges of FE(NO).

Adolescent↗
PubMed2005

Abnormalities in nitric oxide and its derivatives in lung cancer.

RATIONALE: A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer. OBJECTIVE: To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis. METHODS: We analyzed levels of NO, nitrite (NO2-), nitrate (NO3-), and the location of the protein nitration and identified the proteins that are modified. MEASUREMENTS AND MAIN RESULTS: Although exhaled NO and NO2- were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non-tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis. CONCLUSIONS: This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.

Aged↗
PubMed2005

Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma.

RATIONALE: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway are correlated to airflow limitation and hyperreactivity. We hypothesized that asthmatic individuals with higher levels of oxidative stress may have greater loss of SOD activity, which would be reflected systemically in loss of circulating SOD activity and clinically by development of severe asthma and/or worsening airflow limitation. METHODS: To investigate this, serum SOD activity and proteins, the glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in subjects with asthma and healthy control subjects. RESULTS: SOD activity, but not Mn-SOD or Cu,Zn-SOD protein, was lower in asthmatic serum as compared with control, and activity loss was significantly related to airflow limitation. Further, serum SOD activity demonstrated an inverse correlation with circulating levels of 3-bromotyrosine, a posttranslational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified Cu,Zn-SOD to physiologically relevant levels of eosinophil peroxidase-generated reactive brominating species, reactive nitrogen species, or tyrosyl radicals in vitro confirmed that eosinophil-derived oxidative pathways promote enzyme inactivation. CONCLUSION: These findings are consistent with greater oxidant stress in asthma leading to greater inactivation of SOD, which likely amplifies inflammation and progressive airflow obstruction.

Adult↗
PubMed2005

Detection of lung cancer by sensor array analyses of exhaled breath.

RATIONALE: Electronic noses are successfully used in commercial applications, including detection and analysis of volatile organic compounds in the food industry. OBJECTIVES: We hypothesized that the electronic nose could identify and discriminate between lung diseases, especially bronchogenic carcinoma. METHODS: In a discovery and training phase, exhaled breath of 14 individuals with bronchogenic carcinoma and 45 healthy control subjects or control subjects without cancer was analyzed. Principal components and canonic discriminant analysis of the sensor data was used to determine whether exhaled gases could discriminate between cancer and noncancer. Discrimination between classes was performed using Mahalanobis distance. Support vector machine analysis was used to create and apply a cancer prediction model prospectively in a separate group of 76 individuals, 14 with and 62 without cancer. MAIN RESULTS: Principal components and canonic discriminant analysis demonstrated discrimination between samples from patients with lung cancer and those from other groups. In the validation study, the electronic nose had 71.4% sensitivity and 91.9% specificity for detecting lung cancer; positive and negative predictive values were 66.6 and 93.4%, respectively. In this population with a lung cancer prevalence of 18%, positive and negative predictive values were 66.6 and 94.5%, respectively. CONCLUSION: The exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose. The results provide feasibility to the concept of using the electronic nose for managing and detecting lung cancer.

Adult↗
PubMed2005

Pleural effusions: evaluation and management.

Pleural effusions are very common, and physicians of all specialties encounter them. A pleural effusion represents the disruption of the normal mechanisms of formation and drainage of fluid from the pleural space. A rational diagnostic workup, emphasizing the most common causes, will reveal the etiology in most cases.

Clinical Laboratory Techniques↗
PubMed2004

Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO.

Blood Pressure↗
PubMed2004

Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.

Arginase↗
PubMed2003

Dysregulation of endogenous carbon monoxide and nitric oxide production in patients with advanced ischemic or nonischemic cardiomyopathy.

Carbon monoxide (CO) and nitric oxide (NO) are endogenous vasoregulatory molecules whose role in heart failure is not fully known. Exhaled CO and NO measurement provide novel noninvasive assessment of their endogenous production. We compared exhaled CO and NO in 24 patients with advanced ischemic and nonischemic cardiomyopathy and in 13 control subjects without known cardiac disease at rest and at 1 and 5 minutes after exercise testing. Exhaled CO was lower in patients with cardiomyopathy at rest (1.66 +/- 0.2 vs 1.80 +/- 0.5 ppm, p = 0.02) and 1 minute after exercise (1.35 +/- 0.2 vs 1.81 +/- 0.5 ppm, p = 0.009), with a similar trend at 5 minutes after exercise (1.45 +/- 0.3 vs 1.81 +/- 0.5 ppm, p = 0.14). Exhaled CO decreased in patients with cardiomyopathy after exercise (p <0.001 and p = 0.02 at rest vs 1 and 5 minutes after exercise, respectively) but was maintained in controls. Exhaled NO did not differ between patients with cardiomyopathy and controls at rest (9.48 +/- 1.4 vs 9.68 +/- 1.5 ppb, p = NS) and after exercise (1 minute: 10.91 +/- 1.8 vs 9.19 +/- 1.2 ppb; 5 minutes: 10.52 +/- 1.5 vs 8.90 +/- 1.2 ppb, p = NS). Exhaled NO increased after exercise in patients with cardiomyopathy (p = 0.01 and p = 0.04 rest vs exercise at 1 and 5 minutes, respectively), but was maintained in controls. Exhaled CO and NO were not correlated with peak oxygen consumption in patients with cardiomyopathy. The differential responses in exhaled CO and NO at rest or with exercise between patients with cardiomyopathy and normal controls may point to dysregulation in endogenous CO and NO production.

Adult↗
PubMed2003

Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge.

Exhaled nitric oxide (NO) levels are high in asthmatic subjects and increase with exacerbations. We hypothesized that higher levels of NO observed during asthma exacerbations are due to increased synthesis of NO. Exhaled NO and peak flows were measured in 11 asthmatic and 9 healthy control subjects before and after experimental asthmatic response induced by whole lung allergen challenge. Baseline peak flows of asthmatics were significantly lower than controls and decreased significantly immediately after challenge (P = 0.004). NO was measured by collecting exhaled breaths without breath hold (NO0) and after a 15-s breath hold (NO15). The rate of NO accumulation over time [parts/billion per second (ppb/s)] was calculated by DeltaNO/Deltat = (NO15 - NO0)/15, where Delta denotes a change and t is time. The NO accumulation rates in asthmatic and control subjects were similar at baseline; however, NO accumulation at 24 h increased threefold from baseline in asthmatic compared with control subjects (asthmatic subjects, 0.6 +/- 0.2 ppb/s; control subjects, 0.2 +/- 0.1 ppb/s; P = 0.01). Our study suggests that increased NO during an asthma exacerbation is due to increased synthesis, perhaps by increased expression of NO synthases.

Adolescent↗
PubMed2003

Beryllium dermatitis.

Chronic beryllium disease is a granulomatous disorder characterized by a cell-mediated immune response to beryllium. Most reports of chronic beryllium disease discuss pulmonary and noncutaneous immunologic findings. This report of occupational chronic beryllium disease emphasizes cutaneous findings and discusses the potential role of skin exposure in the disease.

Adult↗
PubMed2003

Primary pulmonary hypertension: an overview of epidemiology and pathogenesis.

Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.

Endothelial Growth Factors↗
PubMed2002

Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency.

Quantitations of exhaled nitric oxide (NO) and carbon monoxide (CO) have been proposed as noninvasive markers of airway inflammation. We hypothesized that exhaled CO is increased in individuals with alpha(1)-antitrypsin (AT) deficiency, who have lung inflammation and injury related to oxidative and proteolytic processes. Nineteen individuals with alpha(1)-AT deficiency, 22 healthy controls, and 12 patients with non-alpha(1)-AT-deficient chronic obstructive pulmonary disease (COPD) had NO, CO, CO(2), and O(2) measured in exhaled breath. Individuals with alpha(1)-AT deficiency had lower levels of NO and CO than control or COPD individuals. Alpha(1)-AT-deficient and COPD patients had lower exhaled CO(2) than controls, although only alpha(1)-AT-deficient patients had higher exhaled O(2) than healthy controls. NO was correlated inversely with exhaled O(2) and directly with exhaled CO(2), supporting a role for NO in regulation of gas exchange. Exhaled gases were not significantly related to corticosteroid use or lung function. Demonstration of lower than normal CO and NO levels may be useful as an additional noninvasive method to evaluate alpha(1)-AT deficiency in individuals with a severe, early onset of obstructive lung disease.

Administration, Inhalation↗