Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly!
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Gene Expression Regulation↗
Biomedical subjects
R A Dweik
Publications and source records attributed to R A Dweik.
Exhaled breath condensate: methodological recommendations and unresolved questions.
Collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lungs. EBC contains large number of mediators including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, nitrogen oxides, peptides and cytokines. Concentrations of these mediators are influenced by lung diseases and modulated by therapeutic interventions. Similarly EBC pH also changes in respiratory diseases. The aim of the American Thoracic Society/European Respiratory Society Task Force on EBC was to identify the important methodological issues surrounding EBC collection and assay, to provide recommendations for the measurements and to highlight areas where further research is required. Based on the currently available evidence and the consensus of the expert panel for EBC collection, the following general recommendations were put together for oral sample collection: collect during tidal breathing using a noseclip and a saliva trap; define cooling temperature and collection time (10 min is generally sufficient to obtain 1-2 mL of sample and well tolerated by patients); use inert material for condenser; do not use resistor and do not use filter between the subject and the condenser. These are only general recommendations and certain circumstances may dictate variation from them. Important areas for future research involve: ascertaining mechanisms and site of exhaled breath condensate particle formation; determination of dilution markers; improving reproducibility; employment of EBC in longitudinal studies; and determining the utility of exhaled breath condensate measures for the management of individual patients. These studies are required before recommending this technique for use in clinical practice.
Biomarkers↗
Alterations in exhaled gas profile during allergen-induced asthmatic response.
The source of exhaled carbon monoxide (CO) and the relationship to airway inflammation are not clear. If CO is produced by the inflamed airway, we hypothesized that inflammation induced by allergen challenge would increase exhaled CO of atopic asthmatics. Eight atopic asthmatics underwent whole lung allergen challenge. CO, nitric oxide (NO), oxygen, and carbon dioxide (CO(2)) were measured simultaneously in exhaled breath which was collected into Mylar balloons before (baseline), immediately after, and at subsequent times after allergen. NO was higher in asthmatics than control subjects at baseline, increased further in seven of the eight asthmatics after allergen, and was inversely correlated to specific conductance. In contrast, exhaled CO of asthmatics was not higher than that of control individuals at baseline, decreased immediately after allergen, and returned to baseline levels during the late asthmatic response. Thus, allergen-induced airway inflammation did not lead to increased exhaled CO in asthma.
Adult↗
NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response.
A wealth of evidence supports increased NO (NO.) in asthma, but its roles are unknown. To investigate how NO participates in inflammatory airway events in asthma, we measured NO. and NO. chemical reaction products [nitrite, nitrate, S-nitrosothiols (SNO), and nitrotyrosine] before, immediately and 48 h after bronchoscopic antigen (Ag) challenge of the peripheral airways in atopic asthmatic individuals and nonatopic healthy controls. Strikingly, NO(3)(-) was the only NO. derivative to increase during the immediate Ag-induced asthmatic response and continued to increase over 2-fold at 48 h after Ag challenge in contrast to controls [P < 0.05]. NO(2)(-) was not affected by Ag challenge at 10 min or 48 h after Ag challenge. Although SNO was not detectable in asthmatic airways at baseline or immediately after Ag, SNO increased during the late response to levels found in healthy controls. A model of NO. dynamics derived from the current findings predicts that NO. may have harmful effects through formation of peroxynitrite, but also subserves an antioxidant role by consuming reactive oxygen species during the immediate asthmatic response, whereas nitrosylation during the late asthmatic response generates SNO, safe reservoirs for removal of toxic NO. derivatives.
Adult↗
High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy.
Lack of vasodilator substances, such as nitric oxide (NO), has been implicated in the development of pulmonary hypertension, but the pathogenesis of the disease remains speculative. We hypothesized that NO plays a role in the pathogenesis of primary pulmonary hypertension (PPH), and may serve as a sensitive and specific marker of disease progression and/or severity. To test this, exhaled NO and pulmonary artery pressure were measured in individuals with PPH and secondary pulmonary hypertension (SPH) on various therapies, including the potent vasodilator epoprostenol (prostacyclin), compared with healthy controls. NO in exhaled breath of individuals with PPH was lower than SPH or control (p<0.05). In contrast, exhaled NO of individuals with PPH or SPH receiving epoprostenol was strikingly higher than PPH or SPH individuals not receiving epoprostenol, or controls. Concomitant with higher NO levels, right ventricular systolic pressure of individuals significantly decreased with epoprostenol. Importantly, in paired measures of exhaled NO before and after epoprostenol, NO increased in all pulmonary hypertensive individuals 24 h after initiation of epoprostenol therapy (p<0.05). NO may be a useful noninvasive marker of pulmonary hypertension severity and response to prostacyclin therapy.
Adolescent↗
High levels of exhaled nitric oxide (NO) and NO synthase III expression in lesional smooth muscle in lymphangioleiomyomatosis.
Smooth-muscle proliferation is the hallmark of lymphangioleiomyomatosis (LAM). Although little is known about the pathogenesis of LAM, nitric oxide (NO) is a key regulator of smooth-muscle proliferation. NO is linked to the pathogenesis of other lung diseases such as asthma, in part by the finding of higher-than-normal levels of exhaled NO. If NO were involved in the abnormal smooth-muscle proliferation in LAM, we reasoned that exhaled NO from individuals with LAM would also differ from that of healthy control subjects. To evaluate this hypothesis, we studied exhaled NO in individuals with LAM in comparison with healthy and asthmatic women using a chemiluminescent NO analyzer. Women with LAM had higher exhaled NO than did healthy women but lower than asthmatic women (NO [parts per billion] median (25 to 75%): LAM 8 [7 to 15] [n = 28], control 6 [5 to 8] [n = 21], asthma 14 [8 to 25] [n = 22]; Kruskal-Wallis P < 0.001). Immunohistochemical studies on formalin-fixed, paraffin-embedded sections of surgical and autopsy material from lungs of individuals with LAM showed diffuse NO synthase III (NOSIII) expression in the lesional smooth muscle of LAM similar to that in the vascular endothelium. NOSIII expression was limited to the vascular endothelium and bronchial smooth muscle in healthy control lungs. The increased NO and the presence of NOSIII expression in lesional smooth muscle warrants further study into the potential role for NO in the pathogenesis of LAM.
Adult↗
Major histocompatibility locus genetic markers of beryllium sensitization and disease.
Hypersensitivity to beryllium (Be) is found in 1-16% of exposed workers undergoing immunological screening for beryllium disease using the beryllium lymphocyte proliferation test (BeLPT). However, only approximately 50% of BeLPT-positive workers present with lung granulomas (i.e. berylliosis). As berylliosis is associated with the human leukocyte antigen (HLA)-DP supratypic marker DPGlu69, the authors asked whether this marker is differentially associated with disease presentation. A population of 639 workers from a beryllium factory undergoing BeLPT screening was evaluated in a nested case-control study for the prevalence of HLA-DPGlu69, the HLA-DPB1, HLA-DQ and HLA-DR alleles and of the biallelic tumour necrosis factor (TNF)-alpha polymorphism TNF-alpha-308 in 23 individuals presenting as "sensitized" (i.e. BeLPT-positive without lung granulomas) and in 22 presenting as "diseased" (i.e. BeLPT-positive with granulomas in the lung biopsy). The HLA-DPGlu69 marker was associated with "disease" (odds ratio (OR) 3.7, p=0.016, 95% confidence interval (CI) 1.4-10.0), whilst the high TNF-alpha production-related TNF-alpha-308*2 marker was associated with both a positive BeLPT (OR 7.8, corrected p<0.0001, 95% CI 3.2-19.1) with no difference between "sensitization" and "disease". Furthermore, the HLA-DRArg74 marker was associated with "sensitization" without disease (OR 3.96, p=0.005, 95%, CI 1.5-10.1). The data indicate that tumour necrosis factor-alpha, human leukocyte antigen-DR and human leukocyte antigen-DP markers play different roles in beryllium sensitization and granuloma formation in beryllium-exposed workers.
Adult↗
The promise and reality of nitric oxide in the diagnosis and treatment of lung disease.
Endogenously produced nitric oxide plays a major role in lung physiology and pathology. Inhaled nitric oxide given exogenously has been studied extensively as a treatment for many lung diseases, and the results suggest that it may help improve oxygenation in some patients. Several issues need to be addressed, however, before it can be used in routine clinical practice.
Altitude Sickness↗
Drug-induced lung disease.
Drug-induced lung disease is a major source of iatrogenic injury. We review the various drugs known to induce injury and the various patterns of injury seen.
Drug-Related Side Effects and Adverse Reactions↗
Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis.
Evidence supporting increased nitric oxide (NO) in asthma is substantial, although the cellular and molecular mechanisms leading to increased NO are not known. Here, we provide a clear picture of the events regulating NO synthesis in the human asthmatic airway in vivo. We show that human airway epithelium has abundant expression of NO synthase II (NOSII) due to continuous transcriptional activation of the gene in vivo. Individuals with asthma have higher than normal NO concentrations and increased NOSII mRNA and protein due to transcriptional regulation through activation of Stat1. NOSII mRNA expression decreases in asthmatics receiving inhaled corticosteroid, treatment effective in reducing inflammation in asthmatic airways. In addition to transcriptional mechanisms, post-translational events contribute to increased NO synthesis. Specifically, high output production of NO is fueled by a previously unsuspected increase in the NOS substrate, l -arginine, in airway epithelial cells of asthmatic individuals. Finally, nitration of proteins in airway epithelium provide evidence of functional consequences of increased NO. In conclusion, these studies define multiple mechanisms that function coordinately to support high level NO synthesis in the asthmatic airway. These findings represent a crucial cornerstone for future therapeutic strategies aimed at regulating NO synthesis in asthma.
Adult↗
Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response.
Loss of superoxide dismutase activity occurs within minutes of an acute asthmatic response to segmental antigen instillation into the lung of individuals with atopic asthma. Decreased activity undoubtedly contributes to airway inflammation and injury through increased formation of reactive oxygen and nitrogen species, and suggests that enrichment of lung antioxidants is therapeutic for asthma.
Adult↗
Eosinophils generate brominating oxidants in allergen-induced asthma.
Eosinophils promote tissue injury and contribute to the pathogenesis of allergen-triggered diseases like asthma, but the chemical basis of damage to eosinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyrosine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine serves as a specific "molecular fingerprint" for proteins modified through the eosinophil peroxidase-H(2)O(2) system in the presence of plasma levels of halides. We applied a localized allergen challenge to model the effects of eosinophils and brominating oxidants in human lung injury. Endobronchial biopsy specimens from allergen-challenged lung segments of asthmatic, but not healthy control, subjects demonstrated significant enrichments in eosinophils and eosinophil peroxidase. Baseline levels of 3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic asthmatic individuals were modestly but not statistically significantly elevated over those in control subjects. After exposure to segmental allergen challenge, lung segments of asthmatics, but not healthy control subjects, exhibited a >10-fold increase in BAL 3-bromotyrosine content, but only two- to threefold increases in 3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived myeloperoxidase. These results identify reactive brominating species produced by eosinophils as a distinct class of oxidants formed in vivo. They also reveal eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory tissue injury in humans.
Allergens↗
Primary pulmonary hypertension and thyroid disease.
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Diagnosis, Differential↗
Hypertensive urgency induced by an interaction of mirtazapine and clonidine.
Mirtazapine is a new antidepressant with a tetracyclic chemical structure that is not related to selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. The antidepressant effect results from stimulation of the noradrenergic system through antagonism at central (alpha2-inhibitory receptors. Clonidine exerts its antihypertensive effect by stimulating these receptors to cause a reduction in endogenous release of norepinephrine. Therefore, the two agents have mechanisms of action that potentially oppose one another. We report a case of hypertensive urgency that ensued after a patient stabilized on clonidine began taking mirtazapine.
Adrenergic alpha-Agonists↗
A 65-year-old factory worker with dyspnea on exertion and a normal chest x-ray.
Chronic beryllium disease is an occupationally acquired granulomatous lung disease similar to sarcoidosis. It is caused by exposure to beryllium in genetically susceptible persons. It should be suspected in patients with beryllium exposure who present with pulmonary symptoms or have a positive screening blood beryllium-specific lymphocyte proliferation test. The diagnosis is confirmed by the finding of granulomas on transbronchial biopsy in the appropriate clinical and epidemiologic setting. Although there is no cure, treatment with corticosteroids is usually beneficial. In view of the potential side effects, treatment is reserved for patients with symptoms or a decline in pulmonary function.
Aged↗
Primary pulmonary hypertension: update on pathogenesis and novel therapies.
Primary pulmonary hypertension is a progressive and fatal disease that chiefly affects young adults. Although its etiology is a mystery, recent research has uncovered several biochemical derangements in this disorder, and new therapies are prolonging survival.
Female↗
Nitric oxide regulation of asthmatic airway inflammation with segmental allergen challenge.
BACKGROUND: Despite evidence of increased nitric oxide (NO) in asthmatic compared with healthy individuals, the role of NO in airway inflammation is unclear. OBJECTIVE: The purpose of the study was to determine the in vivo effects of localized allergen challenge on airway NO levels and transcription factor activation. METHODS: In this study localized allergen challenge was used as a model of asthmatic exacerbation to determine the relationship of NO to airway inflammation. RESULTS: With allergen challenge, asthmatic patients had a rise in airway NO levels, whereas NO levels in healthy controls did not change. The increased NO in asthma with allergen challenge compared with healthy control subjects was associated with an increase in inflammatory cytokines (GM-CSF and macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To investigate the mechanisms of cytokine gene expression, activation of the transcription factors activator protein-1 and nuclear factor-kappaB (NF-kappaB) in cells from BAL were evaluated. Activator protein-1 was not activated before or after local allergen challenge. In contrast, NF-kappaB activation was less in BAL cells from asthmatic patients with increased NO in comparison with controls. CONCLUSION: Our studies are the first to suggest an inverse correlation between NF-kappaB and airway NO in a localized segmental allergen challenge model in allergic asthmatic patients. The current study demonstrates that activation of the inflammatory response (eg, cytokines, cellular infiltrate) in allergic asthmatic patients is temporally associated with increased airway NO. We propose that NO that is up-regulated by cytokines is part of an autoregulatory feedback loop (ie, allergen challenge stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production).
Adult↗
Future of flexible bronchoscopy.
Despite some potential "threats" (Table 3), the future of bronchoscopy is likely full with ever expanding applications in clinical medicine and research (Tables 1 and 2). The role of bronchoscopy in lung cancer continues to expand and the usefulness of newer techniques needs to be established. The role of FB is also ever expanding in the immuno compromised host and critically ill patients. Future studies, however, should concentrate on patient outcome, especially survival and performance status. Therapeutic bronchoscopy has been extended to many areas and the emphasis of future research will likely continue to be at the molecular level rather than on studies of better instruments for retrieval purposes. The most exciting developments are likely to be in the field of gene therapy, which has made remarkable progress in the past decade. Gene therapy can be a powerful technology, but several hurdles must be overcome to make gene therapy a reality for treating human disease in the future. As the cost of technology continues to challenge health care delivery systems, a major challenge for the future of bronchoscopy is to evaluate new technologies and applications based on their impact on patient outcome, survival, and management of cost.
Bronchoscopes↗