Olga Torre

Effects of Aminoguanidine, an Inhibitor of Inducible Nitric Oxide Synthase, on Nitric Oxide Production and Its Metabolites in Healthy Control Subjects, Healthy Smokers, and COPD Patients

BACKGROUNDnNitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS. NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD.nnnMETHODSnTo examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers, and healthy nonsmoking subjects. We investigated whether aminoguanidine had any effect on exhaled NO produced in the central lung (flux of NO from the airways [Jno] and peripheral lungs (concentration of NO in peripheral lung [Calv], on NO metabolites (nitrite [NO(2)(-)]/nitrate [NO(3)(-)], peroxinitrite [ONOO(-)], nitrotyrosine), and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum.nnnRESULTSnAminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in healthy subjects, smokers, and COPD patients. Calv in smokers and in COPD patients was not completely inhibited 1 h after aminoguanidine inhalation, in marked contrast to previous results in asthma. Moreover, ONOO(-) and NO(2)(-)/NO(3)(-) levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following aminoguanidine inhalation. 8-Isoprostane levels were also increased in smokers and in COPD patients but were not reduced after aminoguanidine inhalation.nnnCONCLUSIONSnThese results suggest that the constitutive NOS isoform as well as iNOS might be involved in NO release and contribute to the high Calv and ONOO(-) production in patients with COPD.nnnTRIAL REGISTRATIONnClinicaltrials.gov Identifier: NCT00180635.

Feasibility and interpretation of FENO measurements in asthma patients in general practice

BACKGROUNDnExhaled NO (FE(NO)) is a useful biomarker for the monitoring of asthma control and response to therapy. However, there is a lack of data on FE(NO) levels and their interpretation in Primary Care asthma population depending on their treatment and smoking habit. Besides, the majority of current FE(NO) tests have been done by stationary chemiluminescence analysers whose use is limited to research laboratories.nnnMETHODSnFE(NO) measurements by the novel hand-held NO monitoring device (NIOX MINO) were made in 96 asthma patients (32 males, mean age 53+/-12) at five local General Practices during their scheduled 15-20 min visits for lung function assessment.nnnRESULTSnSuccess rate was 78% and the intra-subject coefficient of variation was 8.7%. Inhaled corticosteroid treatment had an overall reducing effect on the FE(NO) value (30.5 [19.8-49.8]) vs. patients not on the ICS (26.5 [19-94]) (p<0.044). FE(NO) levels in the ICS treated current or ex-smokers group of patients were still significantly above the normal values (p<0.0001). FE(NO) levels were similar in patients receiving ICS whether there were current, ex-smokers or non-smokers. The highest FE(NO) levels (94 [15.8-151]) were found in asthmatic current smokers and not receiving treatment with ICS. The most normalised FE(NO) levels (35.3 [13.5-35.3]) were seen in ex-smokers.nnnCONCLUSIONSnFE(NO) measurements performed with a new hand-held monitoring device are reproducible and feasible in General Practice in the majority of patients of different ages and asthma severities. A high percentage of patients with different severities of asthma and regardless of their treatment with ICS and current smoking habit (current and/or ex-smokers) had highly elevated FE(NO) values, suggesting that their current therapy was possibly insufficient to control the underlying degree of airway inflammation and asthma symptoms.

Sirolimus Therapy for Patients With Lymphangioleiomyomatosis Leads to Loss of Chylous Ascites and Circulating LAM Cells

A young woman received a diagnosis of abdominal, sporadic lymphangioleiomyomatosis (LAM) and multiple abdominal lymphangioleiomyomas and was referred for recurrent chylous ascites responding only to a fat-free diet. On admission, pulmonary function test (PFT) results showed a moderate reduction in the transfer factor for carbon monoxide with normal exercise performance. The serum vascular endothelial growth factor D (VEGF-D) level was 2,209 pg/mL. DNA sequences, amplified at loci kg8, D16S3395, D16S3024, D16S521, and D16S291 on chromosome 16p13.3, showed a loss of heterozygosity (LOH) only for kg8. Fat-free total parenteral nutrition in association with sirolimus (2xa0mg po daily) was initiated. Serum sirolimus levels were maintained at concentrations between 5 and 15xa0ng/mL. After 1xa0month, reintroduction of a low-fat oral feeding was achieved without recurrence of ascites. PFT results were stable. Interestingly, clinical improvement was associated with a reduction in the VEGF-D serum level (1,558 pg/mL). LOH at the kg8 biomarker in blood LAM cells was no longer detected.

Severe idiopathic pulmonary fibrosis: what can be done?

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease to manage. Two drugs are now available that can slow disease progression in patients with mild-to-moderate IPF. This means that early diagnosis is mandatory, because there are no proven effective therapies for severe IPF. This lack of proven therapies may be at least partially due to the fact that severe IPF patients are usually not enrolled in randomised, prospective, multicentre, international trials. Clinical observation experiences and preliminary results of long-term, open-label extensions of clinical trials suggest that both pirfenidone and nintedanib may also slow or decrease progression in patients with severe IPF. However, data are sparse and obtained from a relatively small number of patients. Lung transplantation should be taken into account early and discussed with patients, when indicated. Rehabilitative strategies are important and effective supportive therapies. The needs of patients with severe IPF are similar to those of patients with an advanced neoplastic disease. Palliative care and psychological support play an important role in the relief of symptoms of anxiety and depression. Accordingly, these therapeutic approaches should start early in IPF patients. Patients with severe IPF require a global approach similar to patients with advanced cancer disease http://ow.ly/1apy30dYRjU

The Lymphangioleiomyomatosis Lung Cell and Its Human Cell Models

Abstract Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle‐like LAM cells, with mutations and loss of heterozygosity in the TSC1 or, more frequently, TSC2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture, and most studies of LAM lung cells involve mixtures of TSC2 wild‐type and TSC2‐null cells. A clonal population of LAM lung cells has not been established, making analysis of the cells challenging. Cell lines have been established from angiomyolipomas, a common manifestation of LAM, and from tumors from patients with TSC. Circulating LAM cells have also been isolated from blood and other body fluids. LAM cells may also be identified in clusters apparently derived from lymphatic vessels. Genetics, patterns of antigen expression, and signaling pathways have been studied in LAM lung tissue and in LAM cell models, although rarely all in the same study. We show here that LAM cells manifest differences in these characteristics, depending on the source investigated, suggesting further studies.

New insights in lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis

Lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) are rare diseases that lead to progressive cystic destruction of the lungs. Despite their distinctive characteristics, these diseases share several features. Patients affected by LAM or PLCH have similar radiological cystic patterns, a similar age of onset, and the possibility of extrapulmonary involvement. In this review, the recent advances in the understanding of the molecular pathogenesis, as well as the current and most promising biomarkers and therapeutic approaches, are described. Understanding of LAM/PLCH pathogenesis has improved over the past years, leading to new therapeutic approaches http://ow.ly/7wjR30erSJY

Hemodynamic Mechanisms of Exercise-Induced Pulmonary Hypertension in Patients with Lymphangioleiomyomatosis: The Role of Exercise Stress Echocardiography

Background: The pathogenesis of pulmonary hypertension (PH) in lymphangioleiomyomatosis (LAM) has not yet been completely clarified. The aim of this study was to conduct a noninvasive evaluation of the main hemodynamic mechanisms of exercise‐induced PH in patients with LAM, assessed using exercise stress echocardiography. Methods: Fifteen patients with LAM (mean age, 47 ± 13 years; all women) without resting PH were enrolled in a prospective single‐center study and compared with 15 healthy female control subjects (mean age, 45.2 ± 8 years; P = .65). A complete echocardiographic study with Doppler tissue imaging was performed at baseline and during semisupine symptom‐limited exercise testing to evaluate (1) left ventricular systolic and diastolic function, (2) right ventricular contractile function, (3) estimated pulmonary capillary wedge pressure, (4) estimated systolic and mean pulmonary artery pressure, and (5) estimated pulmonary vascular resistance. Results: Compared with healthy control subjects, patients with LAM during exercise showed echocardiographic signs of right ventricular overload and right ventricular systolic dysfunction and significant increases in mean pulmonary artery pressure (14.4 ± 6.5 vs 4.2 ± 3.1 mm Hg, P < .0001), pulmonary vascular resistance (+68.3 ± 42.1 vs −0.1 ± 18.3 dyne‐sec/cm5, P < .0001), and, unexpectedly, pulmonary capillary wedge pressure (+8.3 ± 5.3 vs −0.5 ± 1.3 mm Hg, P < .0001). Conclusions: Exercise‐induced PH in patients with LAM could be related not only to hypoxic pulmonary vascular vasoconstriction during exercise (precapillary PH) but also to a significant exercise‐induced increase in estimated pulmonary capillary wedge pressure, probably secondary to diastolic dysfunction (postcapillary PH). HIGHLIGHTSThe mechanisms of effort intolerance in patients with LAM remain unclear.ESE allows a complete left and right heart evaluation of patients with lung diseases.A stress echocardiographic protocol in patients with LAM was tested.Exercise‐induced PH in LAM could have both a pre‐ and a postcapillary component.