Early inhaled nitric oxide at high dose enhances rat lung development after birth.

RATIONAL: Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life. METHODS: Pregnant rats were placed in a chamber containing 5 ppm (iNO-5 ppm group) and 20 ppm NO (iNO-20 ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7 days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14. RESULTS: Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20 ppm) were higher than controls (P<0.05; P<0.001). Pulmonary vessel number was significantly increased in iNO-20 ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20 ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20 ppm group. CONCLUSIONS: We concluded that inhaled NO at 20 ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.

Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice' care for the diagnosis, treatment and prevention of post-COVID-19 lung disease.METHODS: A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement).RESULTS: Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient's needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session.CONCLUSION: This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease.

Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis.

Elevated serum CC chemokine ligand (CCL)18 reflects lung fibrosis activity in systemic sclerosis (SSc) and could be an early marker of lung function worsening. Therefore, we sought to evaluate whether serum CCL18 levels at baseline could predict worsening of lung disease in SSc. In this prospective study, 83 SSc patients were analysed longitudinally over a 4-yr observation period for the risk of occurrence of combined deleterious events, defined as a 10% decrease from baseline of total lung capacity or forced vital capacity % predicted, or death, according to serum CCL18 at inclusion. Receiver operating characteristic (ROC) curve analysis was performed for prediction of events during the first year after inclusion. The best cut-off level of serum CCL18 for prediction of a combined event within the follow-up period was 187 ng · mL(-1), with 53% sensitivity and 96% specificity (area under the ROC curve 0.86; p < 0.001). After a mean ± SD follow-up of 33.7 ± 10.8 months, a higher rate of disease progression occurred in the group with serum CCL18 levels >187 ng · mL(-1). The adjusted hazard ratio was 5.36 (95% CI 2.44-11.75; p < 0.001). In summary, serum CCL18 is an accurate predictive biomarker for the identification of patients with a higher risk of subsequent scleroderma lung disease worsening.

Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function.

Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function. Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought. Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls. Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.

Study of the beneficial role of exhaled nitric oxide in combination with GINA guidelines for titration of inhaled corticosteroids in children with asthma.

BACKGROUND: The use of FENO in association with current guidelines in the treatment of asthma has not been studied thoroughly. This study aimed to evaluate the beneficial role of FENO in combination with GINA (Global Initiative for Asthma) guidelines for titration of inhaled corticosteroids (ICS) in asthmatic children. METHODS: It was a prospective and descriptive study. Uncontrolled asthmatic children were randomized to two groups: group 1 (followed GINA guidelines) or group 2 (followed GINA guidelines + FENO modification for ICS titration). The two groups were followed-up for 12 months. RESULTS: The mean age of the patients in the study was 10 ± 4 years for group 1 (n = 116) and 11 ± 5 years for group 2 (n = 108). There were 87.9% patients in group 1 and 82.4% in group 2 that had a familial allergic history. There were 58.6% of moderate asthma and 41.4% of severe asthma in group 1, versus 56.4% and 43.6% in group 2, respectively. The percentage of moderate and severe asthma was also significantly modified after 6th and 12th month versus at inclusion (43.1% and 35.3% versus 58.6%, P < 0.01 and P < 0.005; 23.2% and 12.9% versus 41.4%, P < 0.005 and P < 0.001, respectively). The total daily dose of ICS in group 2 at 12th months was significantly lower than that in group 1 (3515 ± 1175 versus 4785 ± 1235 mcg; P < 0.005). The daily cost of ICS treatment in group 2 was also lower than that of group 1 (18 ± 4 versus 27 ± 3 USD; P < 0.05). CONCLUSION: The use of FENO in combination with GINA guidelines for ICS titration is useful in reducing the daily ICS dose and treatment cost.

Correlations between exhaled nitric oxide, rs28364072 polymorphism of FCER2 gene, asthma control, and inhaled corticosteroid responsiveness in children with asthma.

In children with asthma, the responsiveness of inhaled corticosteroids (ICS) is depended on asthma endotype and phenotype. This study aimed to describe the clinical and biological characteristics, and its correlation with polymorphism of rs28364072 in FCER2 of asthmatic children. This work aimed to study the correlation between fractional concentration of exhaled nitric oxide (FENO) level and rs28364072 polymorphism of FCER2 gene with ICS responsiveness and disease control in children with asthma. This study was a prospective and descriptive study. All clinical characteristics, FENO, blood eosinophil counts (BEC), skin prick test (SPT), total IgE, asthma control test, and FCER2 gene polymorphism were performed for each patient. One hundred and seven asthmatic children who were over 5 years old (9.2 ± 2.6), were included. Patients with FENO > 20 ppb had higher percentage of positive SPT, total IgE level, and BEC (89.2 vs 80.0%, 851.1 vs 656.9 UI ml-1, and 785 ± 576 G L-1 vs 425 ± 364 G L-1; respectively). Among them, there were 54.2% of homozygous TT, 36.4% of heterozygous TC, and 9.4% of homozygous CC of rs28364072 polymorphism in FCER2. The percentage of patients with controlled asthma was increasing after 1 month and 3 months (47.1% and 58.8%; respectively). During the study, the ICS was decreasing as indicated by asthma control (348 ± 118 mcg at 1st month vs 329 ± 119 mcg at 3rd month; p < 0.05). CC genotype had the lowest level of increasing FEV1 compared to that in genotype TC and TT (8.4% vs 8.7% and 27.1%; p > 0.05 and p < 0.05; respectively). The percentage of polymorphism in rs28364072 of FCER2 was significant higher in patients with controlled asthma compared to uncontrolled asthma. Asthmatic children with high FENO and rs28364072 polymorphism in FCER2 gene are good responders to ICS; however, asthmatic children with homozygous variant CC of rs28364072 are poorly responsive to ICS.

[Early detection of smoking related chronic obstructive pulmonary disease in Vietnam]. / Détection précoce de la bronchopneumopathie chronique obstructive post-tabagique au Viet Nam.

INTRODUCTION: Epidemiological studies of chronic obstructive pulmonary disease (COPD) are rare in the developing countries, particularly in Viet Nam where the consumption of tobacco continues to increase. The aim of this study was to evaluate the feasibility of early screening of smokers for bronchial obstruction using the Piko-6 apparatus. MATERIALS AND METHODS: Smokers over 40 years of age who had smoked for more than 10 years were included. The subjects were classified into 3 groups according to the degree of bronchial obstruction measured by the Piko-6. (group 1: FEV1/FEV6>0.8; group 2: 0.7-0.8; group 3:<0.7). The smokers in group 3 and a sample of the smokers in groups 1 and 2 were recalled for full spirometric assessment. RESULTS: 2397 smokers were included, comprising 2130 active smokers and 267 ex-smokers. The mean age was 52 +/- 13 years. The mean smoking history was 24 +/- 13 pack years. 267 smokers from the 3 groups responded to the recall for full investigation. The prevalence of COPD detected by the Piko-6 in the study population was 13.5%. For the threshold FEV1/FEV6<0.7 and with the detected prevalence, the Piko-6 had a sensitivity of 97.8%, a specificity of 93.8%, a positive predictive value of 71% and a negative predictive value of 99.6% (confidence interval 95%). CONCLUSIONS: The Piko-6 is a useful tool for the early screening for COPD in smokers in a developing country where the prevalence of this disease appears to be under estimated.

[Study about the prevalence of the obstructive sleep apnoea syndrome in Vietnam]. / Étude de la prévalence du syndrome d'apnées obstructives du sommeil au Vietnam.

INTRODUCTION: Epidemiological studies on obstructive sleep apnoea syndrome (OSAS) in Asia, South East Asia in particular, are few. The EPSASIE study aimed to determine the prevalence of OSAS in an adult Vietnamese population and to describe its characteristics. METHODS: This is a prospective, observational, multicenter study. Nocturnal ventilatory polygraphy (PV) or polysomnography (PSG) were performed in patients having symptoms evocative of the SAS syndrome and an index of respiratory events (IER)>10/h or>25 in one hour, measured by RU Sleeping. RESULTS: A total of 667/750 validated questionnaires were received. The mean age of the study population was 44±12 years with a mean body mass index of 21.6±5.2kg/m2. PV or PSG were performed on 93 subjects after positive screening by RU Sleeping. OSAS with an apnoea-hypopnoea index (AHI)>5 was found in 57 subjects (8.5%) and in 35 subjects with AHI>15 (5.2% of cases). CONCLUSION: The prevalence of OSAS is quite high in the Vietnamese population and comparable with current literature data.

[Cellular signalling pathways and pathophysiology of pulmonary arterial hypertension]. / Signalisation cellulaire et physiopathologie de l'hypertension artérielle pulmonaire.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a disease of complex aetiology involving in varying degrees both genetic and environmental factors. BACKGROUND: Thanks to progress in biology over the past 15 years the physiological consequences of cellular and molecular abnormalities are much better understood. Recent work has allowed better understanding of the different cellular signalling pathways controlling pulmonary vascular tone and cell growth. It appears that these pathways form a dense and complex network involving several groups of molecules of which NO, cGMP, ET-1 and its receptors, are at the most important. VIEWPOINT: The pathophysiology of PAH may be regarded as a disorder of cellular signaling where molecular abnormalities disturb the balance between the different factors controlling vascular tone and cell proliferation. CONCLUSIONS: PAH may be viewed as a disease of cellular signalling where the molecular abnormalities not only affect a single signalling pathway but involve multiple cross-talks between groups of molecules controlling vascular smooth muscle tone and cell growth and differentiation.

[Pulmonary hypertension: from molecular pathophysiology to haemodynamic abnormalities]. / Hypertension pulmonaire: de la physiopathologie moléculaire aux anomalies hémodynamiques.

Pulmonary hypertension (PH) is a complex disorder resulting from many etiologies that cause disturbances of normal pulmonary haemodynamics. Recent breakthroughs have led to a better understanding of the pathophysiology of the disease. In PH, haemodynamic disturbances are closely linked to structural changes and excessive remodeling of pulmonary vessels, leading to progressive narrowing of the pulmonary vascular lumen. Imbalances between pulmonary vasoconstrictors and vasodilators on the one hand, and factors favoring cell proliferation and apoptosis on the other hand, probably account for most cases of PH. This review aims to update readers with the current knowledge on the molecular physiopathology of PH and how this can progress the therapeutic of this disorder.

Severity of scleroderma lung disease is related to alveolar concentration of nitric oxide.

The alveolar concentration of exhaled nitric oxide (CA,(NO)) is increased in patients with systemic sclerosis (SSc), but whether this increase is related to the severity of interstitial lung disease (ILD) in SSc has not yet been investigated. In total, 58 SSc patients prospectively underwent pulmonary function tests (PFTs), echocardiogram and fibrosis scoring on pulmonary computed tomography (CT). Patients were divided into two groups according to the presence (or not) of ILD. Measurements of CA,(NO) were assessed in all SSc patients and compared with those obtained in 19 healthy volunteers. Relationships were sought between CA,(NO) PFTs and CT scan fibrosis scores. Overall, CA,(NO) was significantly increased in SSc patients (median (range) 6.2 (3.8-9.9) ppb) as compared with controls (2.0 (1.2-3.0) ppb). Among SSc patients, CA,(NO) was significantly higher in patients with ILD compared with patients without ILD (n = 33, 7.5 (5.2-11.9) ppb versus n = 25, 4.9 (3.1-7.0) ppb, respectively). CA,(NO) was inversely related to total lung capacity (r = -0.34) and the diffusing capacity of the lung for carbon monoxide (r = -0.37) and was directly related to CT scan fibrosis scores (r = 0.36). An increased alveolar concentration of exhaled nitric oxide could, at least in part, either reflect or contribute to the severity of lung disease and could be used to noninvasively assess the extent of interstitial lung disease in systemic sclerosis.