[Primary open angle glaucoma and sleep apnea syndrome: A review of the literature]. / Glaucome primitif à angle ouvert et syndrome d'apnée du sommeil : une revue de la littérature.

The relationship between glaucoma and Obstructive Sleep Apnea Syndrome (OSAS) has long been discussed, with conflicting study findings. OSAS appears in the most recent studies to be more of an aggravating factor than an independent risk factor for glaucoma. Patients with OSAS may develop a more rapid progression of primary open-angle glaucoma (POAG). OSAS may damage the optic nerve not only by increasing the intraocular pressure (IOP) but also by altering the blood supply to the optic nerve as shown by more recent work with OCT-Angiography. Although the systemic benefits of Continuous Positive Airway Pressure (CPAP) have been demonstrated, few studies have evaluated its effect on the optic nerve. CPAP might act on glaucomatous neuropathy by improving the blood supply to the optic nerve. The study of this mechanism of action might provide new insights into the relationship between OSAS and glaucoma.

Caspase-independent apoptosis in infected macrophages triggered by sulforaphane via Nrf2/p38 signaling pathways.

Mycobacterium abscessus (Mabs), a non-tuberculous mycobacterium, is an emerging and rapidly growing opportunistic pathogen that is frequently found in patients with cystic fibrosis and in immunosuppressed patients. Its high tolerance to antibiotics is of great concern for public health. In this study, our results showed that human THP-1-derived macrophages infected with M. abscessus presented an increase in ROS production and cell necrosis. In addition, M. abscessus infection triggered activation of the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway, and the induction of HO-1 and NQO1 expression levels. Interestingly, pretreatment of macrophages with sulforaphane (SFN), an activator of the antioxidant key regulator Nrf2, followed by M. abscessus infection significantly decreased mycobacterial burden. We demonstrated that this reduction in mycobacterial growth was due to an activation in cell apoptosis in SFN-pretreated and M. abscessus-infected macrophages. Pretreatment with specific MAPK inhibitors, PD98059, SP600125, and SB203580 to ERK, JNK, and p38 respectively, failed to inhibit induction of Nrf2 expression, suggesting that Nrf2 signaling pathway was upstream of MAPK signaling. Activation of cell apoptosis was caspase 3/7 independent but p38 MAPK dependent. Moreover, p38 MAPK induction was abolished in macrophages transfected with Nrf2 siRNA. In addition, p38 inhibitor abolished Nrf2-dependent apoptosis in infected macrophages. Taken together, our results indicate that modulation of the Nrf2 signaling using Nrf2 activators may help potentiate the actual drug therapies used to treat mycobacterial infection.

Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.

The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.

[Patent foramen ovale and hypoxaemia with or without elevated right heart pressures]. / Foramen ovale perméable et hypoxémie avec ou sans élévation des pressions droites.

The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in approximately 25% of the general population. Anatomically a PFO represents a channel through which unidirectional blood flow from the right to the left atrium may occur. This potential interatrial shunt of unoxygenated venous blood into the oxygenated arterial system may lead to hypoxaemia. Usually right to left shunting across a PFO is transient and without clinical significance. Increased pulmonary arterial pressure may give rise to left-right pressure gradient reversal and right to left shunting across a PFO. High pressure in the right heart chambers, even without pulmonary arterial hypertension, can potentially lead to the reopening of a foramen ovale. In other cases inferior vena cava flow deviation might lead to right to left shunting across a PFO. Right to left shunting without pressure increase inside the right heart chambers is usually transient and even positional and its diagnosis is more difficult.

NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease.

Several convergent destructive mechanisms such as oxidative stress, alveolar cell apoptosis, extracellular matrix proteolysis and chronic inflammation contribute to chronic obstructive pulmonary disease (COPD) development. Evidence suggests that oxidative stress contributes to the pathophysiology of COPD, particularly during exacerbations. Nuclear factor erythroid-2-related factor 2 (NRF2), a transcription factor expressed predominantly in epithelium and alveolar macrophages, has an essential protective role in the lungs through the activation of antioxidant response element-regulated antioxidant and cytoprotective genes. Animal models and human studies have identified NRF2 and several NRF2 target genes as a protective system against inflammation and oxidative stress from cigarette smoke, a major causative factor in COPD development. Hence, NRF2 targeting might provide clinical benefit by reducing both oxidative stress and inflammation in COPD.

Oxidative stress targets in pulmonary emphysema: focus on the Nrf2 pathway.

IMPORTANCE OF THE FIELD: Oxidative stress has been implicated in the pathogenesis of pulmonary emphysema. Nuclear factor erythroid-2-related factor 2 (Nrf2) a major antioxidant transcription factor could play a protective role in pulmonary emphysema. AREAS COVERED IN THIS REVIEW: Nrf2 is ubiquitously expressed throughout the lung, but is predominantly found in epithelium and alveolar macrophages. Evidence suggests that Nrf2 and several Nrf2 downstream genes have an essential protective role in the lung against oxidative stress from environmental pollutants and toxicants such as cigarette smoke, a major causative factor for the development and progression of pulmonary emphysema. Application of Nrf2-deficient mice identified an extensive range of protective roles for Nrf2 against the pathogenesis of pulmonary emphysema. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies. WHAT THE READER WILL GAIN: In this review, we discuss recent findings on the association of oxidative stress with pulmonary emphysema. We also address the mechanisms of Nrf2 lung protection against oxidative stress based on emerging evidence from experimental oxidative disease models and human studie. TAKE HOME MESSAGE: The current literature suggests that among oxidative stress targets, Nrf2 is a valuable therapeutic target in pulmonary emphysema.

Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK.

Tobacco may be involved in the decreased macrophage heme oxygenase-1 (HO-1) expression described in smoking-induced severe emphysema, via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach1) pathway. We assessed in vitro effects of cigarette smoke condensate (CS) in the human monocyte/macrophage cell line (THP-1). CS exposure led to increased HO-1 and nuclear Nrf2 expression (6 h) followed by decreased HO-1 expression concomitantly with nuclear Nrf2/Bach1 ratio decrease (72h). CS-induced mitogen-activated protein kinase (MAPK) phosphorylation. Extracellular-signal-regulated kinase(1/2) (ERK(1/2)) and c-Jun NH2-terminal kinase (JNK) inhibition completely abrogated CS effects on HO-1 expression and nuclear Nrf2/Bach1 translocation. These results suggest that ERK(1/2) and JNK are involved in CS-induced biphasic HO-1 expression by a specific regulation of Nrf2/Keap1-Bach1.

Dysregulation of elastin expression by fibroblasts in pulmonary emphysema: role of cellular retinoic acid binding protein 2.

BACKGROUND: All-trans retinoic acid (ATRA) stimulates elastin synthesis by lung fibroblasts and induces alveolar regeneration in animal models of pulmonary emphysema. However, ATRA treatment has had disappointing results in human emphysema. It was hypothesised that a defect in the ATRA signalling pathway contributes to the defect of alveolar repair in the human emphysematous lung. METHODS: Fibroblasts were cultured from the lung of 10 control subjects and eight patients with emphysema. Elastin and retinoic acid receptor (RAR)-beta mRNAs were measured in those cells in the presence of incremental concentrations of ATRA. RARs, retinoic X receptors (RXRs) and cellular retinoic acid binding protein (CRABP) 1 and 2 mRNAs were measured as well as CRABP2 protein content. The effect of CRABP2 silencing on elastin and RAR-beta expression in response to ATRA was measured in MRC5 lung fibroblasts. RESULTS: ATRA at 10(-9) M and 10(-8) M increased median elastin mRNA expression by 182% and 126% in control but not in emphysema fibroblasts. RAR-beta mRNA expression was induced by ATRA in control as well as emphysema fibroblasts. RARs, RXRs and CRABP1 mRNAs were similarly expressed in control and emphysema fibroblasts while CRABP2 mRNA and protein were lower in emphysema fibroblasts. CRABP2 silencing abrogated the induction of elastin but not RAR-beta expression by ATRA in MRC5 fibroblasts. CONCLUSION: Pulmonary emphysema fibroblasts fail to express elastin under ATRA stimulation. CRABP2, which is necessary for elastin induction by ATRA in MRC-5 cells, is expressed at low levels in emphysema fibroblasts. This alteration in the retinoic acid signalling pathway in lung fibroblasts may contribute to the defect of alveolar repair in human pulmonary emphysema. These results are the first demonstration of the involvement of CRABP2 in elastin expression.

Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema.

BACKGROUND: Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema. METHODS AND RESULTS: Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype. CONCLUSIONS: This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.

Cough reflex sensitivity after elective Caesarean section under spinal anaesthesia and after vaginal delivery.

BACKGROUND: In pregnancy, airway oedema and heartburn may increase cough sensitivity, whereas spinal anaesthesia (SA) with local anaesthetics and opiates may decrease it. Decreased cough sensitivity increases the risk for pneumonia or retained secretions. The aim of this study was to determine whether cough sensitivity is increased in pregnant patients and if it is decreased after planned Caesarean section (CS) under SA. METHODS: Twenty-seven non-pregnant volunteers, 27 patients after vaginal delivery (VD group), and 28 patients after CS under SA (CS group) were studied. For SA, hyperbaric bupivacaine 8-12 mg, sufentanil 5 microg, and morphine 100 microg was given. Increasing concentrations of nebulized citric acid were delivered until eliciting cough. The concentration eliciting one (C1) and two coughs (C2) were recorded and log transformed for analysis (log C1 and log C2). RESULTS: Median (inter-quartile) log C1 was 1.3 (0.6) mg ml(-1) in the VD group, 1.6 (0.6) mg ml(-1) in the non-pregnant group (P < 0.01 vs VD group), and 2.2 (0.7) mg ml(-1) in the CS group (P < 0.0001 and P < 0.01 vs VD and non-pregnant groups, respectively). Similar results were observed with log C2. In CS group, log C1 and log C2 remained increased up to 4 h after SA. CONCLUSIONS: Cough sensitivity was increased after VD but decreased for up to 4 h after SA.

[Respiratory manifestations during the course of Sjogren's syndrome]. / Manifestations respiratoires au cours du syndrome de Gougerot-Sjögren.

INTRODUCTION: Sjogren's syndrome is a common auto-immune disease. BACKGROUND: Clinically significant pulmonary involvement affects approximately 10% of patients and may be the first manifestation of the disease, putting the respiratory physician in a position to suspect and confirm the diagnosis. Besides interstitial lung disease and bronchial disorders, cough is a common symptom of the disease and particularly difficult to treat. Lung cysts and amyloid deposits, sometimes associated with lymphoma, have recently been described. The development of a primary pulmonary lymphoma, usually from MALT, is a major complication of the disease. VIEWPOINT: Characterisation of the pathophysiology of pulmonary involvement in Sjogren's syndrome and the institution of specific treatment merits the interest of the respiratory physician. CONCLUSION: The respiratory physician should consider the diagnosis of Sjogren's syndrome in many different clinico-pathological situations.

Changes in airway inflammation following nasal allergic challenge in patients with seasonal rhinitis.

BACKGROUND: Seasonal allergic rhinitis could predispose to the development of chronic bronchial inflammation as observed in asthma. However, direct links between nasal inflammation, bronchial inflammation and airway responsiveness in patients with seasonal allergic rhinitis and without asthma are not fully understood. The aim of this study was to analyse the changes induced by allergic nasal challenge outside the pollen season in airway responsiveness and bronchial inflammation of patients with seasonal allergic rhinitis. METHODS: Nine patients were evaluated after either grass pollens or placebo nasal challenge in a randomized cross-over double-blinded trial. Nasal parameters were recorded hourly and airway responsiveness was assessed by methacholine challenge. Cytological examinations and cytokine measurements were performed in nasal lavage and induced sputum. Eosinophil activation was investigated by eosinophil-cationic protein expression and secretion. RESULTS: Airway responsiveness was increased after allergic nasal challenge. Total eosinophils and eosinophils expressing eosinophil-cationic protein were increased in induced sputum after allergic nasal challenge. Both eosinophil number and eosinophil-cationic protein concentration in induced sputum were correlated to methacholine responsiveness. CONCLUSIONS: These results suggest that eosinophils participate to the bronchial inflammation in patients with seasonal allergic rhinitis following allergic nasal challenge outside the pollen season and might explain changes in airway responsiveness.

Assessment of the cough reflex after propofol anaesthesia for colonoscopy.

BACKGROUND: Dysfunction of the cough reflex as a result of the lingering effects of anaesthetics may lead to aspiration pneumonia or retained secretions after general anaesthesia. It is unknown whether low concentrations of propofol alter the cough reflex in the early period after anaesthesia. The objective of this study was to investigate the effect of low concentrations of propofol on the cough reflex sensitivity as assessed by the cough reflex threshold to an inhaled irritant. METHODS: Fifteen, ASA I-II, non-smoking patients undergoing elective colonoscopy were studied. Anaesthesia was induced and maintained with a blood target-controlled propofol infusion. Cough reflex threshold was measured with citric acid. Increasing concentrations of nebulized citric acid (2.5, 5, 10, 20, 40, 80, 160, 320, and 640 mg ml(-1)) were delivered during inspiration until a cough was evoked. The citric acid concentration eliciting one cough (C1) was defined as the cough reflex threshold. C1 was log transformed for statistical analysis (Log C1). Log C1 was measured before anaesthesia and during the recovery period with estimated decreasing propofol concentrations of 1.2, 0.9, 0.6, and 0.3 microg ml(-1). RESULTS: Log C1 (median; interquartile range) measured with propofol concentrations of 1.2, 0.9, 0.6, 0.3, and 0 microg ml(-1) were 1.9 (0.6), 1.9 (1.0), 1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml(-1) (NS), respectively. However, light sedation was observed with propofol concentrations of 1.2 and 0.9 microg ml(-1). CONCLUSION: This study indicates that residual sedation after propofol anaesthesia for colonoscopy does not adversely affect the cough reflex.

Decreased expression of interleukin 13 in human lung emphysema.

BACKGROUND: The overexpression of interferon (IFN)gamma or interleukin (IL)-13 in the adult murine lung induces the development of changes that mirror human lung emphysema. METHODS: IL-13 and IFNgamma expression was determined in lung samples from five groups of PATIENTS: severe emphysema without alpha(1)-antitrypsin deficiency (SE+, n = 10); severe emphysema with alpha(1)-antitrypsin deficiency (SE-, n = 5); mild localised emphysema (ME, n = 8); non-emphysema smokers (NE-S, n = 9), and non-emphysema non-smokers (NE-NS, n = 11). Lung IL-13 and IFNgamma mRNA were analysed by RT-PCR. Lung concentrations of IL-13 protein were assessed by ELISA. RESULTS: The expression of IFNgamma mRNA was similar in patients with or without emphysema. IL-13 mRNA was markedly decreased in the SE+ group compared with the SE- (p = 0.04), ME (p = 0.02), and non-emphysema groups (p = 0.01). IL-13 mRNA correlated with forced expiratory volume in 1 second (r = 0.5, p = 0.04) and arterial oxygen tension (r = 0.45, p = 0.03) in emphysema patients. In contrast to the non-emphysematous lung, IL-13 protein was below the detection limit of the assay in most emphysematous lung homogenates. CONCLUSION: The lung IL-13 content is reduced in patients with severe emphysema without alpha(1)-antitrypsin deficiency.

Culture at high density improves the ability of human macrophages to control mycobacterial growth.

The mechanisms through which granuloma formation helps control mycobacterial infection are poorly understood, but it is possible that the accumulation of macrophages at high density at sites of infection promotes the differentiation of macrophages into cells with improved mycobactericidal activity. To test this possibility, varying numbers of monocytes were cultured in 96-well plates for 3 days, infected with Mycobacterium bovis bacillus Calmette-Guérin, and mycobacterial number was assessed 7 days after infection based on the measurement of luciferase activity expressed by a mycobacterial reporter strain or by counting CFU. Mycobacterial growth was optimal in cultures containing 5 x 10(4) cells/well, but increasing the number of cells to 2 x 10(5) cells/well resulted in complete inhibition of mycobacterial growth. This effect could not be explained by differences in mycobacterial uptake, multiplicity of infection, acidification of the extracellular medium in high density cultures, enhanced NO production, or paracrine stimulation resulting from secretion of cytokines or other proteins. The morphology of cells cultured at high density was strikingly different from that of monocytes cultured at 5 x 10(4) cells/well, including the appearance of numerous giant cells. The bacteriostatic activity of monocyte-derived macrophages was also dependent on cell number, but fewer of these more mature cells were required to control mycobacterial growth. Thus, the ability of human macrophages to control mycobacterial infection in vitro is influenced by the density of cells present, findings that may help explain why the formation of granulomas in vivo appears to be a key event in the control of mycobacterial infections.

Effect of stimulation of human macrophages on intracellular survival of Mycobacterium bovis Bacillus Calmette-Guerin. Evaluation with a mycobacterial reporter strain.

The mechanisms through which immune and inflammatory responses stimulate the expression of antimycobacterial activity by human macrophages remain poorly defined. To study this question, we developed a method permitting the rapid quantification of viable mycobacteria, based on the detection of luciferase activity expressed by a Mycobacterium bovis Bacillus Calmette-Guerin (BCG) reporter strain, and used this approach to evaluate mycobacterial survival in human monocyte-derived macrophages following stimulation with cytokines and through crosslinking of costimulatory molecules expressed on the cell surface. Modest proliferation, followed by persistence of mycobacteria, was observed in unpretreated macrophages as assessed both by measurement of luciferase activity and by the evaluation of colony forming units. Of the 19 cytokines tested, only granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) were found to improve the mycobactericidal activity of monocyte-derived macrophages. In both cases, this effect was observed only when macrophages were pretreated with the cytokines prior to infection. In contrast, pretreatment of human macrophages with interferon-gamma, either alone or in combination with other mediators (including tumor necrosis factor-alpha and 1,25[OH]2-vitamin D3), did not improve mycobacterial killing. The stimulation of macrophages through several different costimulatory molecules known to participate in macrophage-lymphocyte interactions (CD4, CD40, CD45, CD86, CD95 [Fas/Apo-1]) also failed to improve mycobactericidal activity. This study shows that GM-CSF and IL-3, cytokines whose receptors are known to share a common subunit and to use common second messengers, may contribute to the stimulation of mycobactericidal activity in humans. The ability to rapidly screen the effects of different macrophage stimuli on mycobacterial survival through the detection of luciferase activity should help define additional signals required for optimal antimycobacterial responses.

Langerhans cells in Langerhans cell granulomatosis are not actively proliferating cells.

Pulmonary Langerhans cell granulomatosis (LCG), also called histiocytosis X, is a disorder of unknown etiology characterized by the presence of destructive granulomas containing numerous Langerhans cells (LCs). The process may be localized or multifocal, and it remains unclear whether the same pathogenic mechanism is involved in all forms of the disease. It is often assumed that the massive accumulation of LCs at the sites of the lesions results from the abnormal proliferation of these cells, although it has been suggested that LCG in adults, at least in the lung, could be a reactive disorder initiated by activated LCs. Little is known, however, concerning the mechanisms responsible for the accumulation of large numbers of LCs in the course of the disease, and the relative contribution of recruitment and local proliferation of these cells remains to be established. To investigate this question, the proportion of replicating LCs was evaluated in biopsied granulomas from patients with localized or diffuse form of LCG by means of several histopathological techniques currently used in assessment of cell proliferation. The findings demonstrate that, except for proliferating cell nuclear antigen (PCNA), all parameters measured are low in all forms of the disease. They are similar to those of renewing epithelial cells and clearly less than those of neoplastic cells. These data strongly suggest that LCs in LCG granulomas are not a rapidly dividing cell population and that local LC replication makes only a minimal contribution to granuloma maintenance. Caution appears to be necessary in the use of PCNA as a marker of growth fraction.