Background: The overexpression of interferon (IFN)γ or interleukin (IL)-13 in the adult murine lung induces the development of changes that mirror human lung emphysema. Methods: IL-13 and IFNγ ...expression was determined in lung samples from five groups of patients: severe emphysema without α1-antitrypsin deficiency (SE+, n = 10); severe emphysema with α1-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 IFNγ mRNA were analysed by RT-PCR. Lung concentrations of IL-13 protein were assessed by ELISA. Results: The expression of IFNγ 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 α1-antitrypsin deficiency.
Oxidative stress is thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease, characterized by impaired lung function. A large number (=33) of GT repeats (L-allele) ...in the gene of the powerful antioxidant enzyme heme oxygenase-1 has been associated with susceptibility to accelerated lung function decline. In contrast, beta-carotene may help to protect against accelerated decline. To determine whether high serum levels of beta-carotene might counterbalance the greater susceptibility of L-allele carriers, the authors analyzed the annual decline in forced expiratory volume in 1 second (FEVsub1) in a general population sample of 523 French subjects (20-44 years, 50% men) examined in 1992 and 2000 as part of the European Community Respiratory Health Survey. Analysis of covariance, adjusted for sex as well as baseline age, body mass index, smoking, and FEVsub1, showed that, among subjects with low beta-carotene levels, L-allele carriers experienced a steeper mean FEVsub1 decline than did noncarriers (mean = -58.8, 95% confidence interval: -73.2, -44.5 vs. mean = -34.7, 95% confidence interval: -38.9, -29.8 ml/year) (p = 0.009), whereas among subjects with high beta-carotene levels, the FEVsub1 decline was not different in L-allele carriers and noncarriers (two-sided p = 0.9). The results suggest that high levels of beta-carotene might counterbalance the effects on FEVsub1 decline of a genetically determined deficiency in antioxidant response. PUBLICATION ABSTRACT
Nitric oxide (NO), a free radical that is negatively inotropic in the heart and skeletal muscle, is produced in large amounts during sepsis by an NO synthase inducible (iNOS) by LPS and/or cytokines. ...The aim of this study was to examine iNOS induction in the rat diaphragm after Escherichia Coli LPS inoculation (1.6 mg/kg i.p.), and its involvement in diaphragmatic contractile dysfunction. Inducible NOS protein and activity could be detected in the diaphragm as early as 6 h after LPS inoculation. 6 and 12 h after LPS, iNOS was expressed in inflammatory cells infiltrating the perivascular spaces of the diaphragm, whereas 12 and 24 h after LPS it was expressed in skeletal muscle fibers. Inducible NOS was also expressed in the left ventricular myocardium, whereas no expression was observed in the abdominal, intercostal, and peripheral skeletal muscles. Diaphragmatic force was significantly decreased 12 and 24 h after LPS. This decrease was prevented by inhibition of iNOS induction by dexamethasone or by inhibition of iNOS activity by N(G)-methyl-L-arginine. We conclude that iNOS was induced in the diaphragm after E. Coli LPS inoculation in rats, being involved in the decreased muscular force.
Allergie respiratoire et pollution atmosphérique Aubier, M.
Revue française d'allergologie et d'immunologie clinique,
1998, 1998-1-00, Letnik:
38, Številka:
5
Journal Article, Conference Proceeding
Les hypothèses pathogéniques visant à expliquer les liens entre polluants atmosphériques et allergie s'appuient sur des travaux expérimentaux récents qui mettent en exergue le rôle favorisant de ...certains polluants dans la sensibilisation IgE dépendante. Outre les changements morphologiques et fonctionnels induits au niveau de l'épithélium bronchique et pouvant favoriser la pénétration de l'allergène et de la sécrétion de cytokines pro-inflammatoires, une attention particulière doit être réservée au rôle adjuvant des particules Diesel dans la production des IgE. Des travaux récents montrent l'influence de l'exposition des particules Diesel sur la sécrétion préférentielle par les cellules B d'immunoglobines de la classe des IgE ; ils démontrent également l'augmentation de cellules productrices d'IgE dans le liquide de lavage nasal chez l'homme après mise en contact préalable avec des solutions contenant des allergènes et des particules Diesel. Les études épidémiologiques étudiant les relations entre pollution atmosphérique (notamment particules Diesel) et allergie sont cependant encore discordantes.
Pathogenic hypotheses put forward to explain the links between air pollution and allergies rest on recent experimental studies demonstrating that some pollutants precipitate IgE-dependent sensitization. Air pollutants induce structural and functional modifications of the bronchial epithelium that can facilitate the penetration of allergens and the production of proinflammatory cytokines. The adjuvant role of diesel fuel particles in the production of IgEs deserves special attention. Recent studies have demonstrated preferential secretion by B cells of immunoglobulins belonging to the IgE class after exposure to diesel fuel particles. Increased counts of IgE-producing cells have been found in nasal lavage fluid from humans previously exposed to solutions containing allergens and diesel fuel particles. However, the results of epidemiologic studies of relationships between air pollution (diesel fuel particles in particular) and allergies remain conflicting.
Somatostatin receptor scintigraphy (SRS) has been shown to reveal sarcoidosis sites. The aim of this study was to prospectively compare SRS and gallium scintigraphy in the evaluation of pulmonary and ...extrapulmonary involvement in patients with proven sarcoidosis.
Eighteen patients with biopsy-proven sarcoidosis were included. Nine were or recently had been receiving steroid therapy at the time of the examination. Planar gallium scintigraphy (head, chest, abdomen, and pelvis) and thoracic SPECT were performed at 48-72 h after injection of a mean dose of 138 +/- 21 MBq 67Ga. Planar SRS and thoracic SPECT were performed at 4 and 24 h after injection of a mean dose of 148 +/- 17 MBq 111n-pentetreotide.
Gallium scintigraphy found abnormalities in 16 of 18 patients (89%) and detected 64 of 99 clinically involved sites (65%). SRS found abnormalities in 18 of 18 patients and detected 82 of 99 clinically involved sites (83%). Of the 9 treated patients, gallium scintigraphy found abnormalities in 7 (78%), detecting 23 of 39 clinically involved sites (59%), whereas SRS found abnormalities in 9, detecting 32 of 39 clinically involved sites (82%).
This study suggests that, compared with gallium scintigraphy, SRS appears to be accurate and contributes to a better evaluation of organ involvement in sarcoidosis patients, especially those treated with corticosteroids.
Although asthma and rhinitis often occur together, the reason for this common comorbidity is still a matter of debate.
We sought to assess whether the coexistence of asthma and rhinitis could be ...explained by common risk factors.
International cross-sectional study of representative samples of young adults, who completed a detailed questionnaire and underwent lung function tests, bronchoprovocation challenge, IgE measurements, and skin prick tests.
In all countries, asthma and bronchial hyperreactivity were more frequent in subjects with rhinitis than in those without (odds ratio OR, 6.63; 95% CI, 5.44-8.08; and OR, 3.02 95% CI, 2.66-3.43, respectively). Seventy-four percent to 81% of subjects with asthma reported rhinitis, depending on sensitization to specific allergens. Conversely, the risk of asthma increased from 2.0% in subjects without rhinitis to 6.7% in subjects with rhinitis only when exposed to pollen, 11.9% in subjects with rhinitis when exposed to animals, and 18.8% in subjects with rhinitis either when exposed to pollen or to animals. The association between rhinitis and asthma remained significant after adjustment for total IgE, parental history of asthma, and allergen sensitization (OR, 3.41; 95% CI, 2.75-4.2 suggesting that the coexistence of asthma and rhinitis is not solely due to atopic predisposition to these 2 diseases.
Although there were some variations in the association between asthma and rhinitis according to sensitization to individual allergens, the strong association between asthma and rhinitis was not fully explained by shared risk factors, including atopy. Our findings are consistent with the hypothesis that rhinitis might increase the risk of asthma.
ABSTRACTWe investigated a possible beneficial role for bilirubin, one of the products of heme degradation by the cytoprotective enzyme heme oxygenase‐1 in counteracting Escherichia coli ...endotoxin‐mediated toxicity. Homozygous jaundice Gunn rats, which display high plasma bilirubin levels due to deficiency of glucuronyl transferase activity, and Sprague‐Dawley rats subjected to sustained exogenous bilirubin administration were more resistant to endotoxin (LPS)‐induced hypotension and death compared with nonhyperbilirubinemic rats. LPS‐stimulated production of nitric oxide (NO) was significantly decreased in hyperbilirubinemic rats compared with normal animals; this effect was associated with reduction of inducible NO synthase (NOS2) expression in renal, myocardial, and aortic tissues. Furthermore, NOS2 protein expression and activity were reduced in murine macrophages stimulated with LPS and preincubated with bilirubin at concentrations similar to that found in the serum of hyperbilirubinemic animals. This effect was secondary to inhibition of NAD(P)H oxidase since 1) inhibition of NAD(P)H oxidase attenuated NOS2 induction by LPS, 2) bilirubin decreased NAD(P)H oxidase activity in vivo and in vitro, and 3) down‐regulation of NOS2 by bilirubin was reversed by addition of NAD(P)H. These findings indicate that bilirubin can act as an effective agent to reduce mortality and counteract hypotension elicited by endotoxin through mechanisms involving a decreased NOS2 induction secondary to inhibition of NAD(P)H oxidase.
Objective
Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with ...polyangiitis (Wegener's) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.
Methods
Long‐term outcomes in patients enrolled in the WEGENT trial were analyzed according to their randomized treatment group (AZA or MTX). Parameters at trial entry were evaluated as potential prognostic factors for death, relapse, or damage in multivariate models.
Results
Data from 10 years of followup were available for 112 (88.8%) of the 126 original trial participants. The median followup time was 11.9 years (95% confidence interval 95% CI 11.3–12.5 years). In patients receiving AZA and those receiving MTX, the 10‐year overall survival rates were 75.1% (95% CI 64.8–86.9%) and 79.9% (95% CI 70.3–90.8%) (P = 0.56), respectively, and relapse‐free survival rates were 26.3% (95% CI 17.3–40.1%) and 33.5% (95% CI 23.5–47.7%) (P = 0.29), respectively. No between‐treatment differences were observed with regard to rates of relapse, adverse events, damage, survival without severe side effects, and survival without relapse and severe side effects. In analyses limited to the 97 patients with GPA, no between‐treatment differences in survival rates were observed. The 10‐year relapse‐free survival rate was lower in patients with GPA than in patients with MPA. However, in the multivariate analysis, anti–proteinase 3 antineutrophil cytoplasmic antibody (ANCA) positivity, and not GPA, was retained as being independently associated with the relapse rate.
Conclusion
The results of this long‐term analysis confirm that AZA and MTX are comparable treatment options for maintaining remission of GPA or MPA. Despite achieving good overall survival with these treatments, relapse rates, adverse events, and damage remain matters of concern and further studies are needed to reduce their frequency in these ANCA‐associated vasculitides.
Les leucotriènes participent à l'inflammation observée dans les voies aériennes des patients asthmatiques. Ils constituent donc une cible privilégiée pour la prise en charge thérapeutique de ces ...patients. En effet si les corticoïdes inhalés sont actuellement la pierre angulaire de l'asthme, ils ne sont probablement pas dénués d'effets systémiques, d'une part à forte dose (supérieure à 1 000 γg) et d'autre part dans les utilisations prolongées notamment dans les asthmes légers à modérés. Le traitement anti-inflammatoire est préconisé à partir du stade d'asthme persistant à léger (stade 2 des dernières recommandations internationales) ainsi que bien sûr dans les stades plus sévères. Cette revue a pour objet de déterminer la place potentielle des anti-leucotriènes dans les différents stades de sévérité de la maladie asthmatique à partir du moment où un traitement anti-inflammatoire est envisagé. En effet, par rapport aux autres corticoïdes inhalés, une forme orale, comme cela est le cas pour de nombreux inhibiteurs de leucotriène, peut aider à améliorer l'observance. Par ailleurs cette classe thérapeutique pourrait être préconisée dans les asthmes légers à modérés ou dans les asthmes sévères où il pourrait permettre un effet d'épargne des corticoïdes inhalés.
Leukotrienes participate in inflammation of the airways observed in asthmatic patients and therefore constitute a preferential target for the therapeutic management of these patients. Although inhaled corticosteroids are currently the cornerstone of the treatment of asthma, they are probably not devoid of systemic effects at high doses (greater than 1 000 μg) and during prolonged use, especially in mild to moderate asthma. Anti-inflammatory treatment is recommended from the stage of mild persistent asthma (stage 2 of the latest international recommendations) and obviously in more severe stages. The objective of this review article is to define the potential place of leukotriene inhibitors in the various stages of severity of asthma, whenever anti-inflammatory treatment is considered. Compared to other inhaled corticosteroids, an oral form, as is the case for many leukotriene inhibitors, can help to improve compliance. This therapeutic category can also be recommended in patients with mild to moderate asthma or severe asthma, in which it may allow a reduction of the doses of inhaled corticosteroid.
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