Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of ...dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.
Highlights • During pregnancy gefitinib appears to have a good pharmacological profile. • Residual concentration for gefitinib for the mother is within the lower range. • Pharmacological data exhibit ...a low placental transfer of gefitinib. • No accumulation was observed in fetus.
Chronic Granulomatosis Disease (CGD) is an inherited immune deficiency due to a mutation in the genes coding for the subunits of the NADPH oxidase enzyme that affects the oxidative capacity of ...phagocytic cells. It is characterized by increased susceptibility to bacterial and fungal infections, particularly Aspergillus, as well as complications associated with hyperinflammation and granulomatous tissue infiltration. There exist two types of frequently encountered pulmonary manifestations: (1) due to their being initially pauci-symptomatic, possibly life-threatening infectious complications are often discovered at a late stage. Though their incidence has decreased through systematic anti-bacterial and anti-fungal prophylaxis, they remain a major cause of morbidity and mortality; (2) inflammatory complications consist in persistent granulomatous mass or interstitial pneumoniae, eventually requiring immunosuppressive treatment. Pulmonary complications recurring since infancy generate parenchymal and bronchial sequelae that impact functional prognosis. Hematopoietic stem cell allograft is a curative treatment; it is arguably life-sustaining and may limit the morbidity of the disease. As a result of improved pediatric management, life expectancy has increased dramatically. That said, new challenges have appeared with regard to adults: difficulties of compliance, increased inflammatory manifestations, acquired resistance to anti-infectious therapies. These different developments underscore the importance of the transition period and the need for multidisciplinary management.
Background
Respiratory allergies rely on a defect of IL‐10‐secreting regulatory CD4+T‐cells (IL‐10‐Tregs) leading to excessive Th2‐biased immune responses to allergens. According to clinical data, ...the restoration of allergen‐specific IL‐10‐Tregs is required to control respiratory allergies and cure patients. The discovery of mechanisms involved in the generation of IL‐10‐Tregs will thus help to provide effective treatments. We previously demonstrated that dendritic cells (DCs) expressing high levels of the glucocorticoid‐induced leucine zipper protein (GILZ) generate antigen‐specific IL‐10‐Tregs.
Objective
We suspect a defective expression of GILZ in the DCs of respiratory allergic patients and speculate that increasing its expression might restore immune tolerance against allergens through the induction of IL‐10‐Tregs.
Methods
We assessed GILZ expression in blood DCs of patients and healthy nonallergic donors by qPCR. We compared the ability of patients' DCs to induce allergen‐specific IL‐10‐Tregs before and after an in vivo up‐regulation of GILZ expression by steroid administration, steroids being inducers of GILZ.
Results
We report lower levels of GILZ in DCs of respiratory allergic patients that return to normal levels after steroid administration. We show that patients' DCs with increased levels of GILZ generate allergen‐specific IL‐10‐Tregs again. We further confirm unequivocally that GILZ is required in patients' DCs to activate these IL‐10‐Tregs.
Conclusion
This proof of concept study shows that the re‐establishment of GILZ expression in patients' DCs to normal levels restores their capacity to activate allergen‐specific IL‐10‐Tregs. We thus highlight the up‐regulation of GILZ in DCs as a new interventional approach to restore the immune tolerance to allergens.
Des associations dilatations des bronches (DDB) et vascularite à ANCA (VAA) ont été ponctuellement rapportées 3. L’évolution favorable des DDB sous traitement immunosuppresseur interroge sur un lien ...physiopathologique entre DDB et genèse de la vascularite 1,2. Notre objectif était de décrire les caractéristiques cliniques, biologiques et radiologiques de patients atteints de DDB et de VAA, ainsi que leur profil évolutif et leur pronostic.
Il s’agissait d’une étude rétrospective observationnelle et descriptive, à partir d’une série de patients ayant une VAA selon les critères de l’American College of Rhumatology (ACR) et des DDB confirmées radiologiquement. Les cas ont été sélectionnés dans la cohorte du Groupe français d’étude des vascularites (GFEV) et par appel national à observations auprès des sociétés françaises de pneumologie et de médecine interne. Ils proviennent de 13 centres hospitaliers français.
Parmi les 61 patients inclus, 27 (44 %) avaient une polyangéite microscopique (PAM), 26 (43 %) une granulomatose avec polyangéite (GPA), 7 (2 %) une granulomatose éosinophilique avec polyangéite (GEPA), et un une VAA indifférenciée. Quarante-cinq patients (74 %) avaient des symptômes respiratoires au diagnostic de la VAA. Les autres manifestations étaient rénales (n=20, 33 %), neurologiques (n=26, 43 %), rhino-sinusiennes (n=31, 51 %) et rhumatismales (n=29, 48 %). Les DDB étaient considérées comme idiopathiques chez 40 patients (65,5 %) et post-infectieuses chez 15 patients (24,5 %). La médiane de survie était de 7 ans (4–13), avec 9 décès (15 %). Trois d’entre eux étaient dus à une insuffisance respiratoire (33 %) et trois à une complication directe de la VAA (33 %). Au moins une rechute de VAA est survenue chez 26 patients (43 %). Une ou plusieurs surinfections de DDB nécessitant une antibiothérapie ou une hospitalisation est survenue chez 32 patients (52 %). Le taux médian de surinfections de DDB était de 0,35 par an (0,2–1). Les DDB ont été classées en deux groupes : soit antérieures au diagnostic de VAA (25 cas, 41 %), soit diagnostiquées parallèlement à la vascularite ou apparaissant durant le suivi (36 cas, 59 %). Les caractéristiques radiologiques, estimées selon le score radiologique de Bhalla, étaient comparables dans les deux groupes. Les DDB connues avant la VAA étaient plus souvent de cause post-infectieuse (48 % versus 8 %, p<0,01), étaient significativement associées à la survenue d’une PAM (64 % versus 31 %, p=0,02) et associées à une mortalité plus importante (32 % versus 3 %, p=0,02).
Notre série d’associations VAA et DDB suggère que les DDB apparaissant au cours d’une vascularite pourraient être spécifiques de la VAA. La préexistence de DDB avant le diagnostic de vascularite influence la présentation phénotypique des VAA et leur pronostic. Les complications infectieuses mortelles ne sont pas liées à la présence de DDB qui ne contre-indiquent pas la prescription des immunosuppresseurs sous couvert d’une prophylaxie adaptée.
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