ABSTRACT
Activin-A is a pleiotropic cytokine that regulates allergic inflammation. Its role in the regulation of angiogenesis, a key feature of airways remodelling in asthma, remains unexplored. Our objective was to investigate the expression of activin-A in asthma and its effects on angiogenesis in vitro.Expression of soluble/immunoreactive activin-A and its receptors was measured in serum, bronchoalveolar lavage fluid (BALF) and endobronchial biopsies from 16 healthy controls, 19 patients with mild/moderate asthma and 22 severely asthmatic patients. In vitro effects of activin-A on baseline and vascular endothelial growth factor (VEGF)-induced human endothelial cell angiogenesis, signalling and cytokine release were compared with BALF concentrations of these cytokines in vivo.Activin-A expression was significantly elevated in serum, BALF and bronchial tissue of the asthmatics, while expression of its protein receptors was reduced. In vitro, activin-A suppressed VEGF-induced endothelial cell proliferation and angiogenesis, inducing autocrine production of anti-angiogenic soluble VEGF receptor (R)1 and interleukin (IL)-18, while reducing production of pro-angiogenic VEGFR2 and IL-17. In parallel, BALF concentrations of soluble VEGFR1 and IL-18 were significantly reduced in severe asthmatics in vivo and inversely correlated with angiogenesis.Activin-A is overexpressed and has anti-angiogenic effects in vitro that are not propagated in vivo, where reduced basal expression of its receptors is observed particularly in severe asthma.
Subject(s)
Activins/metabolism , Asthma/metabolism , Bronchi/pathology , Cytokines/metabolism , Neovascularization, Pathologic/metabolism , Vascular Endothelial Growth Factor A/metabolism , Activins/genetics , Adult , Bronchoalveolar Lavage Fluid , Case-Control Studies , Cell Line , Cell Proliferation , Endothelial Cells/cytology , Female , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-17/metabolism , Interleukin-18/metabolism , Male , Middle Aged , Receptors, Vascular Endothelial Growth Factor/genetics , Receptors, Vascular Endothelial Growth Factor/metabolism , Severity of Illness Index , Vascular Endothelial Growth Factor A/geneticsABSTRACT
BACKGROUND: Collection of exhaled breath condensate (EBC) is a safe, non-invasive method to collect droplets of the airway surface liquid and measure mediators of airway inflammation and oxidative stress, such as cysteinyl-leukotrienes (cys-LTs) and 8-isoprostane. OBJECTIVE: The aim of our study was to investigate baseline values of inflammatory lipid mediators in EBC and their relation to asthma severity. METHODS: Nineteen healthy subjects, 16 mild, 12 moderate and 15 severe asthmatics were studied. All subjects attended a clinic visit for spirometry and EBC collection. The concentrations of exhaled cys-LTs and 8-isoprostane were measured by means of specific enzyme immunoassays. RESULTS: 8-isoprostane levels were significantly increased in mild (49.1+/-5.2 pg/mL, p<0.001), moderate (49.7+/-5.2 pg/mL, p<0.001) and severe asthmatics (77.7+/-7.3 pg/mL, p<0.001), compared to healthy controls (16.4+/-1.6 pg/mL). Moreover, 8-isoprostane levels were significantly higher in severe compared to mild and moderate asthmatics (p<0.01). Cys-LT levels were significantly higher in moderate (34.6+/-4.4 pg/mL, p<0.05) and severe asthmatics (47.9+/-6.0 pg/mL, p<0.001), while no significant difference was found between healthy controls and mild asthmatics. 8-isoprostane levels in EBC of asthmatics strongly correlated with cys-LT levels (r=0.61, p<0.0001). CONCLUSIONS: 8-isoprostane and cys-LT are detectable in EBC of healthy subjects and their levels progressively increase in asthmatic patients according to disease severity. The correlation found between these two lipid mediators indicating a link between oxidative stress and airway inflammation.
Subject(s)
Asthma/physiopathology , Cysteine/analysis , Dinoprost/analogs & derivatives , Leukotrienes/analysis , Adult , Asthma/metabolism , Breath Tests/methods , Case-Control Studies , Cross-Sectional Studies , Dinoprost/analysis , Female , Forced Expiratory Volume , Greece , Humans , Immunoenzyme Techniques , Male , Middle Aged , Oxidative Stress , SpirometryABSTRACT
Osteopontin (Opn) is important for T helper type 1 (T(H)1) immunity and autoimmunity. However, the role of this cytokine in T(H)2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse T(H)2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of T(H)2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and T(H)2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established T(H)2 responses and protected mice from allergic disease. These effects on T(H)2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.
