Role of chronic exsposure to cigarette smoke on endoglin/CD105 expression in airway epithelium.

Dysregulation of airway epithelial cell function related to cigarette smoke exposure plays an important role in the pathophysiology of COPD and is associated to tissue damage and disease severity. CD105 is a component of the receptor complex of TGF-β, a pleiotropic cytokine involved in cellular proliferation, differentiation and migration. CD105 regulates the expression of different components of the extracellular matrix suggesting a role of CD105 in cellular transmigration and remodeling processes. The aim of the present study was to investigate the expression of endoglin/CD105 in airway epithelium of COPD patients and its involvement in tissue remodeling and progression of COPD. We evaluated the immunoreactivity for CD105 expression in bronchial biopsies isolated from COPD patients and healthy controls (HC). The analysis of metaplastic epithelium was performed in bronchial biopsies by Image Analysis software (Leica Quantimet system). Finally, we investigated the expression of CD105 protein receptor in human bronchial epithelial cells (16HBE cells) exposed to 5% Cigarette Smoke Extract (CSE) for 12 days by western blot. We found that the CD105 immunoreactivity was significantly higher in bronchial epithelium of COPD than HC. Morphometric analysis of bioptic samples of COPD showed an increase of the immunoreactivity for CD105 in the area of metaplastic than in not metaplastic epithelium. Long term exposure to CSE significantly up-regulated CD105 expression in 16HBE. Chronic inflammation due to cigarette smoke might play a critic role on the alteration of CD105 protein expression in COPD, promoting tissue remodeling, angiogenesis and dysregulation of physiological reparative mechanisms, leading to squamous metaplasia

“Leptin and leptin receptor expression in asthma”

Background: The adipokine leptin is a potential new mediator for bronchial epithelial homeostasis. Asthma is a chronic inflammatory disease characterized by airway remodeling that might affect disease chronicity and severity. TGF-b is a tissue growth factor the dysregulation of which is associated with airway remodeling. Objective: We sought to determine whether a bronchial epithelial dysfunction of the leptin/leptin receptor pathway contributes to asthma pathogenesis and severity. Methods: We investigated in vitro the presence of leptin/leptin receptor on human bronchial epithelial cells. Then we studied the effect of TGF-b and fluticasone propionate on leptin receptor expression. Finally, the role of leptin on TGF-b release and cell proliferation was analyzed. Ex vivo we investigated the presence of leptin/leptin receptor in the epithelium of bronchial biopsy specimens from subjects with asthma of various severities and from healthy volunteers, and some features of airway remodeling, such as reticular basement membrane (RBM) thickness and TGF-b expression in the epithelium, were assessed. Results: In vitro bronchial epithelial cells express leptin/leptin receptor. TGF-b decreased and fluticasone propionate increased leptin receptor expression, and leptin decreased the spontaneous release of TGF-b and increased cell proliferation. Ex vivo the bronchial epithelium of subjects with mild, uncontrolled, untreated asthma showed a decrease expression of leptin and its receptor and an increased RBM thickness and TGF-b expression when compared with values seen in healthy volunteers. Furthermore, severe asthma was associated with a reduced expression of leptin and its receptor and an increased RBM thickness with unaltered TGF-b expression. Conclusions: Decreased expression of leptin/leptin receptor characterizes severe asthma and is associated with airway remodeling features

Cigarette smoke alters IL-33 expression and release in airway epithelial cells

AbstractAirway epithelium is a regulator of innate immune responses to a variety of insults including cigarette smoke. Cigarette smoke alters the expression and the activation of Toll Like Receptor 4 (TLR4), an innate immunity receptor. IL-33, an alarmin, increases innate immunity Th2 responses. The aims of this study were to explore whether mini-bronchoalveolar lavage (mini-BAL) or sera from smokers have altered concentrations of IL-33 and whether cigarette smoke extracts (CSE) alter both intracellular expression (mRNA and protein) and release of IL-33 in bronchial epithelial cells. The role of TLR4 in the expression of IL-33 was also explored.Mini-BALs, but not sera, from smokers show reduced concentrations of IL-33. The expression of IL-33 was increased also in bronchial epithelium from smokers. 20% CSE reduced IL-33 release but increased the mRNA for IL-33 by real time PCR and the intracellular expression of IL-33 in bronchial epithelial cells as confirmed by flow cytometry, immunocytochemistry and western blot analysis. The effect of CSE on IL-33 expression was also observed in primary bronchial epithelial cells. IL-33 expression was mainly concentrated within the cytoplasm of the cells. LPS, an agonist of TLR4, reduced IL-33 expression, and an inhibitor of TLR4 increased the intracellular expression of IL-33. In conclusion, the release of IL-33 is tightly controlled and, in smokers, an altered activation of TLR4 may lead to an increased intracellular expression of IL-33 with a limited IL-33 release

Beta defensin-2 is reduced in central but not in distal airways of smoker COPD patients

Background: Altered pulmonary defenses in chronic obstructive pulmonary disease (COPD) may promote distal airways bacterial colonization. The expression/activation of Toll Like receptors (TLR) and beta 2 defensin (HBD2) release by epithelial cells crucially affect pulmonary defence mechanisms. Methods: The epithelial expression of TLR4 and of HBD2 was assessed in surgical specimens from current smokers COPD (s-COPD; n = 17), ex-smokers COPD (ex-s-COPD; n = 8), smokers without COPD (S; n = 12), and from non-smoker non-COPD subjects (C; n = 13). Results: In distal airways, s-COPD highly expressed TLR4 and HBD2. In central airways, S and s-COPD showed increased TLR4 expression. Lower HBD2 expression was observed in central airways of s-COPD when compared to S and to ex-s-COPD. s-COPD had a reduced HBD2 gene expression as demonstrated by real-time PCR on micro-dissected bronchial epithelial cells. Furthermore, HBD2 expression positively correlated with FEV1/FVC ratio and inversely correlated with the cigarette smoke exposure. In a bronchial epithelial cell line (16 HBE) IL-1β significantly induced the HBD2 mRNA expression and cigarette smoke extracts significantly counteracted this IL-1 mediated effect reducing both the activation of NFkB pathway and the interaction between NFkB and HBD2 promoter. Conclusions: This study provides new insights on the possible mechanisms involved in the alteration of innate immunity mechanisms in COPD. © 2012 Pace et al

Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts

We studied the role of PGE2, its biosynthetic enzymes and its receptors, in regulating the functions of lung fibroblasts through the production of Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) in COPD subjects. Lung fibroblasts from Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE2, VEGF, and IL-8 measured in supernatants by ELISA. COX-1/COX-2 and EP receptors expression were assessed by western blot and by RT-PCR. Release of VEGF and IL-8 by human fetal lung fibroblasts (HFL-1; lung, diploid, human) was evaluated under different conditions. PGE2, VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. Low concentrations of synthetic PGE2 increased the release of VEGF in HFL-1, but higher concentrations were needed to induce the release of IL-8. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist. In the airways of COPD subjects, fibroblast-derived PGE2 may regulate angiogenesis and inflammation through the production of VEGF and IL-8 respectively, suggesting that the increase in expression of COX-2, EP2 and EP4 observed in COPD fibroblasts may contribute to steering the role of PGE2 from homeostatic to pro-inflammatory

Phlebology and podiatry

By their tensing and relaxation, the muscles of the leg are thought to be responsible for compressing and relaxing the vascular walls and the lumen of vessels. In order to study the way the muscle structure of the lower limb (in particular the leg and the foot) functions, it is necessary to understand the step and break down its components. The weight of the body is transmitted to the ground by the astralagus which distributes the different forces throughout the fives systems of ossei trabeculae of the astralagus and the heel. The valgus heel determines a continuous traction on the tendon and the hind leg muscle which determines with time a dragging of the foot. When the body goes forward, the weight levels the transverse fore arch. The flexor muscles of the toes bend the phalanxes, gripping them to the ground, they avoid the falling forward of the body with the proximal insertion on the tibia. The sesamoids increase the muscles power as well as that of the kneecap on the quadriceps. The internal curvature of the foot on the ground is furthered by the decreasing length of the metatarsal bones. This is counterbalanced by the long fibular muscle which lowers the medial axis and raises the external axis. The supination of the forefoot depends only in part on the varus valgus of the rear of the foot. The plantar aponeurosis and the flexor tendons have an impact on the metatarsi because they increase the power and bring the insert closer. The complex articular system of the feet depends on the extrinsic and intrinsic muscle structure which, at the same time as a position variation can also play an important part in the venous alteration