Search

Idiopathic Parkinson’s Disease (IPD) is a progressive movement disorder, which is associated with nigro striatal dopaminergic neuron loss. Cardinal clinical symptoms of the disease are tremor at rest, bradykinesia, rigidity and postural instability. Although motor symptoms (NMSs) of IPD are well recognized, non motor symptoms of the disease are not known and hence are not treated adequately. In our study, IPD patients diagnosed according to diagnostic criteria of United Kingdom Brain Bank and followed regularly in Antalya Research and Training Hospital Neurology Clinic Parkinson’s disease and movement disorders outpatient clinic were evaluated retrospectively for clinical evaluation, United Parkinson’s Disease Rating scale (UPDRS) was used. Constipation, anosmia, rapid eye movement (REM) sleep behavior disorder (SBD), history of depression diagnosed previously were inquired in order to investigate non motor symptoms. There were 163 patients included in this study (61.3% was male and 38.7% female). Their mean age was 65.85±10.09 (min. 29-max. 87) and mean duration of disease 4.93±0.36 years. UPDRS score was 23.87±1.1 while 11 patients were on monotherapy, the remaining patients received combination treatment. Anosmia was present in 52 (31.9%), patients and constipation in 85 (52.1%). Rapid Eye Movement Behavior Disorder (RBD) in 84 (51.5%) and history of depression in 45 (27.6%) patients. The diagnosis of non-motor symptoms, that can be encountered in large majority of Parkinson’s disease patients at all stages of the disease and have a negative impact on quality of life is based on clinical characteristics. Early recognition and proper treatment of non-motor symptoms in IPD is important for quality of life of the patients. The first step for this is the inquiry of these symptoms. © 2017, Logos Medical Publishing. All rights reserved.

Abnormal remodeling of the extracellular matrix (ECM) has been implicated in the pathogenesis of bronchopulmonary dysplasia. However, the contribution of lung parenchymal cells to ECM remodeling after mechanical injury is not well defined. The objective of these studies was to investigate in vitro the release of MMP-2 and -9 and their respective inhibitors TIMP-2 and -1, and to explore potential regulation by IL-10.Mouse fetal epithelial cells and fibroblasts isolated on E18-19 of gestation were exposed to 20% cyclic stretch to simulate lung injury. MMP-2 and MMP-9 activity were investigated by zymography and ELISA. TIMP-1 and TIMP-2 abundance were analyzed by Western blot.We found that mechanical stretch increased MMP-2 and decreased TIMP-2 in fibroblasts, indicating that excessive stretch promotes MMP-2 activation, expressed as the MMP-2/TIMP-2 ratio. Incubation with IL-10 did not change MMP-2 activity. In contrast, mechanical stretch of epithelial cells decreased MMP-9 activity and the MMP-9/TIMP-1 ratio by 60-70%. When IL-10 was added, mechanical stretch increased the MMP-9/TIMP-1 ratio by 50%.We conclude that mechanical stretch differentially affects MMP-2/9 and their inhibitors in fetal lung cells. IL-10 modulates MMP-9 activity through a combination of effects on MMP-9 and TIMP-1 levels.

Background Mechanical ventilation plays an important role in the pathogenesis of bronchopulmonary dysplasia. However, the molecular mechanisms by which excessive stretch induces lung inflammation are not well characterized.

An imbalance between pro-inflammatory and anti-inflammatory cytokines is a key factor in the lung injury of premature infants exposed to mechanical ventilation. Previous studies have shown that lung cells exposed to stretch produces reduced amounts of the anti-inflammatory cytokine IL-10. The objective of these studies was to analyze the signaling mechanisms responsible for the decreased IL-10 production in fetal type II cells exposed to mechanical stretch. Fetal mouse type II epithelial cells isolated at embryonic day 18 were exposed to 20% stretch to simulate lung injury. We show that IL-10 receptor gene expression increased with gestational age. Mechanical stretch decreased not only IL-10 receptor gene expression but also IL-10 secretion. In contrast, mechanical stretch increased release of IL-6. We then investigated IL-10 signaling pathway-associated proteins and found that in wild-type cells, mechanical stretch decreased activation of JAK1 and TYK2 and increased STAT3 and SOCS3 activation. However, opposite effects were found in cells isolated from IL-10 knockout mice. Reduction in IL-6 secretion by stretch was observed in cells isolated from IL-10 null mice. To support the idea that stretch-induced SOCS3 expression via IL-6 leads to reduced IL-10 expression, siRNA-mediated inhibition of SOCS3 restored IL-10 secretion in cells exposed to stretch and decreased IL-6 secretion. Taken together, these studies suggest that the inhibitory effect of mechanical stretch on IL-10 secretion is mediated via activation of IL-6-STAT3-SOCS3 signaling pathway. SOCS3 could be a therapeutic target to increase IL-10 production in lung cells exposed to mechanical injury.

Mechanical ventilation plays an important role in the pathogenesis of bronchopulmonary dysplasia. However, the molecular mechanisms by which excessive stretch induces lung inflammation are not well characterized.In this study, we investigated in vitro the contribution of lung mesenchymal cells to the inflammatory response mediated by mechanical stretch and the potential protective role of IL-10.Fetal mouse lung fibroblasts isolated during the saccular stage of lung development were exposed to 20% cyclic stretch to simulate mechanical injury. The phenotype of cultured fibroblasts was investigated by red oil O and alpha-smooth muscle actin (α-SMA) staining. Cell necrosis, apoptosis, and inflammation were analyzed by lactate dehydrogenase release, cleaved caspase-3 activation and release of cytokines and chemokines into the supernatant, respectively.First, we characterized the phenotype of the cultured fibroblasts and found an absence of red oil O staining and 100% positive staining for α-SMA, indicating that cultured fibroblasts were myofibroblasts. Mechanical stretch increased necrosis and apoptosis by two- and three-fold, compared to unstretched samples. Incubation of monolayers with IL-10 prior to stretch did not affect necrosis but significantly decreased apoptosis. Mechanical stretch increased release of pro-inflammatory cytokines and chemokines IL-1β, MCP-1, RANTES, IL-6, KC and TNF-α into the supernatant by 1.5- to 2.5-fold, and administration of IL-10 before stretch blocked that release.Our data demonstrate that lung interstitial cells may play a significant role in the inflammatory cascade triggered by mechanical stretch. IL-10 protects fetal fibroblasts from injury secondary to stretch. Pediatr. Pulmonol. 2011; 46:640-649. © 2011 Wiley-Liss, Inc.

Mechanical forces are critical for fetal lung development. Using surfactant protein C (SP-C) as a marker, we previously showed that stretch-induced fetal type II cell differentiation is mediated via the ERK pathway. Caveolin-1, a major component of the plasma membrane microdomains, is important as a signaling protein in blood vessels exposed to shear stress. Its potential role in mechanotransduction during fetal lung development is unknown. Caveolin-1 is a marker of type I epithelial cell phenotype. In this study, using immunocytochemistry, Western blotting, and immunogold electron microscopy, we first demonstrated the presence of caveolin-1 in embryonic day 19 (E19) rat fetal type II epithelial cells. By detergent-free purification of lipid raft-rich membrane fractions and fluorescence immunocytochemistry, we found that mechanical stretch translocates caveolin-1 from the plasma membrane to the cytoplasm. Disruption of the lipid rafts with cholesterol-chelating agents further increased stretch-induced ERK activation and SP-C gene expression compared with stretch samples without disruptors. Similar results were obtained when caveolin-1 gene was knocked down by small interference RNA. In contrast, adenovirus overexpression of the wild-type caveolin-1 or delivery of caveolin-1 scaffolding domain peptide inside the cells decreased stretch-induced ERK phosphorylation and SP-C mRNA expression. In conclusion, our data suggest that caveolin-1 is present in E19 fetal type II epithelial cells. Caveolin-1 is translocated from the plasma membrane to the cytoplasm by mechanical stretch and functions as an inhibitory protein in stretch-induced type II cell differentiation via the ERK pathway.