Proteinase-activated receptor-2 modulates human macrophage differentiation andeffector function

Proteinase-activated receptor-2 (PAR-2) was shown to influence immune regulation; however, its role in human macrophage subset development and function has not been addressed. Here, PAR-2 expression and activation was investigated on granulocyte macrophage (GM)-CSF(M1) and macrophage (M)-CSF(M2) macrophages. In both macrophages, the PAR-2-activating peptide, SLIGKV, increased PAR-2 expression and regulated TNF-α and IL-10 secretion in a manner similar to LPS. In addition, HLA-DR on M1 cells also increased. Monocytes matured to an M1 phenotype in the presence of SLIGKV had reduced cell area, and released less TNF-α after LPS challenge compared with vehicle (P < 0.05, n = 3). Cells matured to an M2 phenotype with SLIGKV also had a reduced cell area and made significantly more TNF-α after LPS exposure compared to vehicle (P < 0.05, n = 3) with reduced IL-10 secretion (P < 0.05, n = 3). Thus, PAR-2 activation on macrophage subsets regulates HLA-DR and PAR-2 surface expression, and drives cytokine production. In contrast, PAR-2 activation during M1 or M2 maturation induces altered cell morphology and skewing of phenotype, as evidenced by cytokine secretion. These data suggest a complex role for PAR-2 in macrophage biology and may have implications for macrophage-driven disease in which proteinase-rich environments can influence the immune process directly

Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors

A role for endothelium-derived constricting factors (EDCF), and the angiotensin II type 1 receptor (AT1R) pathway, in the vascular impairment found in the rat Freund's complete adjuvant (FCA)-model of rheumatoid arthritis (RA) was examined. FCA arthritis was induced in rats±losartan. Vehicle-treated rats served as controls. Knee-joint swelling and red blood cell (RBC) aggregation were measured as indicators of inflammation and endothelium reactivity assessed by response to acetylcholine (ACh) on aortic rings. Results show that knee-joint swelling and RBC aggregation were elevated in the FCA+vehicle group and restored to control levels in the FCA+losartan-treated animals. ACh-induced relaxation of aortic rings taken from FCA+vehicle animals was significantly impaired compared to vehicle-controls and this vasoreactivity was restored to control levels in the FCA+losartan-treated group. Further examination of aorta from the FCA+vehicle animals revealed an EDCF that was reliant on cyclooxygenase-2 (but not cyclooxygenase-1), generation of superoxide anion generation (but not hydrogen peroxide) and activation of thromboxane-prostanoid receptor. Losartan administration in vivo or ex vivo (to aortic rings) prevented the generation of the EDCF. In summary, this is the first evidence of an EDCF in a model of RA and identifies this mechanism as potentially significant in the cardiovascular disorder associated with the disease

Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

Objective Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis. Methods OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain. Results Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone. Conclusions This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes

Avances en la restauración de bosques de roble en tierras bajas agrícolas del Río Mississippi y sus tributarios

The lowlands associated with the Mississippi River and its tributaries historically supported extensive broadleaf forests that were particularly rich in oak (Quercus spp.) species. Beginning in the 1700s, deforestation for agriculture substantially reduced the extent of the original forest, and fragmented the remainder into small parcels. More recently, declines in agricultural commodity prices, along with increased awareness of conservation have provided opportunities to restore a substantial base of agriculture land to broadleaf forests. While afforestation of former agricultural land began over 40 years ago in the region, organized, large-scale afforestation efforts have peaked over the last 15 years with increased interest in forest sustainability, biodiversity conservation, carbon sequestration, and water quality. Large-scale implementation of afforestation to restore broadleaf forest cover has raised many issues particular to oak species biology and ecology that impact the restoration process. The purpose of this manuscript is to present knowledge gained from research and experience with oak forest afforestation in the eastern United States as a model for developing approaches to initiate oak forest restoration in other regions. To accomplish this, we outline issues associated with the oak regeneration strategy and natural stand development patterns that have hampered large-scale restoration of oak-dominated forests. Furthermore, we present effective afforestation approaches used to reduce the impact of these challenges, and frame these approaches under the context of oak forest afforestation that addresses multiple management objectives and provides for value and function on a sustainable basis.Las zonas bajas asociadas al río Mississippi y sus tributarios albergaron históricamente extensos bosques de latifoliadas particularmente ricos en especies de roble (Quercus spp.). A comienzos del siglo xviii, la deforestación causada por la agricultura sostenible redujo la extensión del bosque original y fragmentó el restante en pequeñas parcelas. Más recientemente, la reducción en los precios de los productos, junto con la creciente conciencia por la conservación, han brindado oportunidades para restaurar una porción considerable de tierras agrícolas en bosques de latifoliadas. Mientras que las primeras reforestaciones de tierras agrícolas comenzaron hace 40 años en la región, los esfuerzos para realizar reforestaciones organizadas y a gran escala han tenido su máximo en los últimos 15 años, debido al creciente interés en la sostenibilidad de los bosques, la conservación de la biodiversidad, el secuestro de carbono y la calidad de las aguas. Implementar la reforestación a gran escala para restaurar bosques de latifoliadas involucra muchos aspectos de la biología y ecología de las especies de roble que impactan el proceso de restauración. El propósito de este artículo es mostrar los conocimientos que se han obtenido a través de investigaciones y experiencias en la reforestación de bosques de roble en el oriente de los Estados Unidos, como modelo para desarrollar avances que permitan iniciar la restauración de los bosques de roble en otras regiones. Para lograr esto delineamos aspectos asociados con las estrategias de regeneración de los robles y los patrones de desarrollo natural de los rodales que han limitado la reforestación a gran escala en bosque dominados por roble. Más aún, presentamos avances efectivos en reforestación usados para reducir el impacto de estos cambios, y enmarcamos estos avances en el contexto de la reforestación de bosques de roble que responde a múltiples objetivos de manejo y brinda valor y función sobre una base sostenible

1969: Abilene Christian College Bible Lectures - Full Text

GOD’S ETERNAL PURPOSE Being the Abilene Christian College Annual Bible Lectures 1969 Published by ABILENE CHRISTIAN COLLEGE BOOK STORE ACC Station Abilene, Texas 7960

Informed development of a multi-species biofilm in chronic obstructive pulmonary disease

Recent evidence indicates that microbial biofilm aggregates inhabit the lungs of COPD patients and actively contribute towards chronic colonization and repeat infections. However, there are no contextually relevant complex biofilm models for COPD research. In this study, a meta-analysis of the lung microbiome in COPD was used to inform development of an optimized biofilm model composed of genera highly associated with COPD. Bioinformatic analysis showed that although diversity matrices of COPD microbiomes were similar to healthy controls, and internal compositions made it possible to accurately differentiate between these cohorts (AUC = 0.939). Genera that best defined these patients included Haemophilus, Moraxella and Streptococcus. Many studies fail to account for fungi; therefore, Candida albicans was included in the creation of an interkingdom biofilm model. These organisms formed a biofilm capable of tolerating high concentrations of antimicrobial therapies with no significant reductions in viability. However, combined therapies of antibiotics and an antifungal resulted in significant reductions in viable cells throughout the biofilm (p < 0.05). This biofilm model is representative of the COPD lung microbiome and results from in vitro antimicrobial challenge experiments indicate that targeting both bacteria and fungi in these interkingdom communities will be required for more positive clinical outcomes