50 research outputs found
RAGE and its ligand amyloid beta promote retinal ganglion cell loss following ischemia-reperfusion injury
IntroductionGlaucoma is a progressive neurodegenerative disease associated with age. Accumulation of amyloid-beta (AĆ) proteins in the ganglion cell layer (GCL) and subsequent retinal ganglion cell (RGC) loss is an established pathological hallmark of the disease. The mechanism through which AĆ provokes RGC loss remains unclear. The receptor for the advanced glycation end product (RAGE), and its ligand AĆ, have been shown to mediate neuronal loss via internalizing AĆ within the neurons. In this study, we investigated whether the RAGEāAĆ axis plays a role in RGC loss in experimental glaucoma.MethodsRetinal ischemia was induced by an acute elevation of intraocular pressure in RAGEā/ā and wild-type (WT) control mice. In a subset of animals, oligomeric AĆ was injected directly into the vitreous of both strains. RGC loss was assessed using histology and biochemical assays. Baseline and terminal positive scotopic threshold (pSTR) were also recorded.ResultsRetinal ischemia resulted in 1.9-fold higher RGC loss in WT mice compared to RAGEā/ā mice (36 Ā± 3% p < 0.0001 vs. 19 Ā± 2%, p = 0.004). Intravitreal injection of oligomeric AĆ resulted in 2.3-fold greater RGC loss in WT mice compared to RAGEā/ā mice, 7-days post-injection (55 Ā± 4% p = 0.008 vs. 24 Ā± 2%, p = 0.02). We also found a significant decline in the positive scotopic threshold response (pSTR) amplitude of WT mice compared to RAGEā/ā (36 Ā± 3% vs. 16 Ā± 6%).DiscussionRAGEā/ā mice are protected against RGC loss following retinal ischemia. Intravitreal injection of oligomeric AĆ accelerated RGC loss in WT mice but not RAGEā/ā. A co-localization of RAGE and AĆ, suggests that RAGEāAĆ binding may contribute to RGC loss
LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE
The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastaseinduced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema
Potential impact of oxidative stress induced growth inhibitor 1 (OSGIN1) on airway epithelial cell autophagy in chronic obstructive pulmonary disease (COPD)
Intergroup Peer Assessment in Problem-Based Learning Tutorials for Undergraduate Pharmacy Students
Objective. To develop, implement, and evaluate a process of intergroup peer assessment and feedback using problem-based learning (PBL) tutorials. Methods. A peer-assessment process was used in a PBL tutorial setting for an integrated pharmacy practice course in which small groups of students graded each others' PBL case presentations and provided feedback in conjunction with facilitator assessment. Assessment. Students' quantitative and qualitative perceptions of the peer assessment process were triangulated with facilitator feedback. Students became more engaged, confident, and motivated, and developed a range of self-directed, life-long learning skills. Students had mixed views regarding the fairness of the process and grade descriptors. Facilitators strongly supported the peer assessment process. Conclusions. Peer assessment is an appropriate method to assess PBL skills and is endorsed by students as appropriate and useful
RAGE and TLRs: relatives, friends or neighbours?
The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE-TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense
Expression and activation of TGFāĪ² isoforms in acute allergenāinduced remodelling in asthma
Induction of Human Airway Smooth Muscle Apoptosis by Neutrophils and Neutrophil Elastase
Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-Ī²
Data_Sheet_1_RAGE and its ligand amyloid beta promote retinal ganglion cell loss following ischemia-reperfusion injury.docx
IntroductionGlaucoma is a progressive neurodegenerative disease associated with age. Accumulation of amyloid-beta (AĆ) proteins in the ganglion cell layer (GCL) and subsequent retinal ganglion cell (RGC) loss is an established pathological hallmark of the disease. The mechanism through which AĆ provokes RGC loss remains unclear. The receptor for the advanced glycation end product (RAGE), and its ligand AĆ, have been shown to mediate neuronal loss via internalizing AĆ within the neurons. In this study, we investigated whether the RAGEāAĆ axis plays a role in RGC loss in experimental glaucoma.MethodsRetinal ischemia was induced by an acute elevation of intraocular pressure in RAGEā/ā and wild-type (WT) control mice. In a subset of animals, oligomeric AĆ was injected directly into the vitreous of both strains. RGC loss was assessed using histology and biochemical assays. Baseline and terminal positive scotopic threshold (pSTR) were also recorded.ResultsRetinal ischemia resulted in 1.9-fold higher RGC loss in WT mice compared to RAGEā/ā mice (36 Ā± 3% p ā/ā mice, 7-days post-injection (55 Ā± 4% p = 0.008 vs. 24 Ā± 2%, p = 0.02). We also found a significant decline in the positive scotopic threshold response (pSTR) amplitude of WT mice compared to RAGEā/ā (36 Ā± 3% vs. 16 Ā± 6%).DiscussionRAGEā/ā mice are protected against RGC loss following retinal ischemia. Intravitreal injection of oligomeric AĆ accelerated RGC loss in WT mice but not RAGEā/ā. A co-localization of RAGE and AĆ, suggests that RAGEāAĆ binding may contribute to RGC loss.</p