scholarly journals The Human Respiratory Microbiome: Implications and Impact

2018 ◽  
Vol 39 (02) ◽  
pp. 199-212 ◽  
Author(s):  
Alicia Mitchell ◽  
Allan Glanville
Keyword(s):  
Ex Vivo ◽  
Tracheobronchial Tree ◽  
Suppressive Therapy ◽  
Disease States ◽  
Rich Diversity ◽  
Improved Outcomes ◽  
Immune Suppressive Therapy ◽  
Extreme Change ◽  
New Generation ◽  
Respiratory Microbiome

AbstractOnce considered a sterile site below the larynx, the tracheobronchial tree and parenchyma of the lungs are now known to harbor a rich diversity of microbial species including bacteria, viruses, fungi, and archaea. Many of these organisms, particularly the viruses which comprise the human respiratory virome, have not been identified, so their true role is unknown. It seems logical to conclude that a “healthy” respiratory microbiome exists which may be modified in disease states and perhaps by therapies such as antibiotics, antifungals, and antiviral treatments. It is likely that there is a critical relationship or equilibrium between components of the microbiome until such time as perturbations occur which lead to a state of dysbiosis or an “unhealthy” microbiome. The act of lung transplantation provides an extreme change to an individual's respiratory microbiome as, in effect, the donor respiratory microbiome is transplanted into the recipient. The mandatory ex-vivo period of the donor lungs appears to be associated with blooms of resident viral species in particular. Subsequently, allograft injury, rejection, and immune suppressive therapy all combine to create periods of dysbiosis which when combined with transient infections such as community acquired respiratory viruses may facilitate the development of chronic allograft dysfunction in predisposed individuals. As our understanding of the respiratory microbiome is rapidly expanding, based on the use of new-generation sequencing tools in particular, it is to be hoped that insights gained into the subtle relationship between the microbiome and the lung allograft will facilitate improved outcomes by directing novel therapeutic endeavors.

scholarly journals Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 898
Author(s):  
Brian H. Kim ◽  
Maciej Jeziorek ◽  
Hur Dolunay Kanal ◽  
Viorica Raluca Contu ◽  
Radek Dobrowolski ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Integrity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Structures ◽  
Improved Outcomes ◽  
Hypoxia Ischemia ◽  
Tgfβ Receptor ◽  
Progressive Neurodegeneration

Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5)—SB505124—three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.

scholarly journals CD1: From Molecules to Diseases

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1909 ◽  
Author(s):  
D. Branch Moody ◽  
Sara Suliman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
High Genetic Diversity ◽  
Disease States ◽  
New Research ◽  
Antigen Presenting ◽  
Cluster Of Differentiation

The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T-cell responses through display of amphipathic lipids, recent studies emphasize the role of direct contacts between the T-cell receptor and CD1 itself. Moving from molecules to diseases, new research approaches emphasize human CD1-transgenic mouse models and the study of human polyclonal T cells in vivo or ex vivo in disease states. Whereas the high genetic diversity of major histocompatibility complex (MHC)-encoded antigen-presenting molecules provides a major hurdle for designing antigens that activate T cells in all humans, the simple population genetics of the CD1 system offers the prospect of discovering or designing broadly acting immunomodulatory agents.

EP.TH.112The Use Ex-Vivo Renal Autotransplantation to Treat Hypertension Secondary to Renal Artery Disease: Two Case Reports

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Noman Saghir ◽  
Reyan Saghir ◽  
Bruno Machado ◽  
Rene Murilo ◽  
Manoj Poojary ◽  
...  
Keyword(s):  
Renal Artery ◽  
Ex Vivo ◽  
Case Reports ◽  
Previous Treatment ◽  
Neoplastic Disease ◽  
Improved Outcomes ◽  
Renal Autotransplantation ◽  
Artery Disease ◽  
The University ◽  
Renal Artery Disease

Abstract Renal Auto transplantation (RAT) is the surgical procedure in which the kidney is initially removed and subsequently re-implanted in a different position, allowing for improved outcomes in conditions involving ureteral pathology, renovascular and neoplastic disease primarily. In this paper, we aim to build upon the understanding of RAT and especially its effectiveness in treating patients with hypertension secondary to renal artery disease, intolerant to previous treatment approaches. In particular, the ex-vivo technique will be focused upon as introduced by Ota et al. in 1967 whereby the use of the workbench is frequently applied for patients requiring in excess of 45 minutes of ischaemic time. We, therefore, put forth two cases managed in co-operation by the University of Arkansas vascular and urology departments. The first of which was a 52-year-old woman with an aneurysmal Lesion reaching the renal artery at the hilum. The second was an 18-year-old woman with Takayasu arteritis. The use of vasopressin had preserved some renal function however at the time of the diagnosis, they were experiencing difficulty in controlling their hypertension, and thus RAT was performed, and the subsequent patient postoperative outcomes and effectiveness have been recorded and analysed as part of this study.

scholarly journals Arcuate Nucleus Proopiomelanocortin Neurons Mediate the Acute Anorectic Actions of Leukemia Inhibitory Factor via gp130

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 606-616 ◽  
Author(s):  
Aaron J. Grossberg ◽  
Jarrad M. Scarlett ◽  
XinXia Zhu ◽  
Darren D. Bowe ◽  
Ayesha K. Batra ◽  
...  
Keyword(s):  
Food Intake ◽  
Proinflammatory Cytokine ◽  
Leukemia Inhibitory Factor ◽  
Arcuate Nucleus ◽  
Ex Vivo ◽  
Inhibitory Factor ◽  
Neural Pathways ◽  
Disease States ◽  
Inhibit Food Intake ◽  
Anorexigenic Peptide

The proinflammatory cytokine leukemia inhibitory factor (LIF) is induced in disease states and is known to inhibit food intake when administered centrally. However, the neural pathways underlying this effect are not well understood. We demonstrate that LIF acutely inhibits food intake by directly activating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. We show that arcuate POMC neurons express the LIF-R, and that LIF stimulates the release of the anorexigenic peptide, α-MSH from ex vivo hypothalami. Transgenic mice lacking gp130, the signal transducing subunit of the LIF-R complex, specifically in POMC neurons fail to respond to LIF. Furthermore, LIF does not stimulate the release of α-MSH from the transgenic hypothalamic explants. These findings indicate that POMC neurons mediate the acute anorectic actions of central LIF administration and provide a mechanistic link between inflammation and food intake.

Impact of Pathogen Reduction Technology Treatment and Storage in New Generation Platelet Additive Solutions (PAS) on Platelet Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2115-2115
Author(s):  
Gines Escolar ◽  
Miguel Lozano ◽  
Patricia Molina ◽  
Susanne Marschner ◽  
Raymond Goodrich ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Function ◽  
Research Funding ◽  
Ex Vivo ◽  
Quality Parameters ◽  
Slight Reduction ◽  
Flow Cytometry Analysis ◽  
Adhesive Properties ◽  
Pathogen Reduction ◽  
New Generation

Abstract Abstract 2115 Poster Board II-92 New strategies for preparing platelet concentrates (PCs) are investigating the combination of pathogen reduction technologies (PRT) with storage of platelets in additive solutions (PAS) containing phosphate buffer. While these approaches have several advantages by reducing adverse effects, improving biological safety and increasing plasma availability, there is a reasonable concern on how these strategies could affect platelet function. In the present study we have evaluated the effect of Marisol® PRT treatment (CaridianBCT Biotechnologies, LLC) in combination with storage in PAS-III (Intersol; Baxter Healthcare Corp) or PAS-IIIM (SSP+; MacoPharma) on analytical and functional characteristics of apheresis PCS. PCs (2.5-3.4×109plts/ml) were split into three aliquots. One was kept untreated and stored in plasma as a control (CON-PPP). One was PRT-treated and stored in the corresponding PAS (PRT-PASIII or PRT-IIIM) with a 35% plasma carryover to achieve a final concentration of 0.7-1.5 × 109 plt/ml. The last aliquot was stored in the corresponding PAS (CON-PASIII or CON-PASIIIM), not subjected to PRT treatment. PCs were stored under standardized conditions and evaluations were performed on days 0, 5 and 7. Cell quality parameters (pH, swirl, lactate and glucose), flow cytometry analysis of major platelet glycoproteins and activation dependent antigens were assessed. Adhesive and aggregating functions of platelets were evaluated using an ex vivo perfusion model with flowing reconstituted blood recirculating through damaged vascular segments. A slight reduction in platelet counts was noticed on day 7 compared to day 0 in PRT-treated PCs (p<0.05), however no statistical differences were observed between the different study groups. All measured cell quality parameters were within ranges previously published. Flow cytometry analysis revealed comparable levels of the analyzed glycoproteins for all conditions evaluated. Only moderate reductions in the expression of GPIb were observed on day 7 of storage in all groups except for CON-PASIIIM. A progressive increase in the expression of P-selectin was observed in both controls and PRT-treated PCs during storage. Lysosomal integral membrane protein (LIMP) expression was increased in PRT-PASIII and PRT-PASIIIM and CON-PASIII, but not CON-PASIIIM PCs. PRT-PASIII PCs showed the highest levels of annexin V binding after 7 days of storage. Studies under flow conditions showed comparable levels of adhesion and aggregation to subendothelium for PRT-treated platelets stored in PAS solutions at 5 days of storage. A detailed morphometric analysis revealed slightly enhanced adhesive functions in CON-PASIII on day 0 and moderate reductions in adhesive properties in PRT-PASIII, but not PRT-PASIIIM PCs after 7 days of storage. Our investigations show that cell quality parameters, glycoproteins levels and platelet functions were preserved in PRT-treated concentrates and stored in new generation PAS for up to 5 days. The relevance of our experimental data on the in vivo performance of PCs exposed to PRT and stored in new generation PAS deserve further investigation in the clinical setting. Disclosures: Escolar: Caridian BCT Technologies: Consultancy, Research Funding. Marschner:Caridian BCT Technologies: Employment. Goodrich:Caridian BCT Technologies: Employment. Galan:Caridian BCT Technologies: Research Funding.

Integrin CD11a/CD18, CD11b/CD18 and CD69 expression in patients after renal transplantation

Open Medicine ◽  
2007 ◽  
Vol 2 (2) ◽  
pp. 154-158 ◽  
Author(s):  
Jacek Rysz ◽  
Eugeniusz Kocur ◽  
Robert Błaszczak ◽  
Robert Stolarek
Keyword(s):  
Renal Failure ◽  
Renal Transplantation ◽  
Chronic Renal Failure ◽  
Serum Concentration ◽  
Suppressive Therapy ◽  
Before And After ◽  
Immune Suppressive Therapy ◽  
Cd69 Expression ◽  
Complete Failure ◽  
Human Polymorphonuclear Leukocytes

AbstractChronic renal failure (CRF) is a complex clinical entity caused by progressive destruction of functional renal parenchyma in the course of various pathological processes resulting in complete failure of renal function and subsequent metabolic, acid base and electrolyte as well as immune disorders. Renal transplantation (RT) is one of the renal replacement therapy options in the terminal stage of chronic renal failure. The replacement of the failing organ with one from a healthy donor may be complicated with immune host response. This study was designed to investigate the changes in serum concentration of integrins CD11a/CD18, CD11b/CD18, CD69 on the surface of human polymorphonuclear leukocytes (PMNL) after the RT within two six-month periods. The study included 25 RT patients (mean 5.4±2.7 yrs after the transplantation, 10 females and 15 males) treated with immune suppressive therapy including cyclosporine A, azathioprine and prednisolone. The expression was assessed with monoclonal antibodies by means of flow cytometry. Also, the expression of CD69 was determined before and after phytohemaglutinine (PHA) stimulation. There was no significant alternation in serum concentration of CD11a/CD18, CD11b/CD18 and CD69 at baseline, six months and twelve months later. The expression of integrins was not altered in renal transplantation patients in the current study setting.

scholarly journals Moderately Inducing Autophagy Reduces Tertiary Brain Injury After Perinatal Hypoxia-Ischemia

2020 ◽  
Author(s):  
Brian H. Kim ◽  
Maciej Jeziorek ◽  
Hur Dolunay Kanal ◽  
Radek Dobrowolski ◽  
Steven W. Levison
Keyword(s):  
Cell Death ◽  
Structural Integrity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Structures ◽  
Improved Outcomes ◽  
Hypoxia Ischemia ◽  
Tgfβ Receptor ◽  
Progressive Neurodegeneration

AbstractRecent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5) – SB505124 – 3 days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. However, those studies did not determine whether 1) SB was acting directly on the CNS and 2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist 3 days after HI reduced actively apoptotic cells by ∼90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting 3 days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.

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