scholarly journals Cell type- and tissue-specific functions of ecto-5′-nucleotidase (CD73)

2019 ◽  
Vol 317 (6) ◽  
pp. C1079-C1092 ◽  
Author(s):  
Marquet Minor ◽  
Karel P. Alcedo ◽  
Rachel A. Battaglia ◽  
Natasha T. Snider
Keyword(s):  
Cortical Plasticity ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Cell Types ◽  
Multiple Organ ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Organ Systems

Ecto-5′-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5′-monophosphate to adenosine. Anti-CD73 inhibitory antibodies are currently undergoing clinical testing for cancer immunotherapy. However, many protective physiological functions of CD73 need to be taken into account for new targeted therapies. This review examines CD73 functions in multiple organ systems and cell types, with a particular focus on novel findings from the last 5 years. Missense loss-of-function mutations in the CD73-encoding gene NT5E cause the rare disease “arterial calcifications due to deficiency of CD73.” Aside from direct human disease involvement, cellular and animal model studies have revealed key functions of CD73 in tissue homeostasis and pathology across multiple organ systems. In the context of the central nervous system, CD73 is antinociceptive and protects against inflammatory damage, while also contributing to age-dependent decline in cortical plasticity. CD73 preserves barrier function in multiple tissues, a role that is most evident in the respiratory system, where it inhibits endothelial permeability in an adenosine-dependent manner. CD73 has important cardioprotective functions during myocardial infarction and heart failure. Under ischemia-reperfusion injury conditions, rapid and sustained induction of CD73 confers protection in the liver and kidney. In some cases, the mechanism by which CD73 mediates tissue injury is less clear. For example, CD73 has a promoting role in liver fibrosis but is protective in lung fibrosis. Future studies that integrate CD73 regulation and function at the cellular level with physiological responses will improve its utility as a disease target.

scholarly journals The Cardioprotective Actions of Hydrogen Sulfide in Acute Myocardial Infarction and Heart Failure

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
David J. Polhemus ◽  
John W. Calvert ◽  
Javed Butler ◽  
David J. Lefer
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Hydrogen Sulfide ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Multiple Organ ◽  
Organ Systems ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

It has now become universally accepted that hydrogen sulfide (H2S), previously considered only as a lethal toxin, has robust cytoprotective actions in multiple organ systems. The diverse signaling profile of H2S impacts multiple pathways to exert cytoprotective actions in a number of pathological states. This paper will review the recently described cardioprotective actions of hydrogen sulfide in both myocardial ischemia/reperfusion injury and congestive heart failure.

scholarly journals An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Ashim Malhotra ◽  
Sundeep Bath ◽  
Fawzy Elbarbry
Keyword(s):  
Matrix Protein ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Multiple Organ ◽  
Extracellular Matrix Protein ◽  
Cardiomyocyte Hypertrophy ◽  
Resveratrol Treatment ◽  
Organ Systems ◽  
The Central Nervous System ◽  
Anti Inflammatory

Resveratrol is a phenolic phytochemical, with a stilbene backbone, derived from edible plants such as grape and peanut. It is a bioactive molecule with physiological effects on multiple organ systems. Its effects range from the neuroprotective to the nephroprotective, including cardiovascular, neuronal, and antineoplastic responses as a part of its broad spectrum of action. In this review, we examine the effects of resveratrol on the following organ systems: the central nervous system, including neurological pathology such as Parkinson’s and Alzheimer’s disease; the cardiovascular system, including disorders such as atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte hypertrophy; the kidneys, including primary and secondary nephropathies and nephrolithiasis; multiple forms of cancer; and metabolic syndromes including diabetes. We emphasize commonalities in extracellular matrix protein alterations and intracellular signal transduction system induction following resveratrol treatment. We summarize the known anti-inflammatory, antioxidative, and cytoprotective effects of resveratrol across disparate organ systems. Additionally, we analyze the available literature regarding the pharmacokinetics of resveratrol formulations used in these studies. Finally, we critically examine select clinical trials documenting a lack of effect following resveratrol treatment.

Autotaxin inhibition attenuates endothelial permeability after ischemia-reperfusion injury

2020 ◽  
Vol 75 (4) ◽  
pp. 399-407
Author(s):  
Aaron Strumwasser ◽  
Caitlin M. Cohan ◽  
Genna Beattie ◽  
Vincent Chong ◽  
Gregory P. Victorino
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Endothelial Permeability ◽  
Hydraulic Permeability ◽  
Dependent Manner ◽  
Endothelial Monolayer ◽  
Monolayer Permeability

BACKGROUND: Autotaxin (ATX-secretory lysophospholipase D) is the primary lysophosphatidic acid (LPA) producing enzyme. LPA promotes endothelial hyper-permeability and microvascular dysfunction following cellular stress. OBJECTIVE: We sought to assess whether ATX inhibition would attenuate endothelial monolayer permeability after anoxia-reoxygenation (A-R) in vitro and attenuate the increase in hydraulic permeability observed after ischemia-reperfusion injury (IRI) in vivo. METHODS: A permeability assay assessed bovine endothelial monolayer permeability during anoxia-reoxygenation with/without administration of pipedimic acid, a specific inhibitor of ATX, administered either pre-anoxia or post-anoxia. Hydraulic permeability (Lp) of rat mesenteric post-capillary venules was evaluated after IRI, with and without ATX inhibition. Lastly, Lp was evaluated after the administration of ATX alone. RESULTS: Anoxia-reoxygenation increased monolayer permeability 4-fold (p < 0.01). Monolayer permeability was reduced to baseline similarly in both the pre-anoxia and post-anoxia ATX inhibition groups (each p < 0.01, respectively). Lp was attenuated by 24% with ATX inhibition (p < 0.01). ATX increased Lp from baseline in a dose dependent manner (p < 0.05). CONCLUSIONS: Autotaxin inhibition attenuated increases in endothelial monolayer permeability during A-R in vitro and hydraulic permeability during IRI in vivo. Targeting ATX may be especially beneficial by limiting its downstream mediators that contribute to mechanisms associated with endothelial permeability. ATX inhibitors may therefore have potential for pharmacotherapy during IRI.

scholarly journals Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

2021 ◽  
Vol 22 (17) ◽  
pp. 9486
Author(s):  
Yun Hwa Choi ◽  
Collin Laaker ◽  
Martin Hsu ◽  
Peter Cismaru ◽  
Matyas Sandor ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Lymphatic Vessels ◽  
Immunological Response ◽  
Cell Types ◽  
Multiple Organ ◽  
Post Stroke ◽  
Organ Systems ◽  
The Brain

Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.

Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation

2008 ◽  
Vol 294 (1) ◽  
pp. G236-G244 ◽  
Author(s):  
Takashi Kaizu ◽  
Atsushi Ikeda ◽  
Atsunori Nakao ◽  
Allan Tsung ◽  
Hideyoshi Toyokawa ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Liver Transplantation ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Neutrophil Accumulation ◽  
Hepatic Ischemia ◽  
Factor C

Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20–250 ppm) for 1 h before and 24 h after OLT and killed 1–48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24–48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-α and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.

Ischemia-mediated aggregation of the actin cytoskeleton is one of the major initial events resulting in ischemia-reperfusion injury

2009 ◽  
Vol 296 (2) ◽  
pp. G339-G347 ◽  
Author(s):  
Tong Shi ◽  
Vaishali R. Moulton ◽  
Peter H. Lapchak ◽  
Guo-Min Deng ◽  
Jurandir J. Dalle Lucca ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cytochalasin D ◽  
Immunoglobulin M ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Natural Igm

Ischemia-reperfusion (IR) injury represents a major clinical challenge, which contributes to morbidity and mortality during surgery. The critical role of natural immunoglobulin M (IgM) and complement in tissue injury has been demonstrated. However, cellular mechanisms that result in the deposition of natural IgM and the activation of complement are still unclear. In this report, using a murine intestinal IR injury model, we demonstrated that the β-actin protein in the small intestine was cleaved and actin filaments in the columnar epithelial cells were aggregated after a transient disruption during 30 min of ischemia. Ischemia also led to deposition of natural IgM and complement 3 (C3). A low dose of cytochalasin D, a depolymerization reagent of the actin cytoskeleton, attenuated this deposition and also attenuated intestinal tissue injury in a dose-dependent manner. In contrast, high doses of cytochalasin D failed to worsen the injury. These data indicate that ischemia-mediated aggregation of the actin cytoskeleton, rather than its disruption, results directly in the deposition of natural IgM and C3. We conclude that ischemia-mediated aggregation of the actin cytoskeleton leads to the deposition of natural IgM and the activation of complement, as well as tissue injury.

scholarly journals TLRs in Hepatic Cellular Crosstalk

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Amelie E. Bigorgne ◽  
Ian Nicholas Crispe
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Cell Types ◽  
Parasitic Infections ◽  
Complex Environment ◽  
Hepatocellular Injury ◽  
Multiple Cell ◽  
Toxic Liver Damage ◽  
Exogenous Ligands

Toll-like receptors (TLRs) are expressed on all major subsets of liver cells. Both exogenous ligands derived from pathogens, and endogenous ligands that are products of cellular injury, engage these receptors and activate aspects of innate immunity. These receptors play a role in viral and parasitic infections of the liver, in ischemia-reperfusion injury, and in toxic liver damage, promoting antipathogen immunity but also hepatocellular injury and fibrogenesis. However, TLRs may also participate in negative feedback that limits tissue injury. In the complex environment of the liver, TLRs participate in pathologic cascades involving multiple cell types, manifesting their effects both through cell-autonomous actions, and via cellular crosstalk. In this paper we survey the involvement of TLRs in these diverse processes.

scholarly journals Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1521
Author(s):  
John E. Brus ◽  
Daniel L. Quan ◽  
Kristin J. Wiley ◽  
Brittney Browning ◽  
Hannah Ter Haar ◽  
...  
Keyword(s):  
Animal Studies ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Chow Diet ◽  
Dependent Manner ◽  
Renal Hypertrophy ◽  
Expression Of Genes

Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available “Western” diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.

scholarly journals Themes in fibrosis and gastrointestinal inflammation

2011 ◽  
Vol 300 (5) ◽  
pp. G677-G683 ◽  
Author(s):  
Claudio Fiocchi ◽  
P. Kay Lund
Keyword(s):  
Wound Healing ◽  
Tissue Injury ◽  
Cell Types ◽  
Loss Of Function ◽  
Intestinal Fibrosis ◽  
Gastrointestinal Health ◽  
Molecular Approaches ◽  
Organ Systems ◽  
Culture Models ◽  
Gastrointestinal Inflammation

Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease.

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Functional Independence ◽  
Outcome Data ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Sixth Edition ◽  
Organ Systems ◽  
Cord Injury ◽  
Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

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