Toxic effects of cell-free hemoglobin on the microvascular endothelium: implications for pulmonary and non-pulmonary organ dysfunction

2021 ◽  
Author(s):  
Jamie E Meegan ◽  
Julie A. Bastarache ◽  
Lorraine B. Ware
Keyword(s):  
Organ Dysfunction ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Severity Of Illness ◽  
Therapeutic Strategies ◽  
Free Hemoglobin ◽  
Microvascular Endothelium ◽  
Endothelial Inflammation ◽  
Signaling Mechanisms ◽  
Novel Therapeutic Strategies

Levels of circulating cell-free hemoglobin are elevated during hemolytic and inflammatory diseases and contribute to organ dysfunction and severity of illness. Though several studies have investigated the contribution of hemoglobin to tissue injury, the precise signaling mechanisms of hemoglobin-mediated endothelial dysfunction in the lung and other organs are not yet completely understood. The purpose of this review is to highlight the knowledge gained thus far and the need for further investigation regarding hemoglobin-mediated endothelial inflammation and injury in order to develop novel therapeutic strategies targeting the damaging effects of cell-free hemoglobin.

scholarly journals Autophagy Intertwines with Different Diseases—Recent Strategies for Therapeutic Approaches

Diseases ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 15 ◽  
Author(s):  
Janani Ramesh ◽  
Larance Ronsard ◽  
Anthony Gao ◽  
Bhuvarahamurthy Venugopal
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Open Reading Frames ◽  
Signaling Cascades ◽  
Progression Rate ◽  
Therapeutic Approaches ◽  
Genes Encoding ◽  
Novel Therapeutic Strategies ◽  
Reading Frames

Autophagy is a regular and substantial “clear-out process” that occurs within the cell and that gets rid of debris that accumulates in membrane-enclosed vacuoles by using enzyme-rich lysosomes, which are filled with acids that degrade the contents of the vacuoles. This machinery is well-connected with many prevalent diseases, including cancer, HIV, and Parkinson’s disease. Considering that autophagy is well-known for its significant connections with a number of well-known fatal diseases, a thorough knowledge of the current findings in the field is essential in developing therapies to control the progression rate of diseases. Thus, this review summarizes the critical events comprising autophagy in the cellular system and the significance of its key molecules in manifesting this pathway in various diseases for down- or upregulation. We collectively reviewed the role of autophagy in various diseases, mainly neurodegenerative diseases, cancer, inflammatory diseases, and renal disorders. Here, some collective reports on autophagy showed that this process might serve as a dual performer: either protector or contributor to certain diseases. The aim of this review is to help researchers to understand the role of autophagy-regulating genes encoding functional open reading frames (ORFs) and its connection with diseases, which will eventually drive better understanding of both the progression and suppression of different diseases at various stages. This review also focuses on certain novel therapeutic strategies which have been published in the recent years based on targeting autophagy key proteins and its interconnecting signaling cascades.

scholarly journals Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

2018 ◽  
Vol 49 (1) ◽  
pp. 349-358 ◽  
Author(s):  
Wei-Yu Chen ◽  
Tzu-Hsien Tsai ◽  
Jenq-Lin Yang ◽  
Lung-Chih Li
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Lymphoid Cells ◽  
Gastrointestinal System ◽  
Immune Functions ◽  
Central Nerve System ◽  
Nerve System

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

scholarly journals TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5020
Author(s):  
Girijesh Kumar Patel ◽  
Sayanika Dutta ◽  
Mosharaf Mahmud Syed ◽  
Sabarish Ramachandran ◽  
Monica Sharma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Strategies ◽  
Signaling Mechanisms ◽  
Neuroendocrine Prostate Cancer ◽  
Signaling Axis ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Novel Therapeutic Strategies ◽  
Tbx2 Expression ◽  
Aggressive Subtype

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.

scholarly journals Metallothionein 1: A New Spotlight on Inflammatory Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanying Dai ◽  
Lu Wang ◽  
Lingyun Li ◽  
Zhong Huang ◽  
Liang Ye
Keyword(s):  
Immune Cells ◽  
Inflammatory Diseases ◽  
Stress Protein ◽  
Therapeutic Strategies ◽  
Innate And Adaptive Immunity ◽  
Biological Features ◽  
Central Nervous System Disorders ◽  
Novel Therapeutic Strategies ◽  
Immunosuppressive Factors

MT1 has been demonstrated to be an essential stress protein in maintaining physiological balance and regulating immune homeostasis. While the immunological involvement of MT1 in central nervous system disorders and cancer has been extensively investigated, mounting evidence suggests that MT1 has a broader role in inflammatory diseases and can shape innate and adaptive immunity. In this review, we will first summarize the biological features of MT1 and the regulators that influence MT1 expression, emphasizing metal, inflammation, and immunosuppressive factors. We will then focus on the immunoregulatory function of MT1 on diverse immune cells and the signaling pathways regulated by MT1. Finally, we will discuss recent advances in our knowledge of the biological role of MT1 in several inflammatory diseases to develop novel therapeutic strategies.

Sulphonamides as Anti-Inflammatory Agents: Old Drugs for New Therapeutic Strategies in Neutrophilic Inflammation?

1995 ◽  
Vol 88 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Luciano Ottonello ◽  
Patrizia Dapino ◽  
Maria C. Scirocco ◽  
Alessandro Balbi ◽  
Maurizio Bevilacqua ◽  
...  
Keyword(s):  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Specific Inhibitor ◽  
Therapeutic Strategies ◽  
Dependent Manner ◽  
Neutrophilic Inflammation ◽  
Starting Point ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (α1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of α1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent α1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the α1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation.

Regulation of vascular function by haemoglobin

2004 ◽  
Vol 71 ◽  
pp. 135-142 ◽  
Author(s):  
Jack H. Crawford ◽  
Balu K. Chacko ◽  
Rakesh P. Patel
Keyword(s):  
Vascular Function ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Blood Substitutes ◽  
Critical Element ◽  
Red Cell ◽  
Cell Disease ◽  
High Concentrations ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

A critical element in the ability of endothelial NO to function in the vasculature is preventing its reaction with erythrocytic Hb (haemoglobin). Emerging concepts suggest that the biophysical and rheological properties of the red blood cell are important in meeting this criterion. It has been recognized for some time that cell-free Hb may react with endothelial NO and that this may underlie the problems with Hb-based blood substitutes. More recent data extend these concepts to haemolytic diseases, including sickle cell disease, and have also identified novel therapeutic strategies to prevent interactions of cell-free Hb with NO. In this overview we have hypothesized that production of high concentrations of NO can overcome the diffusional barriers presented by the red cell and result in formation of S-nitrosohaemoglobin. By doing so, it is hypothesized that Hb may mediate the vasodilatory potential of NO and contribute to the hypotensive responses observed in acute inflammatory diseases, including sepsis.

scholarly journals Patients with COVID-19: in the dark-NETs of neutrophils

2021 ◽  
Author(s):  
Maximilian Ackermann ◽  
Hans-Joachim Anders ◽  
Rostyslav Bilyy ◽  
Gary L. Bowlin ◽  
Christoph Daniel ◽  
...  
Keyword(s):  
Immune Responses ◽  
Organ Dysfunction ◽  
Tissue Injury ◽  
Organ Damage ◽  
Therapeutic Strategies ◽  
Neutrophil Extracellular Trap ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Major Threat ◽  
Extracellular Trap

AbstractSARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

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