Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Abstract The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional “receptor” and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the “cytokine storm.” Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

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Cardioprotective Effect of Linalool against Isoproterenol-Induced Myocardial Infarction

Life ◽

10.3390/life11020120 ◽

2021 ◽

Vol 11 (2) ◽

pp. 120

Author(s):

Maged E. Mohamed ◽

Mohamed S. Abduldaium ◽

Nancy S. Younis

Keyword(s):

Myocardial Infarction ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Antioxidant Activities ◽

Interleukin 1 ◽

Cardioprotective Effect ◽

Cardiac Enzymes ◽

Necrosis Factor Alpha ◽

Group Iii ◽

Apoptotic Markers

Background: Myocardial infarction (MI), a life-threatening disorder, arises from the imbalance between oxygen supply and myocardial demand. Linalool is a naturally occurring monoterpenes with proved numerous pharmacological actions. This study investigated the cardioprotective effect of Linalool on isoproterenol (ISO)-induced MI in rat models and explored part of the underlying molecular mechanisms. Methods: Rats were divided into five groups; groups I and II served as normal and linalool control groups, Group III administered ISO alone; groups V and VI received two different doses of Linalool and were challenged by ISO. Different biochemical parameters were determined, including hemodynamic, infarction size, cardiac enzymes, apoptotic markers, and inflammatory mediators. Results: Linalool limited the infarcted area size and diminished the elevated cardiac enzymes. Linalool escalated HO-1 and Nrf2, both nuclear and cytosol fractions, and reduced Keap 1. Linalool enhanced cardiac antioxidant activities, reduced inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), nuclear factor-κ-B (NF-κB), interleukin 1 beta (IL-1β), interleukin 6 (IL-6)), apoptotic markers (Caspase-3, Caspase-9, and Bax), and elevated Bcl2. Conclusion: Linalool could act as an effective cardioprotective agent in the MI model through improving the oxidative condition, probably via the Nrf2/HO-1 pathway and by abolishing both apoptotic and inflammatory responses.

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Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System

Hypertension ◽

10.1161/hypertensionaha.120.15948 ◽

2020 ◽

Vol 76 (5) ◽

pp. 1350-1367 ◽

Cited By ~ 2

Author(s):

Matthew A. Sparks ◽

Andrew M. South ◽

Andrew D. Badley ◽

Carissa M. Baker-Smith ◽

Daniel Batlle ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Renin Angiotensin System ◽

Organ Damage ◽

Experimental Models ◽

Multiple Organ ◽

Host Cells ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Organ Systems

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

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Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2

Frontiers in Medicine ◽

10.3389/fmed.2020.594495 ◽

2020 ◽

Vol 7 ◽

Author(s):

Francesca Salamanna ◽

Melania Maglio ◽

Maria Paola Landini ◽

Milena Fini

Keyword(s):

Multiple Organ ◽

Host Cells ◽

Specific Patient ◽

Angiotensin Converting Enzyme 2 ◽

Body Distribution ◽

Organ Failures ◽

Personalized Approach ◽

Potential Interactions

The explosion of the new coronavirus (SARS-CoV-2) pandemic has brought the role of the angiotensin converting enzyme 2 (ACE2) back into the scientific limelight. Since SARS-CoV-2 must bind the ACE2 for entering the host cells in humans, its expression and body localization are critical to track the potential target organ of this infection and to outline disease progression and clinical outcomes. Here, we mapped the physiological body distribution, expression, and activities of ACE2 and discussed its potential correlations and mutal interactions with the disparate symptoms present in SARS-CoV-2 patients at the level of different organs. We highlighted that despite during SARS-CoV-2 infection ACE2-expressing organs may become direct targets, leading to severe pathological manifestations, and subsequent multiple organ failures, the exact mechanism and the potential interactions through which ACE2 acts in these organs is still heavily debated. Further scientific efforts, also considering a personalized approach aimed to consider specific patient differences in the mutual interactions ACE2-SARS-CoV-2 and the long-term health effects associated with COVID-19 are currently mandatory.

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PPARγExpression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

PPAR Research ◽

10.1155/2012/383829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 52

Author(s):

Patricia E. Almeida ◽

Alan Brito Carneiro ◽

Adriana R. Silva ◽

Patricia T. Bozza

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Mycobacterial Infection ◽

Receptor Activation ◽

Host Cells ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Bacterial Killing ◽

Peroxisome Proliferator Activated Receptor ◽

And Function

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control.Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγduring mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγexpression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγexpression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγexpression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγexpression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγenhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγin favoring the establishment of chronic infection. Collectively, PPARγis emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

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Macrophage Internalization of Fungal β-Glucans Is Not Necessary for Initiation of Related Inflammatory Responses

Infection and Immunity ◽

10.1128/iai.73.10.6340-6349.2005 ◽

2005 ◽

Vol 73 (10) ◽

pp. 6340-6349 ◽

Cited By ~ 43

Author(s):

Frances McCann ◽

Eva Carmona ◽

Vishwajeet Puri ◽

Richard E. Pagano ◽

Andrew H. Limper

Keyword(s):

Cell Wall ◽

Actin Polymerization ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Cytochalasin D ◽

Fungal Cell ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Phagocytic Cups ◽

Host Identification

ABSTRACT Cell wall β-glucans are highly conserved structural components of fungi that potently trigger inflammatory responses in an infected host. Identification of molecular mechanisms responsible for internalization and signaling of fungal β-glucans should enhance our understanding of innate immune responses to fungi. In this study, we demonstrated that internalization of fungal β-glucan particles requires actin polymerization but not participation of components of caveolar uptake mechanisms. Using fluorescence microscopy, we observed that uptake of 5-([4,6-dichlorotriazin-2-yl] amino)-fluorescein hydrochloride-Celite complex-labeled Saccharomyces cerevisiae β-glucan by RAW macrophages was substantially reduced in the presence of cytochalasin D, which antagonizes actin-mediated internalization pathways, but not by treatment with nystatin, which blocks caveolar uptake. Interestingly, β-glucan-induced NF-κB translocation, which is necessary for inflammatory activation, and tumor necrosis factor alpha production were both normal in the presence of cytochalasin D, despite defective internalization of β-glucan particles following actin disruption. Dectin-1, a major β-glucan receptor on macrophages, colocalized to phagocytic cups on macrophages and exhibited tyrosine phosphorylation after challenge with β-glucan particles. Dectin-1 localization and other membrane markers were not affected by treatment with cytochalasin D. Furthermore, dectin-1 receptors rather than Toll-like receptor 2 receptors were shown to be necessary for both efficient internalization of β-glucan particles and cytokine release in response to the fungal cell wall component.

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Alamandine: Potential Protective Effects in SARS-CoV-2 Patients

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1155/2021/6824259 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Ava Soltani Hekmat ◽

Kazem Javanmardi

Keyword(s):

Pulmonary Fibrosis ◽

Renin Angiotensin System ◽

The Body ◽

Host Cells ◽

Protective Effects ◽

Ang Ii ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Anti Inflammatory ◽

G Protein Coupled

Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor—as such, an individual’s susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.

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Quantifying Renin-Angiotensin-System Alterations in COVID-19

Cells ◽

10.3390/cells10102755 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2755

Author(s):

Fabrizio Pucci ◽

Filippo Annoni ◽

Robson Augusto Souza dos Santos ◽

Fabio Silvio Taccone ◽

Marianne Rooman

Keyword(s):

Meta Analysis ◽

Renin Angiotensin System ◽

Host Cells ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Physiological Processes ◽

Open Questions ◽

Clinical Investigations ◽

Conflicting Evidence

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.

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Significance of TNF in hemorrhage-related hemodynamic alterations, organ injury, and mortality in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.5.h2219 ◽

1997 ◽

Vol 272 (5) ◽

pp. H2219-H2226 ◽

Cited By ~ 4

Author(s):

S. Bahrami ◽

Y. M. Yao ◽

G. Leichtfried ◽

H. Redl ◽

I. Marzi ◽

...

Keyword(s):

Survival Rate ◽

Hemorrhagic Shock ◽

Peripheral Resistance ◽

Resistance Index ◽

Organ Damage ◽

Multiple Organ ◽

Organ Injury ◽

Tnf Alpha ◽

Control Group ◽

Necrosis Factor Alpha

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in hemodynamic alterations, multiple organ damage, and mortality caused by hemorrhagic shock, we employed a monoclonal antibody to TNF-alpha (TNF-alpha MAb) in anesthetized rats subjected to prolonged hemorrhagic shock (mean arterial pressure of 30–x35 mmHg for 180 min) followed by resuscitation over 50 min. Treatment of rats with 20.0 mg/kg TNF-alpha MAb 15 min after the end of resuscitation significantly decreased the total peripheral resistance index (P = 0.031) and provided remarkable protection from multiple organ damage compared with controls. The 48-h survival rate was significantly higher in the treatment group (73.3%) than in the control group (26.7%; P = 0.029). The results suggest that TNF-alpha induced by hemorrhagic shock in rats is an important mediator of pathophysiological alterations associated with cardiovascular abnormalities, multiple organ injury, and even lethality. Postresuscitation treatment with TNF-alpha MAb, even after an initial TNF-alpha formation had occurred, significantly attenuated the cardiovascular consequences and improved the survival rate. Thus monoclonal antibodies to TNF-alpha might provide new prospects in the treatment of hemorrhage-related disorders.

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Novel Evidence of Acute Kidney Injury in COVID-19

Journal of Clinical Medicine ◽

10.3390/jcm9113547 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3547

Author(s):

Ti-I Chueh ◽

Cai-Mei Zheng ◽

Yi-Chou Hou ◽

Kuo-Cheng Lu

Keyword(s):

Acute Kidney Injury ◽

Angiotensin Converting Enzyme ◽

Kidney Injury ◽

Host Cells ◽

Current Evidence ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

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RNA-seq Reveals Dysregulation of Novel Melanocyte Genes upon Oxidative Stress: Implications in Vitiligo Pathogenesis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2841814 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Konduru Seetharama Sastry ◽

Haroon Naeem ◽

Younes Mokrab ◽

Aouatef Ismail Chouchane

Keyword(s):

Oxidative Stress ◽

Drug Targets ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Late Phase ◽

Global Gene Expression ◽

Dependent Manner ◽

Rna Seq ◽

Notch Pathways ◽

Underlying Mechanisms

Oxidative stress is known to induce melanocyte death, but the underlying mechanisms are incompletely understood. To identify oxidative stress-induced global gene expression changes in melanocytes, we treated PIG1 melanocytes with H2O2 in a dose- and time-dependent manner and performed RNA-seq. This approach allowed us to capture the events occurring early as well as late phase after treatment with H2O2. Our bioinformatics analysis identified differentially expressed genes involved in various biological processes of melanocytes which are known to contribute to the vitiligo development, such as apoptosis, autophagy, cell cycle regulation, cell adhesion, immune and inflammatory responses, melanocyte pluripotency, and developmental signaling such as WNT and NOTCH pathways. We uncovered several novel genes that are not previously described to be involved in melanocytic response to stress nor in vitiligo pathogenesis. Quantitative PCR and western blot analysis of selected proteins, performed on PIG1 and primary human epidermal melanocytes, confirmed the RNA-seq data. Interestingly, we discovered an aberrant regulation of several transcription factors that are involved in diabetes, neurological, and psychiatric diseases, all of which are comorbid conditions in patients with vitiligo. Our results may lead to a better understanding of the molecular mechanisms underlying vitiligo pathogenesis and help developing new drug targets for effective treatment.

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