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1.
Signal Transduct Target Ther ; 6(1): 428, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1585884

ABSTRACT

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.


Subject(s)
COVID-19/metabolism , Cell Degranulation , Lung Injury/metabolism , Mast Cells/metabolism , Pulmonary Alveoli/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , Cell Line, Tumor , Female , Humans , Lung Injury/genetics , Lung Injury/virology , Macaca mulatta , Male , Mice, Inbred BALB C , Mice, Transgenic , Pulmonary Alveoli/virology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
2.
Respir Physiol Neurobiol ; 296: 103804, 2022 02.
Article in English | MEDLINE | ID: covidwho-1472157

ABSTRACT

The coronavirus disease (COVID-19) caused by SARS-CoV-2 can result in severe injury to the lung. Computed tomography images have revealed that the virus preferentially affects the base of the lung, which experiences larger tidal stretches than the apex. We hypothesize that the expression of both the angiotensin converting enzyme-2 (ACE2) receptor for SARS-CoV-2 and the transmembrane serine protease 2 (TMPRSS2) are sensitive to regional cell stretch in the lung. To test this hypothesis, we stretched precision cut lung slices (PCLS) for 12 h with one of the following protocols: 1) unstretched (US); 2) low-stretch (LS), 5% peak-to-peak area strain mimicking the lung base; or 3) high-stretch (HS), the same peak-to-peak area strain superimposed on 10% static area stretch mimicking the lung apex. PCLS were additionally stretched in cigarette smoke extract (CSE) to mimic an acute inflammatory exposure. The expression of ACE2 was higher whereas that of TMPRSS2 was lower in the control samples following LS than HS. CSE-induced inflammation substantially altered the expression of ACE2 with higher levels following HS than LS. These results suggest that ACE2 and TMPRSS2 expression in lung cells is mechanosensitive, which could have implications for the spatial distribution of COVID-19-mediated lung injury and the increased risk for more severe disease in active smokers and patients with COPD.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , Lung Injury/metabolism , Lung/metabolism , Mechanotransduction, Cellular/physiology , SARS-CoV-2/metabolism , Animals , Cells, Cultured , Lung/cytology , Male , Rats , Rats, Sprague-Dawley
3.
Cells ; 10(5)2021 04 21.
Article in English | MEDLINE | ID: covidwho-1436054

ABSTRACT

Extracellular vesicles (EVs) refer to a heterogenous population of membrane-bound vesicles that are released by cells under physiological and pathological conditions. The detection of EVs in the majority of the bodily fluids, coupled with their diverse cargo comprising of DNA, RNA, lipids, and proteins, have led to the accumulated interests in leveraging these nanoparticles for diagnostic and therapeutic purposes. In particular, emerging studies have identified enhanced levels of a wide range of specific subclasses of non-coding RNAs (ncRNAs) in EVs, thereby suggesting the existence of highly selective and regulated molecular processes governing the sorting of these RNAs into EVs. Recent studies have also illustrated the functional relevance of these enriched ncRNAs in a variety of human diseases. This review summarizes the current state of knowledge on EV-ncRNAs, as well as their functions and significance in lung infection and injury. As a majority of the studies on EV-ncRNAs in lung diseases have focused on EV-microRNAs, we will particularly highlight the relevance of these molecules in the pathophysiology of these conditions, as well as their potential as novel biomarkers therein. We also outline the current challenges in the EV field amidst the tremendous efforts to propel the clinical utility of EVs for human diseases. The lack of published literature on the functional roles of other EV-ncRNA subtypes may in turn provide new avenues for future research to exploit their feasibility as novel diagnostic and therapeutic targets in human diseases.


Subject(s)
Extracellular Vesicles/physiology , Lung Injury/metabolism , Pneumonia, Bacterial/metabolism , Pneumonia, Viral/metabolism , RNA, Untranslated/physiology , Animals , Biomarkers/metabolism , Humans , Lung/metabolism , Lung/pathology
4.
Mol Med Rep ; 24(4)2021 Oct.
Article in English | MEDLINE | ID: covidwho-1395036

ABSTRACT

Chronic alcohol abuse increases the risk of mortality and poor outcomes in patients with acute respiratory distress syndrome. However, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the effects of chronic alcohol consumption on lung injury and clarify the signaling pathways involved in the inhibition of alveolar fluid clearance (AFC). In order to produce rodent models with chronic alcohol consumption, wild­type C57BL/6 mice were treated with alcohol. A2a adenosine receptor (AR) small interfering (si)RNA or A2bAR siRNA were transfected into the lung tissue of mice and primary rat alveolar type II (ATII) cells. The rate of AFC in lung tissue was measured during exposure to lipopolysaccharide (LPS). Epithelial sodium channel (ENaC) expression was determined to investigate the mechanisms underlying alcohol­induced regulation of AFC. In the present study, exposure to alcohol reduced AFC, exacerbated pulmonary edema and worsened LPS­induced lung injury. Alcohol caused a decrease in cyclic adenosine monophosphate (cAMP) levels and inhibited α­ENaC, ß­ENaC and γ­ENaC expression levels in the lung tissue of mice and ATII cells. Furthermore, alcohol decreased α­ENaC, ß­ENaC and γ­ENaC expression levels via the A2aAR or A2bAR­cAMP signaling pathways in vitro. In conclusion, the results of the present study demonstrated that chronic alcohol consumption worsened lung injury by aggravating pulmonary edema and impairing AFC. An alcohol­induced decrease of α­ENaC, ß­ENaC and γ­ENaC expression levels by the A2AR­mediated cAMP pathway may be responsible for the exacerbated effects of chronic alcohol consumption in lung injury.


Subject(s)
Acute Lung Injury/metabolism , Alveolar Epithelial Cells/metabolism , Epithelial Sodium Channels/drug effects , Epithelial Sodium Channels/metabolism , Ethanol/pharmacology , Receptors, Adenosine A2/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Alveolar Epithelial Cells/pathology , Animals , Cyclic AMP/metabolism , Cytokines , Lipopolysaccharides/adverse effects , Lung/metabolism , Lung Injury/chemically induced , Lung Injury/metabolism , Lung Injury/pathology , Mice , Mice, Inbred C57BL , Pulmonary Alveoli/metabolism , Pulmonary Edema/chemically induced , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolism , Rats , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Signal Transduction
5.
Nat Commun ; 12(1): 4664, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1338538

ABSTRACT

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.


Subject(s)
COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Inflammasomes/metabolism , Inflammation/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/virology , Cells, Cultured , Cytokines/metabolism , HEK293 Cells , Humans , Inflammasomes/genetics , Lung Injury/genetics , Lung Injury/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Phosphoproteins/metabolism , Protein Binding , SARS-CoV-2/physiology , THP-1 Cells
6.
J Med Virol ; 93(10): 6008-6015, 2021 10.
Article in English | MEDLINE | ID: covidwho-1298507

ABSTRACT

INTRODUCTION: Coronavirus disease-2019 (COVID-19) is a respiratory disease whose clinical manifestation ranges from asymptomatic to severe respiratory failure. The purpose of this study was to investigate the place of serum surfactant-D (SP-D) and angiopoetin-2 (Ang-2) levels in predicting severity of disease in patients diagnosed with COVID-19. METHODS: Sixty-four patients diagnosed with COVID-19 between September 2020 and February 2021, 50 patients diagnosed with community-acquired pneumonia and a 50-member healthy control group were included in the study. Plasma samples and clinical data were collected within 72 h after admission, during hospital stay. Serum SP-D and Ang-2 concentrations were measured using the enzyme-linked immunosorbent assay. RESULTS: SP-D and Ang-2 levels were significantly higher in the mild-moderate pneumonia and severe/critical patient groups compared to the asymptomatic and noncomplicated COVID-19 patients (p < 0.001 for all groups). Serum SP-D and Ang-2 levels of severe-critical COVID-19 patients were significantly higher than CAP patients (p < 0.001). Powerful correlation was present between clinical severity of COVID-19 and SP-D and Ang-2 levels (r = 0.885 p < 0.001 and r = 0.913 p < 0.001, respectively). Cut-off values of 37.7 ng/ml (AUC = 0.763, p < 0.001, 95% confidence interval [CI] = 0.667-0.860) for SP-D and 4208.3 pg/ml (AUC = 0.659, p = 0.004, 95% CI = 0.554-0.763) for Ang-2 were identified as predictors of COVID-19 disease at receiver operating characteristic curve analysis. CONCLUSION: SP-D and Ang-2 are predictive factors in differentiating COVID-19 patients and determining severity of disease. These data may be important for the initiation of treatment in the early stage of the disease in patients with COVID-19.


Subject(s)
Angiopoietin-2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , Lung Injury/metabolism , Pulmonary Surfactant-Associated Protein D/metabolism , Adult , Aged , Biomarkers/blood , Community-Acquired Infections/diagnosis , Community-Acquired Infections/virology , Diagnostic Tests, Routine , Female , Humans , Lung Injury/virology , Male , Middle Aged , Prognosis , Prospective Studies , ROC Curve , Severity of Illness Index
7.
Pharmacol Rep ; 73(3): 712-727, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1195205

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-ß) is a key factor that is released during SARS-CoV-2 infection. TGF-ß, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. DRUG SUGGESTION: Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-ß) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. CONCLUSION: The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Inflammation/drug therapy , Lung Injury/metabolism , Pyridones/therapeutic use , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/virology , Humans , Inflammation/metabolism , Lung Injury/virology , SARS-CoV-2/pathogenicity
8.
Mol Cell Biochem ; 476(1): 93-107, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-737128

ABSTRACT

Mesenchymal stem cells (MSCs) can alleviate acute respiratory distress syndrome (ARDS), but the mechanisms involved are unclear, especially about their specific effects on cellular mitochondrial respiratory function. Thirty mice were allocated into the Control, LPS, and LPS + Bone marrow mesenchymal stem cell (BMSC) group (n = 10/group). Mouse alveolar epithelial cells (MLE-12) and macrophage cells (RAW264.7) were divided into the same groups. Pathological variation, inflammation-related factors, reactive oxygen species (ROS), ATP levels, and oxygen consumption rate (OCR) were analyzed. Pathologic features of ARDS were observed in the LPS group and were significantly alleviated by BMSCs. The trend in inflammation-related factors among the three groups was the LPS group > LPS + BMSC group > Control group. In the MLE-12 co-culture system, IL-6 was increased in the LPS group but not significantly reduced in the LPS + BMSC group. In the RAW264.7 co-culture system, IL-1ß, TNF-α, and IL-10 levels were all increased in the LPS group, IL-1ß and TNF-α levels were reduced by BMSCs, while IL-10 level kept increasing. ROS and ATP levels were increased and decreased respectively in both MLE-12 and RAW264.7 cells in the LPS groups but reversed by BMSCs. Basal OCR, ATP-linked OCR, and maximal OCR were lower in the LPS groups. Impaired basal OCR and ATP-linked OCR in MLE-12 cells were partially restored by BMSCs, while impaired basal OCR and maximal OCR in RAW264.7 cells were restored by BMSCs. BMSCs improved the mitochondrial respiration dysfunction of macrophages and alveolar epithelial cells induced by LPS, alleviated lung tissue injury, and inflammatory response in a mouse model of ARDS.


Subject(s)
Epithelium/metabolism , Mesenchymal Stem Cells/cytology , Mitochondria/metabolism , Pulmonary Alveoli/metabolism , Respiratory Distress Syndrome/metabolism , Adenosine Triphosphate/metabolism , Animals , Bone Marrow Cells/cytology , Coculture Techniques , Inflammation , Interleukin-10/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/metabolism , Lung Injury/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Oxygen Consumption , RAW 264.7 Cells
9.
Biofactors ; 47(1): 6-18, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-950385

ABSTRACT

Specialized proresolving mediators (SPMs) are endogenous lipid metabolites of long-chain polyunsaturated fatty acids that are involved in promoting the resolution of inflammation. Many disease conditions characterized by excessive inflammation have impaired or altered SPM biosynthesis, which may lead to chronic, unresolved inflammation. Exogenous administration of SPMs in infectious conditions has been shown to be effective at improving infection clearance and survival in preclinical models. SPMs have also shown tremendous promise in the context of inflammatory lung conditions, such as acute respiratory distress syndrome and chronic obstructive pulmonary disease, mostly in preclinical settings. To date, SPMs have not been studied in the context of the novel Coronavirus, severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), however their preclinical efficacy in combatting infections and improving acute respiratory distress suggest they may be a valuable resource in the fight against Coronavirus disease-19 (COVID-19). Overall, while the research on SPMs is still evolving, they may offer a novel therapeutic option for inflammatory conditions.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Docosahexaenoic Acids/therapeutic use , Lipoxins/therapeutic use , Lung Injury/drug therapy , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Distress Syndrome/drug therapy , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Herpes Simplex/drug therapy , Herpes Simplex/metabolism , Herpes Simplex/pathology , Humans , Influenza, Human/drug therapy , Influenza, Human/metabolism , Influenza, Human/pathology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/virology , Periodontitis/drug therapy , Periodontitis/metabolism , Periodontitis/pathology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Disease, Chronic Obstructive/virology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Sepsis/drug therapy , Sepsis/metabolism , Sepsis/pathology , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/metabolism , Tuberculosis, Pulmonary/pathology
10.
Transl Res ; 231: 55-63, 2021 05.
Article in English | MEDLINE | ID: covidwho-939331

ABSTRACT

Although some evidence showed the activation of complement systems in COVID-19 patients, proinflammatory status and lectin pathway remain unclear. Thus, the present study aimed to demonstrate the role of MBL and ficolin-3 in the complement system activation and compared to pandemic Influenza A virus H1N1 subtype infection (H1N1pdm09) and control patients. A total of 27 lungs formalin-fixed paraffin-embedded samples (10 from H1N1 group, 6 from the COVID-19 group, and 11 from the control group) were analyzed by immunohistochemistry using anti-IL-6, TNF-alfa, CD163, MBL e FCN3 antibodies. Genotyping of target polymorphisms in the MBL2 gene was performed by real-time PCR. Proinflammatory cytokines such as IL-6 and TNF-alpha presented higher tissue expression in the COVID-19 group compared to H1N1 and control groups. The same results were observed for ICAM-1 tissue expression. Increased expression of the FCN3 was observed in the COVID-19 group and H1N1 group compared to the control group. The MBL tissue expression was higher in the COVID-19 group compared to H1N1 and control groups. The genotypes AA for rs180040 (G/A), GG for rs1800451 (G/A) and CC for rs5030737 (T/C) showed a higher prevalence in the COVID-19 group. The intense activation of the lectin pathway, with particular emphasis on the MBL pathway, together with endothelial dysfunction and a massive proinflammatory cytokines production, possibly lead to a worse outcome in patients infected with SARS-Cov-2. Moreover, 3 SNPs of our study presented genotypes that might be correlated with high MBL tissue expression in the COVID-19 pulmonary samples.


Subject(s)
COVID-19/pathology , Lectins/metabolism , Lung Injury/metabolism , Lung Injury/pathology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Autopsy , Case-Control Studies , Complement Activation/physiology , Cytokines/genetics , Cytokines/metabolism , Female , Genotype , Humans , Immunohistochemistry , Influenza A Virus, H1N1 Subtype , Influenza, Human/metabolism , Influenza, Human/pathology , Lung/pathology , Lung/virology , Lung Injury/virology , Male , Middle Aged , Polymorphism, Single Nucleotide , Young Adult
11.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-872677

ABSTRACT

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Lung Injury/genetics , Pneumonia, Viral/genetics , Proteome/genetics , Proteomics/methods , Severe Acute Respiratory Syndrome/genetics , Aged , Autopsy , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/virology , Male , Metabolic Networks and Pathways , Molecular Sequence Annotation , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proteome/metabolism , SARS-CoV-2 , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction
12.
ACS Chem Neurosci ; 11(15): 2156-2158, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-679395

ABSTRACT

Lung injury with COVID-19 may be due to a complex underlying pathophysiology. Cytokine release syndrome appears to be a catalyst of different inflammatory pathways promoting lung parenchymal injury and thromboembolic phenomena ("dual hit" injury). Recently, severe neurological manifestations such as acute disseminated encephalomyelitis, which may be not linked to lung pathology, have been identified in COVID-19, contributing thus further to the versatility of its clinical features.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Cytokines/metabolism , Lung Injury/metabolism , Pneumonia, Viral/metabolism , Animals , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/physiopathology , Humans , Lung Injury/etiology , Lung Injury/physiopathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/physiopathology , SARS-CoV-2
13.
Clin Med (Lond) ; 20(4): e72-e75, 2020 07.
Article in English | MEDLINE | ID: covidwho-264006

ABSTRACT

COVID-19, caused by infection with SARS-CoV-2, is a disease characterised by cough, fever and fatigue, which progresses to life-threatening lung injury in approximately 5% of patients. The SARS-CoV-2 virus enters the cell via ACE2. ACE2 is a component of the renin-angiotensin system (RAS) which has an important counterregulatory effect on the classical ACE-dependent pathway. Several antihypertensives increase ACE2 expression or activity, leading to concern that this may facilitate SARS-CoV-2 entry and worsen COVID-19 disease. However, ACE2 is protective against lung injury while ANG II (which is catabolised by ACE2) is associated with lung injury both in mice and humans. We propose that medications which inhibit the RAS ACE-dependent pathway may be beneficial in treating COVID-19 and should be explored in animal models and clinical trials. Here we give an overview of the RAS pathway with respect to COVID-19 and argue that strategies which manipulate this pathway might reduce the destructive lung manifestations of COVID-19 and improve patient outcomes.


Subject(s)
Angiotensin II/metabolism , Antihypertensive Agents/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Renin-Angiotensin System , Amides/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Fumarates/therapeutic use , Humans , Lung Injury/metabolism , Lung Injury/virology , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Virus Internalization
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