Abstract:
:Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and triggers the production of type I interferons and proinflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently, the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. Here, we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.
journal_name
Mediators Inflammjournal_title
Mediators of inflammationauthors
Aboudounya MM,Heads RJdoi
10.1155/2021/8874339subject
Has Abstractpub_date
2021-01-14 00:00:00pages
8874339eissn
0962-9351issn
1466-1861journal_volume
2021pub_type
杂志文章,评审abstract:OBJECTIVE:To investigate the effects and mechanisms of hydroxytyrosol (HT) during the pathogenesis of myocardial ischemia reperfusion (I/R) in rat hearts. METHODS:The rats were randomized into five groups: sham group, I/R group, HT+I/R group, HT+LY294002+I/R group, and LY+I/R group. Myocardial infarct size, markers of...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2016/1232103
更新日期:2016-01-01 00:00:00
abstract::Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). The risk factors of CRC in IBD patients include long disease duration, extensive colitis, severe histological inflammation, and coexistence with primary sclerosing cholangitis (PSC). Several molecular pathway...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2017/5126048
更新日期:2017-01-01 00:00:00
abstract:Objective:Renal ischemia/reperfusion injury (RI/RI) is the main cause of acute kidney injury. Total glucosides of paeony (TGP) are a traditional Chinese medicine. This study was aimed at exploring the role of TGP in RI/RI and its underlying mechanism of action. Methods:Rat RI/RI models were constructed by surgical ope...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2020/8869511
更新日期:2020-11-24 00:00:00
abstract::We investigated whether TNB alters colonic tissue levels of PAF at the expense of changes in colonic motility in the isolated perfused rabbit left colon. Colonic inflammation was induced by the intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of trinitrobenzene. Strain gauge transducers were sewn...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/S0962935195000032
更新日期:1995-01-01 00:00:00
abstract::The effects of anti-inflammatory plant extracts, such as black tea extract (BTE) and resveratrol (RSV) could modulate cell activation leading to atherosclerosis, however there is little comparative information about how different endothelial cell types are affected by these compounds. In order to compare human endothe...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2009/146872
更新日期:2009-01-01 00:00:00
abstract::The expression of cytochrome P4501A1 (CYP1A1) enzyme is changed in various organs during the host response to inflammation or infection, leading to alterations in the metabolism of endogenous and exogenous compounds. Results of this study showed that CYP1A1 expression was significantly downregulated in the mammary tis...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2018/4093285
更新日期:2018-02-28 00:00:00
abstract::In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN- γ have been observed in peripheral blood. The balance between Th1, Th17, and FoxP3(+) CD4(+) T cell subsets in sarcoidosis remains unclear. Bronchoalveolar lavage fluid ce...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2014/438070
更新日期:2014-01-01 00:00:00
abstract:Background:Gut barrier dysfunction with alterant mucosal permeability during sepsis is a challenge problem in clinical practice. Intestinal epithelial cells (IECs) are strongly involved in mucosal oxidative stress and inflammatory response. The current study aimed at investigating the effect of MitoQ, a mitochondrial t...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2020/3276148
更新日期:2020-04-11 00:00:00
abstract::Delayed rectifier K(+)-channels (Kv1.3) are predominantly expressed in T lymphocytes. Based on patch-clamp studies, the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models, in vivo ...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2015/436572
更新日期:2015-01-01 00:00:00
abstract::Tumor necrosis factor alpha (TNF-α) is a cytokine which plays opposing roles in the context of infectious disease pathogenesis. TNF-α is essential for the development of a protective immune response to some pathogens, for example, Mycobacterium tuberculosis, by synergizing with other cytokines. However, exorbitant or ...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2015/619480
更新日期:2015-01-01 00:00:00
abstract::Respiratory syncytial virus (RSV) is the most common respiratory virus and is associated with pediatric pneumonia, causing bronchiolitis and significant mortality in infants and young children. MicroRNAs (miRNAs) are endogenous noncoding small RNAs that function in gene regulation and are associated with host immune r...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2020/8919534
更新日期:2020-05-01 00:00:00
abstract::Endothelial dysfunction is regarded as an important factor in the pathogenesis of vascular disease in obesity-related type 2 diabetes. The imbalance in repair and injury (hyperglycemia, hypertension, dyslipidemia) results in microvascular changes, including apoptosis of microvascular cells, ultimately leading to diabe...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2010/792393
更新日期:2010-01-01 00:00:00
abstract::The mechanism of pain reduction involves bidirectional processes of pain blocking (nociception) and reductions in the levels of proinflammatory cytokines in the blood. Does transcutaneous electrical nerve stimulation (TENS) reduce blood levels of proinflammatory cytokines? For this systematic review, we searched in si...
journal_title:Mediators of inflammation
pub_type: 杂志文章,meta分析,评审
doi:10.1155/2018/1094352
更新日期:2018-04-02 00:00:00
abstract::Procalcitonin (PCT) is one of the best diagnostic and prognostic markers in clinical practice, widely used to evaluate the evolution of bacterial infections. Although it is mainly produced by thyroid, during sepsis almost all the peripheral tissues are involved in PCT production. Parenchymal cells have been suggested ...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2014/248963
更新日期:2014-01-01 00:00:00
abstract::This study examined the role of lymphotoxin (LT)-alpha in host defense against airborne infection with Francisella tularensis, a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Following a low-dose aerosol infection with the highly virulent type A strain of F. tularensis, mice d...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2008/239740
更新日期:2008-01-01 00:00:00
abstract:Background:Acute lung injury (ALI) and subsequent pulmonary infection are the most severe and usually fatal complications for elderly hip fracture patients. It is necessary to find some biomarkers for early diagnosis and prognosis of it. Objective:This study is aimed at examining the differential expression of miR-146...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2018/8101359
更新日期:2018-10-28 00:00:00
abstract::Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defi...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2015/820934
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND:In aromatherapy, essential oils are used as anti-inflammatory remedies, but experimental studies on their action mechanisms are very limited. AIMS OF THE STUDY:To assess their anti-inflammatory activities, the effects of essential oils on neutrophil recruitment in mice were examined in vivo. METHOD:The eff...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1080/09629350410001664798
更新日期:2004-02-01 00:00:00
abstract::Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions ...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2017/4786170
更新日期:2017-01-01 00:00:00
abstract::Human periodontal ligament (hPDL) fibroblasts play a major role during periodontitis and orthodontic tooth movement, mediating periodontal inflammation, osteoclastogenesis, and collagen synthesis. The highly COX-2-selective NSAID etoricoxib has a favorable systemic side effect profile and high analgesic efficacy, part...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2019/2514956
更新日期:2019-03-10 00:00:00
abstract::Both alveolar macrophages (AMs) and alveolar epithelial cells (AECs) are main targets of Mycobacterium tuberculosis (M. tuberculosis (Mtb)). Intercellular communications between mucosal AECs and AMs have important implications in cellular responses to exogenous insults. However, molecular mechanisms underpinning inter...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2018/3685948
更新日期:2018-09-26 00:00:00
abstract:BACKGROUND:We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1β levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1β pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early R...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2014/195327
更新日期:2014-01-01 00:00:00
abstract::Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study wa...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2017/6848430
更新日期:2017-01-01 00:00:00
abstract::Interleukin-37 (IL-37) is unique in the IL-1 family since it broadly suppresses innate immunity and elevates in humans with inflammatory and autoimmune diseases. IL-37 shows definite groups and transcripts for human IL37 gene, but it is still not completely understood the effect and mechanisms of inflammatory response...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2019/2650590
更新日期:2019-01-08 00:00:00
abstract::Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims o...
journal_title:Mediators of inflammation
pub_type: 杂志文章,评审
doi:10.1155/2010/903295
更新日期:2010-01-01 00:00:00
abstract::Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems parado...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2016/5972302
更新日期:2016-01-01 00:00:00
abstract::Mechanical ventilation (MV) is a major life support technique for the management of trauma-associated hemorrhagic shock (HS). Ventilator-induced diaphragm dysfunction (VIDD), one of the most common complications of MV, has been well demonstrated in animal and human studies. However, few data are available concerning t...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/2019/3738409
更新日期:2019-11-14 00:00:00
abstract:BACKGROUND:Airway smooth muscle (ASM) is considered to be a target for mediators released during airway inflammation. AIMS:To investigate the expression of c-fos, a constituent of the transcription factor activator protein-1, in human ASM cells. In addition, to measure the release of interleukin (IL)-6 into the condit...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1080/09629350124155
更新日期:2001-06-01 00:00:00
abstract::There is much evidence that degradation of the extracellular matrix is essential for the development of cholesteatomas and that this is induced by activation of matrix metalloproteinases (MMPs). Vitamin D3 (VD3) has several well-recognised biological activities, including suppression of MMP production. The present stu...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/MI.2005.210
更新日期:2005-08-31 00:00:00
abstract::Stimulation of phosphoinositide hydrolysis in myocardium from autoimmune myocarditis mice by ThEA and histamine was assayed. Myocardium from autoimmune heart, but not the normal forms, specifically increased phosphoinositide turnover in the presence of histaminergic agonists. This increment was blocked by a specific H...
journal_title:Mediators of inflammation
pub_type: 杂志文章
doi:10.1155/S0962935193000444
更新日期:1993-01-01 00:00:00