Coxsackievirus A2 Leads to Heart Injury in a Neonatal Mouse Model

Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of the causes of death. However, the mechanisms of CVA2-induced heart injury have not been well understood. In this study, we used a neonatal mouse model of CVA2 to investigate the possible mechanisms of heart injury. We detected CVA2 replication and apoptosis in heart tissues from infected mice. The activity of total aspartate transaminase (AST) and lactate dehydrogenase (LDH) was notably increased in heart tissues from infected mice. CVA2 infection also led to the disruption of cell-matrix interactions in heart tissues, including the increases of matrix metalloproteinase (MMP)3, MMP8, MMP9, connective tissue growth factor (CTGF) and tissue inhibitors of metalloproteinases (TIMP)4. Infiltrating leukocytes (CD45+ and CD11b+ cells) were observed in heart tissues of infected mice. Correspondingly, the expression levels of inflammatory cytokines in tissue lysates of hearts, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL6 and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in CVA2 infected mice. Inflammatory signal pathways in heart tissues, including phosphatidylinositol 3-kinase (PI3K)-AKT, mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB), were also activated after infection. In summary, CVA2 infection leads to heart injury in a neonatal mouse model, which might be related to viral replication, increased expression levels of MMP-related enzymes and excessive inflammatory responses.

Download Full-text

Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

Journal of Virology ◽

10.1128/jvi.75.17.8268-8282.2001 ◽

2001 ◽

Vol 75 (17) ◽

pp. 8268-8282 ◽

Cited By ~ 36

Author(s):

Seng-Thuon Khuth ◽

Hideo Akaoka ◽

Axel Pagenstecher ◽

Olivier Verlaeten ◽

Marie-Françoise Belin ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mouse Model ◽

Neurological Disorders ◽

Dynamic Balance ◽

Brain Structures ◽

Cytokine Expression ◽

Tissue Inhibitors Of Metalloproteinases ◽

Cns Infection ◽

Necrosis Factor Alpha

ABSTRACT Viral infection of the central nervous system (CNS) can result in perturbation of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures, which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.

Download Full-text

Cytokine patterns in a comparative model of arenavirus haemorrhagic fever in guinea pigs

Journal of General Virology ◽

10.1099/vir.0.2008/002048-0 ◽

2008 ◽

Vol 89 (10) ◽

pp. 2569-2579 ◽

Cited By ~ 17

Author(s):

Erin P. Scott ◽

Judith F. Aronson

Keyword(s):

Innate Immunity ◽

Inflammatory Responses ◽

Febrile Illness ◽

Target Cells ◽

Lassa Virus ◽

Mrna Levels ◽

Haemorrhagic Fever ◽

Blood Leukocytes ◽

Necrosis Factor Alpha ◽

Monocyte Chemoattractant Protein 1

Arenaviruses such as Lassa virus cause a spectrum of disease in humans ranging from mild febrile illness to lethal haemorrhagic fever. The contributions of innate immunity to protection or pathogenicity are unknown. We compared patterns of expression of cytokines of innate immunity in mild versus severe arenavirus disease using an established guinea pig model based on the macrophage-tropic arenavirus Pichinde virus (PICV). Cytokine transcripts were measured by using real-time RT-PCR in target organs and blood during mild infection (caused by PICV, P2 variant) and lethal haemorrhagic fever (caused by PICV, P18 variant). In the initial peritoneal target cells, virulent P18 infection was associated with significantly increased gamma interferon (IFN-γ) and monocyte chemoattractant protein-1 (MCP-1, CCL2) mRNA levels relative to P2 infection. Peritoneal cells from P18-infected animals had decreased tumour necrosis factor alpha (TNF-α), interleukin (IL)-8 (CXCL-8) and IL-12p40 transcripts relative to mock-infected animals. Late in infection, P18-infected peripheral blood leukocytes (PBL) had decreased TNF-α, IFN-γ, and regulated upon activation, normal T cell expressed and secreted (RANTES, CCL-5) cytokine transcripts relative to P2-infected PBL. We conclude that, in severe arenavirus disease, patterns of cytokine expression in the initially infected cells favour recruitment of additional target monocytes, while inhibiting some of their pro-inflammatory responses. Suppression rather than overexpression of pro-inflammatory cytokines accompanied the terminal shock in this model of arenavirus haemorrhagic fever.

Download Full-text

Diagnostic Value of miR-106a-5p in Patients with Psoriasis and its Regulatory Role in Inflammatory Responses

10.21203/rs.3.rs-60976/v1 ◽

2020 ◽

Author(s):

Xiaolin Miao ◽

Xinyun Tong ◽

Jingsang Hu ◽

Juan Wang

Keyword(s):

Inflammatory Responses ◽

Positive Association ◽

Diagnostic Value ◽

Tnf Alpha ◽

Enzyme Linked Immunosorbent Assay ◽

Operating Characteristics ◽

Necrosis Factor Alpha ◽

Expression Levels ◽

Promote Cell Proliferation ◽

Specificity And Sensitivity

Abstract Background: Psoriasis is a multifactorial, recurring, and chronic inflammatory skin disease. This study was designed to explore the potential role of microRNA-106a-5p (miR-106a-5p) in psoriasis.Methods: The expression levels of miR-106a-5p in the serum of psoriasis patients and healthy individuals were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic value of miR-106a-5p in serum was evaluated by the receiver operating characteristics curve (ROC). The levels of interleukin-22 (IL-22), interleukin-17A (IL-17A), and tumor necrosis factor-alpha (TNF-alpha) were determined by enzyme-linked immunosorbent assay.Results: The serum expression of miR-106a-5p was found to be up-regulated in psoriasis patients. ROC curve showed that miR-106a-5p had high specificity and sensitivity in the diagnosis of psoriasis. The correlation between the serum expression level of miR-106a-5p and PASI was positive. The relative expression levels of IL-17A, IL-22 and TNF-alpha in serum of psoriasis patients were significantly upregulated compared with that in healthy control, and showed positive association with serum miR-106a-5p levels. Cell experiments demonstrated that upregulation of miR-106a-5p could promote cell proliferation, and the levels of IL-22, IL-17A and TNF-alpha were upregulated significantly in M5-induced HaCaT cells.Conclusion: Considering the novel and vital role in psoriasis progression, miR-106a-5p is expected to be a new potent target for treatment of psoriasis. MiR-106-5p was expected to use for more immunity diseases research and therapy.

Download Full-text

Deletion of Metallothionein Exacerbates Intermittent Hypoxia-Induced Oxidative and Inflammatory Injury in Aorta

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/141053 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Shanshan Zhou ◽

Yonggang Wang ◽

Yi Tan ◽

Xiaohong Cai ◽

Lu Cai ◽

...

Keyword(s):

Growth Factor ◽

Intermittent Hypoxia ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Tissue Growth ◽

Necrosis Factor Alpha ◽

Knock Out ◽

Oxidative Damages ◽

Cellular Apoptosis ◽

Knock Out Mice

The present study was to explore the effect of metallothionein (MT) on intermittent hypoxia (IH) induced aortic pathogenic changes. Markers of oxidative damages, inflammation, and vascular remodeling were observed by immunohistochemical staining after 3 days and 1, 3, and 8 weeks after IH exposures. Endogenous MT was induced after 3 days of IH but was significantly decreased after 8 weeks of IH. Compared with the wild-type mice, MT knock-out mice exhibited earlier and more severe pathogenic changes of oxidative damages, inflammatory responses, and cellular apoptosis, as indicated by the significant accumulation of collagen, increased levels of connective tissue growth factor, transforming growth factorβ1, tumor necrosis factor-alpha, vascular cell adhesion molecule 1,3-nitrotyrosine, and 4-hydroxy-2-nonenal in the aorta. These findings suggested that chronic IH may lead to aortic damages characterized by oxidative stress and inflammation, and MT may play a pivotal role in the above pathogenesis process.

Download Full-text

Diagnostic value of miR-106a-5p in patients with psoriasis and its regulatory role in inflammatory responses

10.21203/rs.3.rs-48872/v1 ◽

2020 ◽

Author(s):

Xiaolin Miao ◽

Xinyun Tong ◽

Jingsang Hu ◽

Juan Wang

Keyword(s):

Inflammatory Responses ◽

Positive Association ◽

Diagnostic Value ◽

Tnf Alpha ◽

Enzyme Linked Immunosorbent Assay ◽

Operating Characteristics ◽

Necrosis Factor Alpha ◽

Expression Levels ◽

Promote Cell Proliferation ◽

Specificity And Sensitivity

Download Full-text

Delayed Inflammatory Response to Primary Pneumonic Plague Occurs in Both Outbred and Inbred Mice

Infection and Immunity ◽

10.1128/iai.00403-06 ◽

2006 ◽

Vol 75 (2) ◽

pp. 697-705 ◽

Cited By ~ 70

Author(s):

Sarah S. Bubeck ◽

Angelene M. Cantwell ◽

Peter H. Dube

Keyword(s):

Bronchoalveolar Lavage ◽

Proinflammatory Cytokines ◽

Inflammatory Responses ◽

Inbred Mice ◽

Lavage Fluid ◽

Mouse Strains ◽

Necrosis Factor Alpha ◽

Pneumonic Plague ◽

Monocyte Chemoattractant Protein 1 ◽

Cytokines And Chemokines

ABSTRACT Yersinia pestis is the causative agent of plague, a disease that can manifest as either bubonic or pneumonic plague. An interesting feature of plague is that it is a rapidly progressive disease, suggesting that Y. pestis either evades and/or suppresses the innate immune response to infection. Therefore, the early host response during the course of primary pneumonic plague was investigated in two mouse strains, the outbred strain CD1 and the inbred strain C57BL/6. A comparative analysis of the course of disease in these two strains of mice indicated that they are susceptible to intranasal Y. pestis CO92 infection and have similar 50% lethal doses and kinetics of infection with respect to colonization of the lung, liver, and spleen. Significantly, in both strains of mice, robust neutrophil recruitment to the lungs was not observed until 48 h after infection, suggesting that there was a delay in inflammatory cell recruitment to the site of infection. In addition, proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, gamma interferon, IL-12p70, monocyte chemoattractant protein 1) and chemokines (KC, MIP-2) in the bronchoalveolar lavage fluids were not readily detected until 48 h after infection, which coincided with the increase in polymorphonuclear leukocyte (PMN) recruitment to the lungs. In comparison, CD1 mice with gram-negative pneumonia caused by Klebsiella pneumoniae exhibited strong inflammatory responses early in infection, with PMNs comprising the majority of the cells in the bronchoalveolar lavage fluid 24 h postinfection, indicating that PMN recruitment to the lungs could occur earlier in this infection than in Y. pestis infection. Together, our results indicate that there is a delay in the recruitment of neutrophils to the lungs in the mouse model of primary plague pneumonia that correlates with delayed expression of proinflammatory cytokines and chemokines in both outbred and inbred mice.

Download Full-text

Tumor Necrosis Factor Alpha Converting Enzyme (TACE) as Possible Therapeutic Target in SARS-CoV-2 Induced Acute Respiratory Distress Syndrome (ARDS)

10.26434/chemrxiv.13174415.v1 ◽

2020 ◽

Author(s):

Joao Batista Junior

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Inflammatory Responses ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Tace Inhibitors ◽

Factor Alpha ◽

Activity State ◽

Necrosis Factor

<div>This study reveals, for the first time, that rosiglitazone and pioglitazone, two thiazolidinedione drugs already approved as therapeutic agents to treat type II diabetes, were found to bind favorably to tumor necrosis factor alpha converting enzyme catalytic site with highlighted binding features.</div><div><br></div>This study suggests that rosiglitazone and pioglitazone, acting as TACE inhibitors agents might avoid or attenuate the hyperexcitability proteolytic activity state of TACE, represent a new potential therapeutic approach to treat SARS-CoV-2 infection-associated severe systemic inflammatory responses observed among severely or critically ill SARS-CoV-2 patients and, consequently, to diminish severe inflammatory‐induced lung injury, ARDS development and death rates.<br><br>

Download Full-text

JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

International Journal of Molecular Sciences ◽

10.3390/ijms22062952 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2952

Author(s):

Tzu-Yu Hou ◽

Shi-Bei Wu ◽

Hui-Chuan Kau ◽

Chieh-Chih Tsai

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Transforming Growth Factor Β1 ◽

Tissue Growth ◽

Mitogen Activated Protein Kinase ◽

Tissue Inhibitors Of Metalloproteinases ◽

Western Blots ◽

Orbital Fibroblasts ◽

Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

Download Full-text

Effects of (–)-Loliolide against Fine Dust Preconditioned Keratinocyte Media-Induced Dermal Fibroblast Inflammation

Antioxidants ◽

10.3390/antiox10050675 ◽

2021 ◽

Vol 10 (5) ◽

pp. 675

Author(s):

Ilekuttige Priyan Shanura Fernando ◽

Mawalle Kankanamge Hasitha Madhawa Dias ◽

Dissanayaka Mudiyanselage Dinesh Madusanka ◽

Hyun-Soo Kim ◽

Eui-Jeong Han ◽

...

Keyword(s):

Inflammatory Responses ◽

Dermal Fibroblast ◽

Pulmonary Complications ◽

Mitogen Activated Protein Kinase ◽

Tissue Inhibitors Of Metalloproteinases ◽

Fine Dust ◽

Elastase Activity ◽

Therapeutic Role ◽

Extracellular Matrix Components

At present air pollution in parts of East Asia is at an alarming level due to elevated levels of fine dust (FD). Other than pulmonary complications, FD was found to affect the pathogenesis of ROS-dependent inflammatory responses via penetrating barrier-disrupted skin, leading to degradation of extracellular matrix components through the keratinocyte-fibroblast axis. The present study discloses the evaluation of human dermal fibroblast (HDF) responses to FD preconditioned human keratinocyte media (HPM) primed without and with (-)-loliolide (HTT). HPM-FD treatment increased the ROS level in HDFs and activated mitogen-activated protein kinase-derived nuclear factor (NF)-κB inflammatory signaling pathways with a minor reduction of viability. The above events led to cell differentiation and production of matrix metalloproteinases (MMP), increasing collagenase and elastase activity despite the increase of tissue inhibitors of metalloproteinases (TIMP). Media from HTT primed keratinocytes stimulated with FD indicated ameliorated levels of MMPs, inflammatory cytokines, and chemokines in HDFs with suppressed collagenase and elastase activity. Present observations help to understand the factors that affect HDFs in the microenvironment of FD exposed keratinocytes and the therapeutic role of HTT as a suppressor of skin aging. Further studies using organotypic skin culture models could broaden the understanding of the effects of FD and the therapeutic role of HTT.

Download Full-text

Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms22020931 ◽

2021 ◽

Vol 22 (2) ◽

pp. 931

Author(s):

Jihyun Lee ◽

Yujin Jung ◽

Seo won Jeong ◽

Ga Hee Jeong ◽

Gue Tae Moon ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Normal Skin ◽

Skin Lesions ◽

Hippo Signaling ◽

Vascular Endothelial ◽

Expression Levels ◽

Hippo Signaling Pathway ◽

Endothelial Growth Factor

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

Download Full-text