Inflammatory Cytokine Cascade Research Articles

The Effects of Recreational and Pharmaceutical Substance Use on Oral Microbiomes and Health

Oral health remains one of the most taken for granted parts of human body health, even though poor oral health has now been linked to various diseases, such as cancers, diabetes, autoimmune complications, neurological disorders, and cardiovascular disease, just to name a few. As we review in this paper, substance use or abuse, including alcohol, smoking, recreational drugs, and pharmaceutical drugs can have significant implications on oral health, which in turn can lead to more systemic diseases. In this paper, we show that oral microbiome dysbiosis and inflammatory cytokine pathways are two of the most significant mechanisms contributing to oral health complications from substance use. When substance use decreases beneficial oral species and increases periodontopathogenic strains, a subsequent cascade of oncogenic and inflammatory cytokines is triggered. In this review, we explore these mechanisms and others to determine the consequences of substance use on oral health. The findings are of significance clinically and in research fields as the substance-use-induced deterioration of oral health significantly reduces quality of life and daily functions. Overall, the studies in this review may provide valuable information for future personalized medicine and safer alternatives to legal and pharmaceutical substances. Furthermore, they can lead towards better rehabilitation or preventative initiatives and policies, as it is critical for healthcare and addiction aid specialists to have proper tools at their disposal.

A review of cytokine-based pathophysiology of Long COVID symptoms.

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Effect of Remote Ischaemic Conditioning on the Inflammatory Cytokine Cascade of COVID-19 (RIC in COVID-19): a Randomized Controlled Trial

PurposePatients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine “storm” that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19.MethodsWe conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days.ResultsEighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938–2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616–2.295, p = 0.61).ConclusionRIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care.Trial RegistrationClinicalTrials.gov Identifier: NCT04699227.

Elevated Levels of Interleukin-21 in Acute Kidney Injury After Cardiopulmonary Bypass Surgery

Background: It is well-established that complications following cardiopulmonary bypass (CPB) such as acute kidney injury (AKI) lead to worse outcomes and higher mortality. Considering the importance of the post-CPB inflammatory cytokine cascade, we first assessed the post-operative interleukin (IL)-21 serum level and its association with AKI development after CPB. Methods: In this experimental before-after study, 40 patients with confirmed CPB-AKI in the Jorjani Heart Center, Bandar Abbas (from January 2017 to September 2018) were compared with 50 non-AKI patients. AKI was defined according to the Acute Kidney Injury Network. The IL-21 serum level was measured using an enzyme-linked immunosorbent assay before and 12 hours after surgery. The association between IL-21 and other variables was evaluated by correlation analyses. Results: The IL-21 serum level was significantly higher post-operation compared to its level before surgery in AKI (21.4±6.3 and 15.7±5.5, P<0.001) and non-AKI (19.1±6.4 and 13.7±6.3, P<0.001) patients, but no significant differences were observed between AKI and non-AKI patients. Age, body mass index, and creatinine were not significantly correlated with the IL-21 serum level 12 hours post operations in AKI and non-AKI subjects. Conclusion: Serum IL-21 concentrations were significantly increased in CPB patients after operation, which may contribute to the post-CPB inflammatory response syndrome. Our data did not confirm any association between increased IL-21 levels and CPB-AKI risk.

Profile and role of immune function changes of T lymphocytes in patients with acute pancreatitis

In recent decades, with the development of the pathogenesis of Acute severe pancreatitis (SAP) and the improvement of clinical treatment techniques, the mortality rate of SAP is still over 10% . Recent studies have shown that immune dysregulation plays an important role in the pathogenesis of AP, especially in SAP. A meta-study points to widespread concern for the discovery of immunosuppression by networked cytokines in the course of AP. In the early stages of AP, high cytokine levels play a leading role in the development of SIRS pathological conditions, which result in a cascade of inflammatory cytokines that induce the release of immunocompetent cells, leading to an excessive immune response. In the later stages of Compensatory anti-inflammatory response syndrome (CARS), the body over-releases anti-inflammatory agents and has an immunosuppressive process, but contributes to the development of the risk of secondary infection and increases the likelihood of Multiple organ disfunction syndrome (MODS). The study was aimed to measure T-lymphocyte immune function changes of patients with acute pancreatitis and to explore BISAP scoring system in clinical applications.

PLXDC2 activation by PX-69 ameliorates rheumatoid arthritis through activation of novel immunometabolic mechanisms

Abstract Rheumatoid arthritis is a chronic inflammatory disorder that affects up to 1% of the population worldwide characterized by the increased presence of infiltrating immune cells, activation of inflammatory cytokine cascades, oxidative stress, abnormal proliferation of fibroblast-like synoviocytes (FLS) and neovascularization at the joint synovium. Plexin domain containing 2 (PLXDC2) is a transmembrane receptor with antioxidant, antiangiogenic and immunomodulatory properties that provide therapeutic activity in animal models of autoimmune disease, including rheumatoid arthritis. PLXDC2 activation suppresses glycolytic metabolism, while decreasing cytokine and chemokine secretion and production of superoxide species, in immune cells and FLS. In a rat model of collagen-induced arthritis, oral administration of the lead PLXDC2-binding agonist, PX-69, ameliorates disease severity, resulting in decreased clinical scores and paw size. Similarly, hind ankles presented structure preservation, reduced cartilage damage and decreased immune cell infiltration and number of blood vessels in the PX-69-treated group relative to vehicle. Immunologically, PX-69 treatment resulted in a 2-fold decrease of TNFα-producing cells while upregulating the proportion of IL-10+ myeloid cells and regulatory T cells in draining lymph nodes. In synovial tissue, pharmacological activation of PLXDC2 provided greater than 50% reduction in expression of inflammatory mediators (TNFα, IL1β, IL6, Cxcl1) and markers of synoviocyte activation (c-myc, c-fos). These results support the role of PLXDC2 signaling in controlling rheumatoid arthritis and validate PLXDC2 as a novel target for the treatment of this disabling inflammatory disorder.

Carvedilol and exercise combination therapy improves systolic but not diastolic function and reduces plasma osteopontin in Col4a3-/- Alport mice.

There are currently no Food and Drug Administration-approved treatments for heart failure with preserved ejection fraction (HFpEF). Here we compared the effects of exercise with and without α/β-adrenergic blockade with carvedilol in Col4a3-/- Alport mice, a model of the phenogroup 3 subclass of HFpEF with underlying renal dysfunction. Alport mice were assigned to the following groups: no treatment control (n = 29), carvedilol (n = 11), voluntary exercise (n = 9), and combination carvedilol and exercise (n = 8). Cardiac function was assessed by echocardiography after 4-wk treatments. Running activity of Alport mice was similar to wild types at 1 mo of age but markedly reduced at 2 mo (1.3 ± 0.40 vs. 4.5 ± 1.02 km/day, P < 0.05). There was a nonsignificant trend for increased running activity at 2 mo by carvedilol in the combination treatment group. Combination treatments conferred increased body weight of Col4a3-/- mice (22.0 ± 1.18 vs. 17.8 ± 0.29 g in untreated mice, P < 0.01), suggesting improved physiology, and heart rates declined by similar increments in all carvedilol-treatment groups. The combination treatment improved systolic parameters; stroke volume (30.5 ± 1.99 vs. 17.8 ± 0.77 μL, P < 0.0001) as well as ejection fraction and global longitudinal strain compared with controls. Myocardial performance index was normalized by all interventions (P < 0.0001). Elevated osteopontin plasma levels in control Alport mice were significantly lowered only by combination treatment, and renal function of the Alport group assessed by urine albumin creatinine ratio was significantly improved by all treatments. The results support synergistic roles for exercise and carvedilol to augment cardiac systolic function of Alport mice with moderately improved renal functions but no change in diastole.NEW & NOTEWORTHY In an Alport mouse model of heart failure with preserved ejection fraction (HFpEF), exercise and carvedilol synergistically improved systolic function without affecting diastole. Carvedilol alone or in combination with exercise also improved kidney function. Molecular analyses indicate that the observed improvements in cardiorenal functions were mediated at least in part by effects on serum osteopontin and related inflammatory cytokine cascades. The work presents new potential therapeutic targets and approaches for HFpEF.

Fighting the storm: could novel anti-TNFα and anti-IL-6 C. sativa cultivars tame cytokine storm in COVID-19?

The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission.Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis.Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies.The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis.Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

In Vitro and In Vivo Effectiveness of GPK/B2O, A Phytocomplex in Two Experimental Flu Virus Models

There is constant quest to prevent and counterfight annual influenza viral epidemics, given the limitations and drawbacks of antivirals chemicals so far. The aim of the present study was to test on an experimental viral model a phytocompound containing herbal ingredients endowed by, albeit scattered, reports of antiviral properties (GPK/B20, Viraxil, Named, Italy). Two influenza models were employed, i.e. H1N1 and H3N2. In vitro test showed that GSK/B20, especially at medium and high dose (50µl/mL to 100µl/mL) significantly reduced the infection of Madin-Darby-Canine-Kidney monolayers cells and progression of cytopathogenic effect over the observation period. More interestingly, when this compound was test 1h after infection on mice, especially at high dose (60g/kg/day), it appeared to significantly blunt the immune/inflammatory cells recruitment and the inflammatory cytokine cascade (at lung tissue level and bronco-alveolar lavage level), curbing also the related gene expression. This was associated to a reduced lung oedema, which is the correlate of respiratory distress in humans, viral load and scanning electron microscopy findings. In the meantime, more detailed experimental studies are warranted to unveil the range of mechanisms of actions that these natural ingredients are likely to be endowed with. Although these data have to be taken with caution having being obtained in an experimental-controlled setting, they suggest a potential safe application in the clinical practice, as recently corroborated for one of the herbal used.

Potential Role of Nrf2 Activators with Dual Antiviral and Anti-Inflammatory Properties in the Management of Viral Pneumonia.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic has already caused a huge burden to the global healthcare system, with the death toll reached tens of thousands. Although some antiviral agents were identified and used to inhibit viral replication, the management of cytokine storm is also a critical issue. In this article, we reviewed the literature on drug candidates for severe acute respiratory syndrome (SARS-CoV-1) and provided a brief overview of a class of drugs that exert antiviral and anti-inflammatory effects. These molecules mitigated inflammatory cytokine cascades induced by viral infections via Nrf2 activating capacity and might have additional anti-fibrotic and anti-remodeling properties. Besides, their effects on the regulation of scavenger receptors expression by macrophages may offer some benefits to the pulmonary antibacterial defense system after viral infection. The potential roles of these agents assessed on the basis of the pathophysiology of viral pneumonia and acute respiratory distress syndrome were also discussed. Further research is needed to ascertain whether Nrf2 activators are useful in the management of viral pneumonia.

Arachidonic Acid Impairs Primary Human Skeletal Muscle Myoblasts Proliferation and Differentiation

Inflammation is a process initiated by cells in response to disease or injury. The cellular response to inflammation begins with the release of inflammatory cytokines such as TNF alpha and IL‐6. This cascade of inflammatory cytokines causes the release of arachidonic acid, a key regulator of inflammation, from the cell membrane, allowing an interaction with cyclooxygenase (COX) enzymes, mediating the synthesis of pro‐inflammatory prostaglandins (PGE2 and PGF2α). Recent studies have indicated that these inflammatory events, and particularly the release of arachidonic acid, have a major impact on how muscle cells and tissue respond to inflammation; these studies, conducted on murine C2C12 cells, demonstrated that arachidonic acid supplementation leads to increased muscle cell growth. We therefore sought to determine if similar arachidonic acid supplementation in both proliferating and differentiating primary human myoblasts leads to increased muscle cell growth. Proliferating and differentiating human myoblasts were exposed to arachidonic acid at concentrations from 50 μM‐ 0.80 μM for up to 48–72 hours respectively. Cell viability was tested using 3‐(4,5‐Dimethylthiazol‐2‐Yl)‐2,5‐Diphenyltetrazolium Bromide (MTT) assay, myotube area was determined by immunocytochemistry and confocal microscopy, and anabolic signaling pathways were evaluated by Western blot and RTPCR. Our data suggests that treatment of primary human myoblasts with high concentrations of arachidonic acid (50 μM and 25 μM) leads to the release of PGE2 and PGF2α at levels higher than that of control treated cells (p&lt;0.001 for all concentrations). High concentrations of arachidonic acid have a deleterious effect on both myoblast proliferation, myotube area, and myotube fusion. Our data demonstrates that arachidonic acid reduced proliferation by 85% and 32%, myotube area by 63% and 38% and myotube fusion index by 93% and 50% respectively (P&lt;0.001 for all). As a potential mechanism for these decreases, we analyzed the AKT proliferation pathway and found a 90% and 37% reduction respectively in Eukaryotic translation initiation factor 4E‐binding protein 1(4EBP1) following the 48 hour arachidonic acid exposure at these concentrations (p&lt;0.001 and p&lt;0.05). Finally, as a potential mechanism for the change in myotube area and fusion index we analyzed the levels of myosin (specifically MYH 1,2,3,7, and 8), a protein critical for the formation of myoblasts into myotubes, by RTPCR. Our data suggests that 50 μM arachidonic acid reduced the expression of all analyzed MHY isoforms by an average of 95% (p&lt;0.001 for all) with normal expression levels not returning until the 3.125 μM dose. Together, our data demonstrates that high doses of arachidonic acid reduce primary human myoblast differentiation. These findings suggests that the response of primary human myoblasts are different than murine C2C12 cells supplemented with high doses of arachidonic acid.Support or Funding InformationThe views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. This abstract has been approved for public release with unlimited distribution.

Phosphatidylserine’s role in Ebola’s inflammatory cytokine storm and hemorrhagic consumptive coagulopathy and the therapeutic potential of annexin V

The phosphatidylserine (PS) molecule is present in cell membranes where it is actively kept on their inner leaflets but when cells are damaged it moves to the surface and become a signal for their removal, the platform upon which the coagulation cascade takes place and a ligand that activates a feedback cycle of inflammatory cytokine secretion and initiates the wakeup call for the innate immune response. These are physiologic responses to PS but the Ebola virus displays PS molecules on its membrane’s surface and the huge numbers of viruses cause a pathologic inflammatory cytokine storm and a hemorrhagic consumptive coagulopathy. Annexin V is an innate molecule that can cloak membrane displayed PS and prevents its Th1 cell’s inflammatory cytokine generation and cascade thrombin generation. The hypothesis presented is that its administration will cloak PS and prevent Ebola’s consumptive coagulopathy and its cytokine storm.

CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model.

Interleukin 23 (IL-23) is a key mediator in neuroinflammation in numerous autoimmune diseases including multiple sclerosis (MS). However, the pathophysiology of IL-23 and how it contributes to neuroinflammation is poorly defined. To further clarify the role of IL-23 in CNS inflammation, we generated a transgenic mouse model (GF-IL23) with astrocyte-targeted expression of both IL-23 subunits, IL-23p19, and IL-23p40. These GF-IL23 mice spontaneously develop a progressive ataxic phenotype, which corresponds to cerebellar tissue destruction, and inflammatory infiltrates most prominent in the subarachnoidal and perivascular space. The CNS-cytokine milieu was characterized by numerous inflammatory mediators such as IL-17a and IFNγ. However, the leukocytic infiltrates were surprisingly predominated by B cells. To further examine the impact of the CNS-specific IL-23 synthesis on an additional systemic inflammatory stimulus, we applied the LPS-induced endotoxemia model. Administration of LPS in GF-IL23 mice resulted in early and pronounced microglial activation, enhanced cytokine production and, in sharp contrast to control animals, in the formation of lymphocytic infiltrates. Our model confirms a critical role for IL-23 in the induction of inflammation in the CNS, in particular facilitating the accumulation of lymphocytes in and around the brain. Thereby, CNS-specific synthesis of IL-23 is able to induce a cascade of inflammatory cytokines leading to microglia activation, astrocytosis, and ultimately tissue damage. The presented transgenic model will be a useful tool to further dissect the role of IL-23 in neuroinflammation.

PD09-08 INTRAPERITONEAL ADMINISTRATION OF MESENCHYMAL STEM CELLS IS EFFECTIVE IN PREVENTING DETRUSOR DYSFUNCTION AFTER PARTIAL BLADDER OUTLET OBSTRUCTION

INTRODUCTION AND OBJECTIVES:Mesenchymal stem cells (MSC) have shown great promise with respect to the prevention and treatment of detrusor dysfunction and fibrosis after partial bladder outlet obstruction (pBOO). Our lab has previously demonstrated short and long-term benefits with a reduction in the inflammatory and hypoxic cytokine cascade, decreased smooth muscle hypertrophy, prevention of fibrosis, and improvement in urodynamic parameters. Although our intravenous administration has demonstrated uptake of MSC into the bladder, we hypothesize the primary mechanism of action is via a systemic downregulation of the inflammatory and hypoxic cascade. Therefore, we repeated the pBOO in our model using the intraperitoneal (IP) administration of MSC to compare the efficacy to intravenous administration.METHODS:5x106 MSC via IP had similar effects to 106 MSC IV, while 106 IP was not as effective. 5 x106 IP showed greater reduction in TGF-B1, MTOR, and Col 1+3 than 106 IV (p<0.05) at 4 weeks. The difference was...

Card9 as a critical regulator of tumor development

Caspase recruitment domain-containing protein 9 (Card9) is a myeloid cell-specific signaling protein that plays a critical role in NF-κB and MAPK activation. This leads to initiation of the inflammatory cytokine cascade, and elicits the host immune response against microbial invasion, especially in fungal infection. Current research indicates that Card9 plays an important role in tumor progression. Here, we review the data from preclinical and clinical studies of Card9 and suggest the potential for Card9-targeted interventions in the prevention or treatment of certain tumors.

Amitriptyline Treatment Mitigates Sepsis-Induced Tumor Necrosis Factor Expression and Coagulopathy.

During sepsis, the early innate response and inflammatory cytokine cascade are associated with activation of the coagulation cascade. Acute hypercoagulability can contribute to lethal sequela of vascular thrombosis, tissue ischemia, and organ failure. We investigated if amitriptyline (AMIT), an antidepressant drug with a number of anti-inflammatory effects, could ameliorate sepsis in a murine model of sepsis-cecal ligation and puncture (CLP). We hypothesized that AMIT treatment would reduce inflammation and mitigate sepsis-induced coagulopathy. Coagulation was measured using thromboelastometry and ferric chloride-induced carotid artery thrombosis. Our findings demonstrate a dynamic early hypercoagulability, followed by delayed hypocoagulability in septic mice. However, septic mice treated with AMIT were unaffected by these coagulation changes and exhibited a coagulation profile similar to sham mice. TNFα was markedly elevated in septic mice, but decreased in AMIT-treated mice. Exogenous administration of recombinant TNFα in naive mice recapitulated the acute sepsis-induced hypercoagulability profile. After sepsis and endotoxemia, peritoneal macrophages were the predominant source of TNFα expression. AMIT treatment significantly decreased macrophage TNFα expression and blunted M1 polarization. Altogether, during polymicrobial sepsis, AMIT treatment suppressed macrophage TNFα expression and the M1 phenotype, mitigating an initial hypercoagulable state, and protecting septic mice from delayed hypocoagulability. We propose that AMIT treatment is a promising therapeutic approach in the treatment of sepsis-associated coagulopathy and prevention of acute thromboembolic events or delayed bleeding complications.

Lack of TNF-α signaling through p55 makes the mice more susceptible to acute infection but does not alter state of latency and reactivation of HSV-1

TNF-α has been shown to play an important role in pathogenesis and latency of HSV-1 infections. TNF-α signals through TNFR1 (p55) and TNFR2 (p75), and signaling through p55 generally results in gene activation leading to induction of inflammatory responses. Here, we studied the role of TNF-α signaling in latent virus reactivation in p55-knock out (KO) mouse model of ocular HSV-1 infection. We found that KO mice are more susceptible to HSV-1 infection compared to wild type C57Bl/6 mice. While the absence of TNFRI signaling enhanced the ganglion latent DNA content by two folds, there was no difference in the maintenance and reactivation of latent HSV-1. Strikingly, interfering with inflammatory responses through PGE2 synthesis by treating latently infected wild type mice with indomethacin (COX inhibitor) prior to UV-exposure prevented HSV-1 reactivation. These results suggest that reactivation of latent HSV-1 might result from the cumulative effects of a cascade of inflammatory cytokines including TNF-α.

Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model

Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model. Some respiratory alterations characteristic of emphysema (decreased airway resistance: Rl; end-expiratory work and pause: EEW, EEP; expiration time: Te; increased tidal mid-expiratory flow: EF50) were detected in anaesthetized C57BL/6 mice, unrestrained plethysmography did not show changes. Typical histopathological signs were peribronchial/perivascular (PB/PV) edema at month 1, neutrophil/macrophage infiltration at month 2, interstitial leukocyte accumulation at months 3–4, and emphysema/atelectasis at months 5–6 quantified by mean linear intercept measurement. Emphysema was proven by micro-CT quantification. Leukocyte number in the bronchoalveolar lavage at month 2 and lung matrix metalloproteinases-2 and 9 (MMP-2/MMP-9) activities in months 5–6 significantly increased. Smoking triggered complex cytokine profile change in the lung with one characteristic inflammatory peak of C5a, interleukin-1α and its receptor antagonist (IL-1α, IL-1ra), monokine induced by gamma interferon (MIG), macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) at months 2–3, and another peak of interferon-γ (IFN-γ), IL-4, 7, 13, 17, 27 related to tissue destruction. Transient systolic and diastolic ventricular dysfunction developed after 1–2 months shown by significantly decreased ejection fraction (EF%) and deceleration time, respectively. These parameters together with the tricuspid annular plane systolic excursion (TAPSE) decreased again after 5–6 months. Soluble intercellular adhesion molecule-1 (sICAM-1) significantly increased in the heart homogenates at month 6, while other inflammatory cytokines were undetectable. This is the first study demonstrating smoking duration-dependent, complex cardiopulmonary alterations characteristic to COPD, in which inflammatory cytokine cascades and MMP-2/9 might be responsible for pulmonary destruction and sICAM-1 for heart dysfunction.

Temporal cascade of inflammatory cytokines and cell-type populations in monocyte chemotactic protein-1 (MCP-1)-mediated aneurysm healing

BackgroundWe have previously shown that monocyte chemotactic protein-1 (MCP-1) promotes aneurysm healing.ObjectiveTo determine the temporal cascade and durability of aneurysm healing.MethodsMurine carotid aneurysms were treated with MCP-1-releasing or poly(lactic-co-glycolic) acid...

α-Lactose Improves the Survival of Septic Mice by Blockade of TIM-3 Signaling to Prevent NKT Cell Apoptosis and Attenuate Cytokine Storm.

Sepsis is the leading cause of death among critically ill patients and natural killer T (NKT) cell activation is essential to induce inflammatory cytokine cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed that T-cell immunoglobulin and mucin domain 3 (Tim-3) expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, interleukin (IL)-12 secreted by dendritic cell exposure to lipopolysaccharide increased the expression of Tim-3 in NKT cells. Administration of α-lactose to block Tim-3 signaling pathway significantly improved the survival of septic mice, concomitant with reduced IL-12 production by dendritic cells, reduced Tim-3 expression, prevented NKT cell apoptosis, and attenuated production of inflammatory cytokines. Collectively, Tim-3 signaling in NKT cells plays a critical role in the immunopathogenesis of sepsis. Thus, α-lactose could be a promising immunomodulatory agent in the treatment of sepsis.