Terms Of Inflammatory Response Research Articles

Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells.

The intestinal epithelium is known for its rapid self-renewal, and glutamine is crucial in providing carbon and nitrogen for biosynthesis. However, understanding how glutamine affects gene expression in the intestinal epithelium is limited, and identifying the essential genes and signals involved in regulating intestinal epithelial cell growth is particularly challenging. In this study, glutamine supplementation exhibited a robust acceleration of intestinal epithelial cell proliferation and stem cell expansion. RNA sequencing indicated diverse transcriptome changes between the control and glutamine supplementation groups, identifying 925 up-regulated and 1152 down-regulated genes. The up-regulated DEGs were enriched in the KEGG pathway of cell cycle and GO terms of DNA replication initiation, regulation of phosphatidylinositol 3-kinase activity, DNA replication, minichromosome maintenance protein (MCM) complex, and ATP binding, whereas the down-regulated DEGs were enriched in the KEGG pathway of p53 signaling pathway, TNF signaling pathway, and JAK-STAT signaling pathway and GO terms of inflammatory response and intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Furthermore, GSEA analysis revealed a significant up-regulation of the cell cycle, DNA replication initiation, ATP-dependent RNA helicase activity, and down-regulation of the TNF signaling pathway. The protein-protein association network of the intersecting genes highlighted the significance of DNA replication licensing factors (MCM3, MCM6, and MCM10) in promoting intestinal epithelial growth in response to glutamine. Based on these findings, we propose that glutamine may upregulate DNA replication licensing factors, leading to increased PI3K/Akt signaling and the suppression of TNF, JAK-STAT, and p53 pathways. Consequently, this mechanism results in the proliferation of porcine intestinal epithelial cells and the expansion of intestinal stem cells.

Comparison of Early Postoperative Outcomes Between Totally Extraperitoneal and Lichtenstein Repair of Inguinal Hernia: A Prospective Randomized Study.

Background: Surgical repair of inguinal hernia is among the most commonly performed surgical interventions in general surgery clinics, with minimal postoperative complications, less pain, and maximum cosmetic results. The aim of this study is to compare the outcomes of patients who underwent Lichtenstein repair (LR), which is currently the most commonly used open surgical procedure to repair inguinal hernias, and laparoscopic totally extraperitoneal (TEP) repair with regard to postoperative cosmesis, patient satisfaction, pain, and inflammatory response. Patients and Methods: The study consisted of male patients 18-65 years of age, who were operated for inguinal hernia with two different methods between February 2022 and January 2023 in the general surgery clinic of Elazig Fethi Sekin City Hospital. C-reactive protein (CRP), white blood cell, and interleukin 6 (IL-6) levels were observed to evaluate the inflammatory response in all patients. Visual Analog Scale and Verbal Rating Score systems were used to monitor the response to pain in the postoperative period. In addition, both groups were evaluated for patient satisfaction in cosmetic terms using the Vancouver Scar Scale and the Modified Stony Brook Scar Evaluation Scale. Results: Postoperative pain sensation in the TEP group was found to be significantly lower compared to the LR group. In terms of inflammatory response, IL-6 and CRP levels were found to be significantly higher in the LR group on postoperative day 1 and 2. Satisfaction with the cosmetic appearance of the surgical scar was significantly higher in the TEP group. Conclusion: TEP, which is a laparoscopic hernia repair method, is a safe surgical technique that can be preferred, especially in patients with less postoperative pain and higher cosmetic expectations. In terms of inflammatory response, significant difference is also in favor of TEP repair.

Liensinine attenuates inflammation and oxidative stress in spleen tissue in an LPS-induced mouse sepsis model.

Sepsis is a complex syndrome caused by multiple pathogens and involves multiple organ failure, particularly spleen dysfunction. In 2017, the worldwide incidence was 48.9 million sepsis cases and 11 million sepsis-related deaths were reported (Rudd et al., 2020). Inflammation, oxidative stress, and apoptosis are the most common pathologies seen in sepsis. Liensinine (LIE) is a bisbenzylisoquinoline-type alkaloid extracted from the seed embryo of Nelumbo nucifera. Lotus seed hearts have high content of LIE which mainly has antihypertensive and antiarrhythmic pharmacological effects. It can exert anti-carcinogenic activity by regulating cell, inflammation, and apoptosis signaling pathways (Manogaran et al., 2019). However, its protective effect from sepsis-induced spleen damage is unknown. In this research, we established a mouse sepsis model induced by lipopolysaccharide (LPS) and investigated the protective effects of LIE on sepsis spleen injury in terms of inflammatory response, oxidative stress, and apoptosis.

Initial biocompatibility of novel resins for 3D printed fixed dental prostheses

ObjectivesSeveral materials for 3D printing of fixed dental prostheses (FDP) have been recently introduced. This study aims to evaluate the initial biocompatibility of novel printable resins for manufacturing temporary and permanent FDP. MethodsSpecimens of five printable resins (VarseoSmile Crown plus, NextDent C&B MFH, VarseoSmile Temp, Temp PRINT, P Pro Crown & Bridge), two types of resins for subtractive manufacturing (Tetric CAD, Telio CAD) and two types of resins with conventional curing processes (Tetric EvoCeram, Protemp 4) were produced and finished. Post-processing was strictly performed according to the manufacturer’s protocol. Biocompatibility was evaluated by eluting specimens with cell culture medium and treating human gingival fibroblast cells with the eluates. A 72-hour continuous read cell viability assay measuring the reducing potential of the cells was performed. The cellular inflammatory response in terms of IL-6 and PGE2 levels was determined with specific ELISAs. Oxidative stress was determined by measuring oxidized glutathione concentrations after exposure to the resin eluates. A luminescence-based apoptosis assay was used to detect apoptosis. ResultsTetric CAD and Telio CAD were slightly toxic. All other resins were moderately to severely cytotoxic. VarseoSmile Crown plus and P Pro Crown & Bridge significantly enhanced PGE2 levels. Higher concentrations of oxidized gluthatione were determined in the presence of Telio CAD, VarseoSmile Temp and P Pro Crown & Bridge. Tetric EvoCeram and Protemp 4 reduced intracellular gluthatione levels. All printable resins slightly induced apoptosis. SignificanceFurther post-processing steps such as additional curing and washing may improve the biocompatibility of printable materials.

Climate resilience in small ruminant and immune system: An old alliance in the new sustainability context

Physiological and immunological responses of small ruminants are affected by heat stress in the attempt to recover animals’ thermal and cellular homeostasis. This review will report scientific investigations related to the complex mechanisms triggered by small ruminants to cope with heat stress that causes perturbation at different level and organ, including endocrinal and cellular response with a bidirectional crosstalk. In particular, during heat stress exposition the role of hormones (prolactin, triiodothyronine, thyroxine, and cortisol), the immune cell reactivity, the initiation of the inflammatory response in terms of cytokines profile, the heat shock cellular response, and oxidative stress will be discussed. Some critical issues for the evaluation of biomarkers of stress resiliency and thermo-tolerance at endocrinal level, immune cell response and heat shock cellular response will be examined. A scientific debate on the effect of heat shock proteins and their use as biomarker of thermo-tolerance for future breeding programs in a context of climate resilient ruminant production will be proposed. Moreover, based on the latest advanced comprehension of the mechanisms involved in heat stress cellular regulation, the circulating miRNAs will be introduced as promising biomarkers for their potential crosstalking with the other inflammatory biomarkers.

PM2.5-induced lung injury is attenuated in macrophage-specific NLRP3 deficient mice

Fine particulate matter (PM2.5) is one of the most important components of environmental pollutants and is associated with lung injury. Pyroptosis, a form of programmed cell death mainly mediated by the NLRP3 inflammasome, has been reported to be involved in sepsis-induced or ischemia/reperfusion-induced lung injury. However, the specific mechanisms of pyroptosis in PM2.5-induced lung injury are not yet clear. We constructed macrophage-specific NLRP3 knockout mice to explore the mechanism of PM2.5-induced lung injury in terms of inflammatory response, oxidative stress, and apoptosis levels, including the relationship between these effects and pyroptosis. The results disclosed that PM2.5 exposure increased the infiltration of macrophages and leukocytes and the secretion of inflammatory cytokines, including TNF-α and IL-6, in lung tissue. The activity of antioxidant enzymes, including SOD, GSH-PX, and CAT, significantly decreased, while MDA, the end product of lipid oxidation, remarkably increased. The level of apoptosis in lung tissue, measured by the TUNEL assay and apoptosis-related proteins (BAX and BCL-2), was significantly increased. Macrophage-specific NLRP3 knockout could offset these effects. We further observed that PM2.5 treatment activated the NLRP3 inflammasome and subsequently induced pyroptosis, as evidenced by the increased production of IL-1β and IL-18 and the increase of the protein levels of NLRP3, ASC, caspase-1, and GSDMD, which were inhibited when NLRP3 was knocked out in macrophages. Taken together, these results revealed that NLRP3-mediated macrophage pyroptosis promoted PM2.5-induced lung injury through aggravating inflammation, oxidative stress, and apoptosis. Targeting the inhibition of NLRP3-mediated macrophage pyroptosis provides a new way to study lung injury induced by the exposure to PM2.5.

A Comparative Transcriptome Analysis of Human and Porcine Choroid Plexus Cells in Response to Streptococcus suis Serotype 2 Infection Points to a Role of Hypoxia.

Streptococcus suis (S. suis) is an important opportunistic pathogen, which can cause septicemia and meningitis in pigs and humans. Previous in vivo observations in S. suis-infected pigs revealed lesions at the choroid plexus (CP). In vitro experiments with primary porcine CP epithelial cells (PCPEC) and human CP epithelial papilloma (HIBCPP) cells demonstrated that S. suis can invade and traverse the CP epithelium, and that the CP contributes to the inflammatory response via cytokine expression. Here, next generation sequencing (RNA-seq) was used to compare global transcriptome profiles of PCPEC and HIBCPP cells challenged with S. suis serotype (ST) 2 infected in vitro, and of pigs infected in vivo. Identified differentially expressed genes (DEGs) were, amongst others, involved in inflammatory responses and hypoxia. The RNA-seq data were validated via quantitative PCR of selected DEGs. Employing Gene Set Enrichment Analysis (GSEA), 18, 28, and 21 enriched hallmark gene sets (GSs) were identified for infected HIBCPP cells, PCPEC, and in the CP of pigs suffering from S. suis ST2 meningitis, respectively, of which eight GSs overlapped between the three different sample sets. The majority of these GSs are involved in cellular signaling and pathways, immune response, and development, including inflammatory response and hypoxia. In contrast, suppressed GSs observed during in vitro and in vivo S. suis ST2 infections included those, which were involved in cellular proliferation and metabolic processes. This study suggests that similar cellular processes occur in infected human and porcine CP epithelial cells, especially in terms of inflammatory response.

In Vitro Macrophage Immunomodulation by Poly(ε-caprolactone) Based-Coated AZ31 Mg Alloy.

Due to its excellent bone-like mechanical properties and non-toxicity, magnesium (Mg) and its alloys have attracted great interest as biomaterials for orthopaedic applications. However, their fast degradation rate in physiological environments leads to an acute inflammatory response, restricting their use as biodegradable metallic implants. Endowing Mg-based biomaterials with immunomodulatory properties can help trigger a desired immune response capable of supporting a favorable healing process. In this study, electrospun poly(ε-caprolactone) (PCL) fibers loaded with coumarin (CM) and/or zinc oxide nanoparticles (ZnO) were used to coat the commercial AZ31 Mg alloy as single and combined formulas, and their effects on the macrophage inflammatory response and osteoclastogenic process were investigated by indirect contact studies. Likewise, the capacity of the analyzed samples to generate reactive oxygen species (ROS) has been investigated. The data obtained by attenuated total reflection Fourier-transform infrared (FTIR-ATR) and X-ray photoelectron spectroscopy (XPS) analyses indicate that AZ31 alloy was perfectly coated with the PCL fibers loaded with CM and ZnO, which had an important influence on tuning the release of the active ingredient. Furthermore, in terms of degradation in phosphate-buffered saline (PBS) solution, the PCL-ZnO- and secondary PCL-CM-ZnO-coated samples exhibited the best corrosion behaviour. The in vitro results showed the PCL-CM-ZnO and, to a lower extent, PCL-ZnO coated sample exhibited the best behaviour in terms of inflammatory response and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated differentiation of RAW 264.7 macrophages into osteoclasts. Altogether, the results obtained suggest that the coating of Mg alloys with fibrous PCL containing CM and/or ZnO can constitute a feasible strategy for biomedical applications.

Pro- and anti-epileptic roles of microglia.

Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis. In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis. Therefore, it remains unclear whether microglial activation acts in a pro-epileptic or anti-epileptic manner. In mesial temporal lobe epilepsy, one of the most common form of epilepsies, microglia exhibit at least two distinct morphologies, amoeboid shape and ramified shape. Amoeboid microglia are often found in sclerotic area, whereas ramified microglia are mainly found in non-sclerotic area; however, it remains unclear whether these structurally distinct microglia share separate roles in the epileptic brain. Here, we review the roles of the two distinct microglial phenotypes, focusing on their pro- and anti-epileptic roles in terms of inflammatory response, regulation of neurogenesis and microglia-neuron interaction.

Evaluating the effect of TLR4-overexpressing on the transcriptome profile in ovine peripheral blood mononuclear cells

BackgroundToll-like receptor 4 (TLR4) plays an important role in the elimination of Gram-negative bacteria infections and the initiation of antiinflammatory response. Using the technology of pronuclear microinjection, genetically modified (GM) sheep with TLR4 overexpression were generated. Previous studies have shown that these GM sheep exhibited a higher inflammatory response to Gram-negative bacteria infection than wild type (WT) sheep. In order to evaluate the gene expression of GM sheep and study the co-expressed and downstream genes for TLR4, peripheral blood mononuclear cells (PBMC) from TLR4-overexpressing (Tg) and wild type (WT) sheep were selected to discover the transcriptomic differences using RNA-Seq.ResultAn average of 18,754 and 19,530 known genes were identified in the Tg and WT libraries, respectively. A total of 338 known genes and 85 novel transcripts were found to be differentially expressed in the two libraries (p < 0.01). A differentially expressed genes (DEGs) enrichment analysis showed that the GO terms of inflammatory response, cell recognition, etc. were significantly (FDR < 0.05) enriched. Furthermore, the above DEGs were significantly (FDR < 0.05) enriched in the sole KEGG pathway of the Phagosome. Real-time PCR showed the OLR1, TLR4 and CD14 genes to be differentially expressed in the two groups, which validated the DEGs data.ConclusionsThe RNA-Seq results revealed that the overexpressed TLR4 in our experiment strengthened the ovine innate immune response by increasing the phagocytosis in PBMC.

Influence of the Menstrual Cycle on Blood Markers of Muscle Damage and Inflammation Following Eccentric Exercise.

The aim of this study was to evaluate whether the menstrual cycle and its underlying hormonal fluctuations affect muscle damage and inflammation in well-trained females following an eccentric exercise. Nineteen eumenorrheic women performed an eccentric squat-based exercise in the early follicular phase, late follicular phase and mid-luteal phase of their menstrual cycle. Sex hormones and blood markers of muscle damage and inflammation –creatine kinase, myoglobin, lactate dehydrogenase, interleukin-6, tumoral necrosis factor-α, and C reactive protein– were analyzed in each phase. No effect of menstrual cycle phase was observed (p > 0.05), while an interaction for interleukin-6 was shown (p = 0.047). Accordingly, a moderate effect size [0.68 (0.53)–0.84 (0.74)], indicated that interleukin-6 values 2 h post-trial (2.07 ± 1.26 pg/mL) were likely to be higher than baseline (1.59 ± 0.33 pg/mL), 24 h (1.50 ± 0.01 pg/mL) and 48 h (1.54 ± 0.13 pg/mL) in the mid-luteal phase. Blood markers of muscle damage and inflammation were not affected by the menstrual cycle in well-trained women. The eccentric exercise barely triggered muscle damage and hence, no inflammation was observed, possibly due to participants training status. The mid-luteal phase was the only phase reflecting a possible inflammatory response in terms of interleukin-6, although further factors than sex hormones seem to be responsible for this finding.

Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma.

Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)T cells has shown impressive results in the treatment of patients with relapsed or refractory hematologic B-cell malignancies. In recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immunotherapy treatments, including CART cells, for patients with multiple myeloma. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an attempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells showed comparable in vitro and in vivo efficacy to that of ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells produced less tumor necrosis factor-and were associated with a milder in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART-cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrated that soluble BCMA and BCMA released in vesicles both affect CAR-BCMA activity. In summary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h-cell treatment for patients with multiple myeloma.

Effects of laparoscopy and laparotomy on stress and hemodynamics in experimental sepsis model in rats

Aim: Laparoscopic abdominal surgery leads to reduced inflammatory response compared with laparotomy. However, there is controversial approaches are present in abdominal diseases complicated by diffuse or localized peritonitis. Materials and Methods: Experimental cecal ligation and puncture method is used in the study. A total of 24 rats were used in the study. We divided all rats randomly four groups: control, sepsis, laparotomy and laparoscopy. After sepsis model was applied, we took blood samples and lung and liver samples as well. In plasma samples we determined 8-OHdG, 3-Nitrotyrosine, HNE, PGF-2 via ELISA methods. The tissue samples were analyzed since the amount of blood samples were inadequate in all subjects. We measured MPO activity to assess the neutrophil infiltration rates. Results: 3-NT mean values in laparotomy and laparoscopy groups were found to be almost the same while the difference between sepsis and laparoscopy groups was statistically significant (p =0.015) and decreased in the group undergoing laparoscopy. MPO levels obtained in rats underwent laparoscopy in liver tissue were found to be lower when compared with control and laparotomy groups and the difference between them was statistically significant. Also, MPO levels was found higher in sepsis laparotomy model as compared sepsis laparoscopy models. Conclusion: Laparoscopy is accepted as golden standard in several elective procedures, since it is less stressful. Our results indicate that laparoscopy is superior to laparotomy in terms of inflammatory response in sepsis and should be preferred in septic patients.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock

BackgroundSeptic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock.MethodsWe performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock.ResultsIn both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend.ConclusionsThis pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS.Trial registrationClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

A Comparative Analysis of Spectrum and Outcome of Common bacterial Infections in Patients with and without Diabetes-a Prospective Hospital Based Study

Objective: In this prospective study we analyzed clinical spectrum of infections and there outcome in patients with diabetes mellitus and compared it with nondiabeticcontrols admitted in Endocrinology division of a tertiary care hospital.Methods: This was a prospective, longitudinal study of 242 diabetic and non-diabetic subjects. Patients were studied in terms of clinical picture, biochemical, hematological and microbiological profile, type and severity of infection, treatment received, and final outcome. There were 142 diabetic patients in group 1 and 100 nondiabetic patients in group 2 served as control. Study subjects were followed for a median period of one year (52 weeks in diabetics, 65 weeks in non-diabetics) after discharge from the ward.Results: Diabetic patients admitted because of infections were older than their non-diabetic counterparts (74% vs 51%&gt; 50 years; p&lt;0.001) and mounted a less inflammatory response in terms of fever and leucocytosis(55% vs 82%:P&lt;0.001).Urinary tract infections were the commonest infections observed among in-hospital diabetic as well as non-diabetic patients (36% vs. 30%; P&gt;0.3). Diabetics contract some specific infections exclusively, like emphysematous pyelonephritis and foot infections, while respiratory infections were more commonly seen in nondiabetic patients (31% vs. 11%; P&lt;0.001).Staphylococcus aureus was the commonest organism involved in soft tissue and diabetic foot infections (32% vs. 19%; P&lt;0.03). Though mean hospital stay was equal in either group it was significantly longer in diabetic subjects when statistically adjusted for APACHE score.Comparative mortality rates were higher in non-diabetics with in-hospital deaths, followup deaths and total deaths of11%, 6.1% and 17.2% vs 4.9%, 4% and 9.1% respectively but re-infections on follow-up occurred more in diabetics (15% vs.2.6%; P=0.005).Conclusion: Poor glycaemic control and less inflammatory response in terms of fever and leucocytosis, longer hospital stay with increased chances of reinfections are poor prognostic indicators for outcomes in diabetic patients admitted with infections. Urinary tract infections and soft tissue infections particularly foot infectionsare causes of concern in our diabetic patients. JMS 2018: 21 (2):84-90

Heterotopic Ossification - Complication or Chance?

So far, there has been no clear explanation of the pathophysiological relationships in the development of HO. There is little experimental data dealing with the post-traumatic inflammatory response in terms of a balance between the repair of damaged muscle cells and the opposite response in its development. There are numerous indications regarding possible predisposing factors, such as existence of surrounding tissue hypoxia or the function of pro-angiogenic (VEGF e.g.) and osteoinductive (BMP e.g.) factors. These different scientific approaches offer the opportunity to clinically intervene. In our opinion, early intervention seems to make the most sense in terms of effectiveness and recurrence of HO. An important pathomechanism seems to be chronic inflammation. Currently, non-steroidal anti-inflammatory drugs are the most commonly prescribed prophylaxis drugs. The effectiveness and efficacy of non-steroidal anti-inflammatory drugs is limited by the time-limited release and the side effect potential. Therefore, it is interesting to focus future research towards the cross-talks between immunosuppressive downregulation of the inflammatory response and its effect on the balance between muscle regeneration and the development of HO.

CCL20 blockade increases the severity of nephrotoxic folic acid-induced acute kidney injury.

The chemokine CCL20 activates the CCR6 receptor and has been implicated in the pathogenesis of glomerular injury. However, it is unknown whether it contributes to acute kidney injury (AKI). We identified CCL20 as upregulated in a systems biology strategy combining transcriptomics of kidney tissue from experimental toxic folic acid-induced AKI and from stressed cultured tubular cells and have explored the expression and function of CCL20 in experimental and clinical AKI. CCL20 upregulation was confirmed in three models of kidney injury induced by a folic acid overdose, cisplatin or unilateral ureteral obstruction. In injured kidneys, CCL20 was expressed by tubular, endothelial, and interstitial cells, and was also upregulated in human kidneys with AKI. Urinary CCL20 was increased in human AKI and was associated with severity. The function of CCL20 in nephrotoxic folic acid-induced AKI was assessed by using neutralising anti-CCL20 antibodies or CCR6-deficient mice. CCL20/CCR6 targeting increased the severity of kidney failure and mortality. This was associated with more severe histological injury, nephrocalcinosis, capillary rarefaction, and fibrosis, as well as higher expression of tubular injury-associated genes. Surprisingly, mice with CCL20 blockade had a lower tubular proliferative response and a higher number of cells in the G2/M phase, suggesting impaired repair mechanisms. This may be related to a lower influx of Tregs, despite a milder inflammatory response in terms of chemokine expression and infiltration by IL-17+ cells and neutrophils. In conclusion, CCL20 has a nephroprotective role during AKI, both by decreasing tissue injury and by facilitating repair. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Engystol reduces onset of experimental respiratory syncytial virus-induced respiratory inflammation in mice by modulating macrophage phagocytic capacity

BackgroundRespiratory viruses such as respiratory syncytial virus (RSV) or rhinovirus are one of the major causes for respiratory tract infections causing common cold disease. Respiratory viral infections range from mild symptoms in adults to serious illness especially in the very young or elderly as well as patients suffering from lung diseases or being immunocompromised due to other reasons. Engystol (EGY-2) is a multicomponent, multitarget preparation consisting of Vincetoxicum hirundinaria and Sulfur in various dilutions. The study objective was to test the effect of EGY-2 on the innate immune response during the early onset of respiratory viral infection in vivo as exemplified in a mouse model of RSV-induced respiratory inflammation.MethodsNaïve BALB/c mice were infected with 1x106 infectious units RSV A2 intranasally to cause a mild respiratory infection. EGY-2 was administered daily per oral gavage starting seven days prior to RSV infection at doses of 0.4 to 5.1 tablets/kg. Control groups received placebo treatment. Animals were sacrificed 1 to 3 days post infection (p.i.) to analyse the infection and induced immune response in the lung. Viral load in bronchoalveolar lavage fluid (BALF) and lung homogenate was determined by TCID50 assay as well as immunofluorescence staining of BALF cells using anti-RSV antibody and microscopic analysis. The RSV induced immune response was assessed by evaluation of BALF differential cell count, BALF cytokine secretion and analysis of the phagocytic capacity of alveolar macrophages.ResultsEGY-2 significantly reduced the RSV induced neutrophil and early lymphocyte influx on day 1 p.i. in BALF. EGY-2 treatment significantly diminished the RSV induced secretion of pro-inflammatory cytokines such as IFN-γ, IL-1β, IL-6, KC and TNF-α at day 1. EGY-2 treatment was not protective for RSV infection per se, as no alteration in the viral load in lung and BALF was detected. Enhanced numbers of phagocytic-active macrophages were observed in EGY-2 treated animals on day 1 and this macrophage population showed strongly enhanced phagocytic activity on day 1 and day 3.ConclusionThe data suggest a beneficial immunomodulatory effect of EGY-2 during early onset of respiratory viral infection in vivo, mediated by stimulation of macrophage phagocytosis, resulting in a reduced innate inflammatory response in terms of neutrophil and early lymphocyte infiltration as well as reduced inflammatory cytokine secretion.

Effects of Intracordal Estradiol and Dexamethasone Injection on Wound Healing in Vocal Fold Injuries

The aim of this study was to investigate the effects of intracordal estradiol and dexamethasone injection on wound healing in vocal fold injuries. A prospective controlled animal study was carried out. This study was conducted at a tertiary center. Ten rabbits were randomly divided into two groups. As surgical procedure, cordotomy technique was performed in the middle third of the vocal folds bilaterally. In the first group, 0.1 mL of dexamethasone was injected into the right side, and 0.1 mL of saline was injected into the left side. In the second group, 0.1 mL of estradiol was injected into the right side, and 0.1 mL of saline was injected into the left side. Animals were sacrificed after 1 month and laryngeal specimens were evaluated histopathologically. No statistically significant difference was observed in terms of inflammatory response, epithelial thickness, type I and III collagen, and hyaluronic acid parameters in dexamethasone and estradiol injections compared to the saline injection. In terms of elastin level, estradiol injection demonstrated statistically higher values compared to the saline injection. Elastin level of dexamethasone injected vocal folds was not statistically different compared to the saline injection. No significant differences were observed in terms of inflammatory response, epithelial thickness, type I and III collagen, and hyaluronic acid parameters between the estradiol and dexamethasone injected vocal folds. It is thought that the effects of estradiol or dexamethasone injections may have similar effects on wound healing in vocal fold injuries. Intracordal estradiol injection has positive effects on tissue elastin levels.

Type II Minimal‐Invasive Extracorporeal Circuit for Aortic Valve Replacement: A Randomized Controlled Trial

Extracorporeal circulation triggers systemic inflammatory response and coagulation disorders which may lead to unfavorable clinical outcome. A type II minimally-invasive extracorporeal circuit (MiECC) is a closed system with markedly reduced artificial surface as compared to conventional extracorporeal circuits (CECC). The aim of this study was to investigate and compare inflammatory responses, complement activation and selected clinical end-points in isolated surgical aortic valve replacement (SAVR) performed with a type II MiECC circuit or a CECC. Fifty patients were prospectively randomized to MiECC or CECC perfusion regimen. Complement activation (sC5b-9), inflammation (IL-6, TNF-α, sCD40-ligand) and activation of the coagulation system (D-dimer, TAT-complex) were determined before operation, at 2 hours and 24 hours after surgery. Clinical end-points included perfusion time, transfusion of allogeneic blood products, postoperative bleeding, sepsis, new onset of atrial fibrillation, stroke and in-hospital mortality. Patient characteristics and baseline plasma markers were similar in both groups. Levels for sC5b-9, TNF-α, sCD40 ligand, TAT-complex and D-dimers were not significantly different between MiECC and CECC at 2 hours and 24 hours after surgery. The IL-6 plasma concentration was lower in the CECC group at 24 hours (P = 0.026, vs. MiECC). Comparisons of the baseline level to values at 2 hours and 24 hours, adjusted for the type of oxygenator and hemoglobin, showed a significantly lower sC5b-9 in MiECC at 2 hours (P = 0.013), but no difference at 24 hours (P=0.990). Compared with CECC, MiECC patients had a shorter perfusion time (P = 0.037) and less transfusion requirements (P = 0.04). In this selected cohort of SAVR patients, the type II MiECC was not inferior to CECC in terms of inflammatory response and complement activation. Thus, MiECC might be an alternative perfusion strategy to conventional.