Effects Of Inflammatory Mediators Research Articles

Lupus dermal fibroblasts are proinflammatory and exhibit a profibrotic phenotype in scarring skin disease.

Fibroblasts are stromal cells known to regulate local immune responses important for wound healing and scar formation; however, the cellular mechanisms driving damage and scarring in patients with cutaneous lupus erythematosus (CLE) remain poorly understood. Dermal fibroblasts in patients with systemic lupus erythematosus (SLE) experience increased cytokine signaling in vivo, but the effect of inflammatory mediators on fibroblast responses in nonscarring versus scarring CLE subtypes is unclear. Here, we examined responses to cytokines in dermal fibroblasts from nonlesional skin of 22 patients with SLE and CLE and 34 individuals acting as healthy controls. Notably, inflammatory cytokine responses were exaggerated in SLE fibroblasts compared with those from individuals acting as healthy controls. In lesional CLE biopsies, these same inflammatory profiles were reflected in single-cell RNA-Seq of SFRP2+ and inflammatory fibroblast subsets, and TGF-β was identified as a critical upstream regulator for inflammatory fibroblasts in scarring discoid lupus lesions. In vitro cytokine stimulation of nonlesional fibroblasts from patients who scar from CLE identified an upregulation of collagens, particularly in response to TGF-β, whereas inflammatory pathways were more prominent in nonscarring patients. Our study revealed that SLE fibroblasts are poised to hyperrespond to inflammation, with differential responses among patients with scarring versus nonscarring disease, providing a potential skin-specific target for mitigating damage.

Probing expression of E-selectin using CRISPR-Cas9-mediated tagging with HiBiT in human endothelial cells

E-selectin is expressed on endothelial cells in response to inflammatory cytokines and mediates leukocyte rolling and extravasation. However, studies have been hampered by lack of experimental approaches to monitor expression in real time in living cells. Here, NanoLuc Binary Technology (NanoBiT) in conjunction with CRISPR-Cas9 genome editing was used to tag endogenous E-selectin in human umbilical vein endothelial cells (HUVECs) with the 11 amino acid nanoluciferase fragment HiBiT. Addition of the membrane-impermeable complementary fragment LgBiT allowed detection of cell surface expression. This allowed the effect of inflammatory mediators on E-selectin expression to be monitored in real time in living endothelial cells. NanoBiT combined with CRISPR-Cas9 gene editing allows sensitive monitoring of real-time changes in cell surface expression of E-selectin and offers a powerful tool for future drug discovery efforts aimed at this important inflammatory protein.

In vitro Exposure to Inflammatory Mediators Affects the Differentiation of Mesenchymal Progenitors.

The increasing prevalence of joint disease, and in particular osteoarthritis (OA), calls for novel treatment strategies to prevent disease progression in addition to existing approaches focusing mainly on the relief of pain symptoms. The inherent properties of mesenchymal stem cells (MSCs) make them an attractive candidate for novel tissue repair strategies, as these progenitors have the potential to differentiate into chondrocytes needed to replace degraded cartilage and can exert a modulating effect on the inflammatory environment of the diseased joint. However, the inflammatory environment of the joint may affect the ability of these cells to functionally integrate into the host tissue and exert beneficial effects, as hinted by a lack of success seen in clinical trials. Identification of factors and cell signalling pathways that influence MSC function is therefore critical for ensuring their success in the clinic, and here the effects of inflammatory mediators on bone marrow-derived MSCs were evaluated. Human MSCs were cultured in the presence of inflammatory mediators typically associated with OA pathology (IL-1β, IL-8, IL-10). While exposure to these factors did not produce marked effects on MSC proliferation, changes were observed when the mediators were added under differentiating conditions. Results collected over 21 days showed that exposure to IL-1β significantly affected the differentiation response of these cells exposed to chondrogenic and osteogenic conditions, with gene expression analysis indicating changes in MAPK, Wnt and TLR signalling pathways, alongside an increased expression of pro-inflammatory cytokines and cartilage degrading enzymes. These results highlight the value of MSCs as a preclinical model to study OA and provide a basis to define the impact of factors driving OA pathology on the therapeutic potential of MSCs for novel OA treatments.

Modelling the dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after cardiac surgery.

Major surgery and critical illness produce a potentially life-threatening systemic inflammatory response. The hypothalamic–pituitary–adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterize the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulse and multiple-pulse dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost—suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

Suffrutines A and B Inhibit the Expression of Inflammatory Mediators in LPS-Induced RAW264.7 Cells by Suppressing the NF-κB Signaling Pathway.

Flueggea suffruticosa is a traditional Chinese medicine that has been commonly used for the treatment of inflammatory ailments, including rheumatism and lumbago. Suffrutines A and suffrutines B are a pair of novel E,E and Z,E isomeric indolizidine alkaloids isolated from the roots of F. suffruticosa. However, their anti-inflammatory activity has not been reported thus far. The aim of this study was to investigate the inhibitory effect of inflammatory mediators and possible mechanisms of suffrutines A and B in lipopolysaccharide-induced RAW264.7 cells. Results showed that suffrutines A and B could remarkably inhibit the production of nitric oxide, prostaglandin E2, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide-induced RAW264.7 cells. Further evaluation demonstrated that compared with suffrutines A, suffrutines B could more significantly inhibit the phosphorylation of IKKα/β, the degradation of IκBα, and the nuclear translocation of the p65 and p52 subunits in the canonical and non-canonical nuclear factor-κB pathways. Therefore, suffrutines B exhibited more potent inhibitory activity on inflammatory mediators than suffrutinesA.

Association of Human Parvovirus B19 with Papillary Thyroid Carcinoma and its Relationship with Tumor Staging and Pathologic Features

Background: Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer. In some studies, parvovirus B19 (PVB19) infection was involved in the pathogenesis of thyroid diseases such as Graves’ disease, Hashimoto thyroiditis, and thyroid cancer. PVB19 induces chronic inflammation in thyroid, which can lead to carcinogenesis through the effect of inflammatory mediators. The association of PVB19 with PTC tumorigenesis is still a matter of controversy. We evaluated the correlation of PVB19 with PTC and, for the first time, pathologic features. Method: This cross-sectional retrospective study focused on the thyroid specimens of 82 patients with PTC and 77 patients with benign thyroid nodules. We conducted the present study from March 2014 to November 2017 in the hospitals affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. We evaluated the presence of PVB19 DNA by nested polymerase chain reaction method in PTC, adjacent non-malignant tissues, and benign thyroid nodules. PVB19 positivity was also compared between PTC and two other groups. We further investigated the association of pathologic features and tumor staging with PVB19 positivity. Results: Of the patients, 81% were female. We detected PVB19 positivity in 9.8% of PTC specimens and 0.01 of adjacent non-malignant tissues (P=0.016). None of the benign thyroid nodule specimens had PVB19 DNA, and they were significantly different from PTC specimens (P=0.007). There was no significant correlation between PVB19 positivity and tumor stages (P=0.988) and histologic types (P=0.560). Conclusion: This research, similar to some other studies, showed a significant association between PTC and PVB19 positivity. For the first time, we showed that no significant relationship existed between PVB19 positivity and tumor stages and histologic types. Further investigations are needed to evaluate the relationship between this virus and PTC.

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics.

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

Differences in Neuregulin 4 Expression in Children: Effects of Fat Depots and Obese Status

ABSTRACT Purpose To observe the expression of Nrg4, uncoupling protein-1 (UCP1), tumor necrosis factor α (TNFα), CD31, VE-cadherin/CDH5 and vascular endothelial growth factor A (VEGF-A) mRNA in abdominal subcutaneous (SC), omental (OM) adipose tissue in children with relation to anthropometric parameters. Further to verify the effect of inflammatory mediators on Nrg4 and UCP1 mRNA expression in adipocytes. Methods Paired SC and OM adipose tissues were obtained from 58 children. In vitro, the adipocytes isolated from primary inguinal adipose tissue of mice were treated with TNFα (50 ng/ml) for 12–48 h. mRNA levels of Nrg4, UCP1 and TNFα were determined by real-time PCR. Results Nrg4, UCP1, VEGF-A and CDH5 mRNA levels in SC were significantly higher than those in OM adipose tissue and the mRNA level of TNFα showed the opposite result. Moreover, Nrg4 and UCP1 mRNA in SC were significantly lower in overweight children compared to normal weight children. Nrg4 in SC and OM was negatively associated with BMISDS, WHtR. CDH55 mRNA in OM was negatively associated with WHR. VEGF-A was positively correlated with Nrg4 in SC. In vitro, Nrg4 and UCP1 mRNA levels in adipocytes were dose- and time-dependently decreased under TNFα treatment. Conclusions Nrg4, UCP1, VEGF-A and CDH5 mRNA expression in adipose tissues display a depot-specific pattern. Nrg4 mRNA levels in adipose tissue are decreased with obesity and associated with WAT browning and angiogenesis. TNFα may be involved in the regulation of Nrg4 level in adipose tissue, which may be one of the causes of the down-regulation of Nrg4 expression in obesity with chronic inflammatory response.

Prostaglandin E2 Affects Interleukin 6 and Monocyte Chemoattractant Protein 1/CCL2 Production by Cultured Stem Cells of Apical Papilla

IntroductionRoot canal treatment of immature necrotic teeth is a major challenge in current endodontics. The effect of inflammatory mediators, such as prostaglandin, on the modulation of stem cells of the apical papilla (SCAP) is not completely understood. The aim of this study was to investigate the role of prostaglandin E2 (PGE2) on SCAP activation by Escherichia coli lipopolysaccharide (LPS) in vitro. MethodsSCAP cultures were established and characterized. Increasing concentrations of lipopolysaccharide (0.1–10 μg/mL) were used to investigate cyclooxygenase-2 (COX-2/PTGS2) and PGE2 receptors (EP1–4) gene expression. Then, SCAP were treated with a COX-2 inhibitor (indomethacin) before treatment with different concentrations of LPS. The levels of the chemokine CCL2/monocyte chemoattractant protein 1 and interleukin (IL)-6 were detected in cell supernatants (24 hours) by enzyme-linked immunosorbent assay. Data analysis was performed using analysis of variance followed by the Tukey post test. ResultsThe expression of COX-2 was up-regulated in the group treated with LPS at 1μg/mL compared with that in the control group. EP1–4 were detected in all experimental conditions at similar levels. SCAP treated with indomethacin presented a down-regulation in the production of LPS-induced CCL2 and the secretion of IL-6. ConclusionsSCAP showed increased COX-2 (PTGS2) gene expression induced by LPS and a PGE2-dependent production of IL-6 and CCL2.

Covid 19 and its cardiovascular effects.

COVID-19 pandemic is mainly related with the pulmonary problems initially but now as the pandemic is growing it is observed that almost all organ systems of the body are affected. Up to 20-30% patients who are admitted in Covid hospitals are showing cardiovascular involvement. Severity of cardiovascular disease in a COVID-19 patient depends whether a patient is having pre-existing cardiac disease or not. Patients with pre-existing cardiac disease have more severe infection and associated mortality. Severe COVID-19 infection shows close association with myocardial damage and various arrythmias. The cardiovascular involvement occurs by either engagement directly with the angiotensin converting enzyme 2 or indirectly by the effect of inflammatory mediators which are generated as a result of viral-host response to infection. The COVID-19 disease is said to produce a wide spectrum of affliction ranging between even asymptomatic patient to Cardiovascular syndrome. Even after recovering from COVID-19 patients can reappear in the hospital with cardiomyopathies and arrythmias.

The investigation of serum levels of ADAMTS 5 and 8 (the A disintegrin and metalloproteinase with thrombospondin motifs) in the etiology of endometrial cancer

The aim of this study was to investigate the serum levels of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 and 8 in patients diagnosed with endometrial cancer. Our study included 41 patients diagnosed with endometrial cancer. The control group consisted of 41 patients diagnosed with benign endometrial pathology. The serum samples were centrifuged and stored at –80 °C. The serum levels of ADAMTS were significantly higher (p<.001), whereas the levels of ADAMTS 8 were significantly lower in patients diagnosed with cancer (p<.001). In addition to the presence of known factors in the aetiology of endometrial cancer, the effect of inflammatory factors and some new proteins has centred on the causes of tumourigenesis in recent years. In this sense, these proteins, called the ADAMTS, are the source of new studies.Impact StatementWhat is already known on this subject? When the recent studies about endometrial cancer are evaluated, it is seen that the effects of chronic inflammation and cytokines have gained importance in its aetiology. The A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) gene family consist of 19 proteases that play essential role in the formation of the extracellular matrix (ECM) and interact with inflammatory cytokines. These proteases and their substrates provide a wide range of functions in different tissues, including ECM remodelling, angiogenesis, fibrosis and coagulation.What the results of this study add? ADAMTS 5, which causes the degradation of the ECM with Aggrecanase activity, was found to be significantly higher in patients diagnosed with cancer and ADAMTS 8 with anti-angiogenesis activity was significantly lower in patients diagnosed with endometrial cancer.What the implications are of these findings for clinical practice and/or further research? In this study, it is understood that the effect of inflammatory mediators is remarkably important in the aetiology of endometrial cancer, as in many types of organ specific cancer.

Building sensory axons: Delivery and distribution of NaV1.7 channels and effects of inflammatory mediators.

Sodium channel NaV1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about NaV1.7 trafficking or membrane distribution along sensory axons, which can be a meter or more in length. We show here with single-molecule resolution the first live visualization of NaV1.7 channels in dorsal root ganglia neurons, including long-distance microtubule-dependent vesicular transport in Rab6A-containing vesicles. We demonstrate nanoclusters that contain a median of 12.5 channels at the plasma membrane on axon termini. We also demonstrate that inflammatory mediators trigger an increase in the number of NaV1.7-carrying vesicles per axon, a threefold increase in the median number of NaV1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of NaV1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of NaV1.7 to inflammatory pain.

Electrophysiological and Pharmacological Analyses of Nav1.9 Voltage-Gated Sodium Channel by Establishing a Heterologous Expression System.

Nav1. 9 voltage-gated sodium channel is preferentially expressed in peripheral nociceptive neurons. Recent progresses have proved its role in pain sensation, but our understanding of Nav1.9, in general, has lagged behind because of limitations in heterologous expression in mammal cells. In this work, functional expression of human Nav1.9 (hNav1.9) was achieved by fusing GFP to the C-terminal of hNav1.9 in ND7/23 cells, which has been proved to be a reliable method to the electrophysiological and pharmacological studies of hNav1.9. By using the hNav1.9 expression system, we investigated the electrophysiological properties of four mutations of hNav1.9 (K419N, A582T, A842P, and F1689L), whose electrophysiological functions have not been determined yet. The four mutations significantly caused positive shift of the steady-state fast inactivation and therefore increased hNav1.9 activity, consistent with the phenotype of painful peripheral neuropathy. Meanwhile, the effects of inflammatory mediators on hNav1.9 were also investigated. Impressively, histamine was found for the first time to enhance hNav1.9 activity, indicating its vital role in hNav1.9 modulating inflammatory pain. Taken together, our research provided a useful platform for hNav1.9 studies and new insight into mechanism of hNav1.9 linking to pain.

Effect of inflammatory mediators on cardiovascular function.

Inflammatory mediators can interfere with cardiovascular system. This article describes some recent findings in this field. In septic cardiomyopathy, direct and indirect interactions of endotoxin with the pacemaker current contribute to cardiac autonomic dysfunction and inadequately high heart rate, worsening prognosis. In myocardial infarction, inflammatory blood cells correlate with impaired coronary microvascular reperfusion. In cardiogenic shock, systemic inflammation and development of multiorgan dysfunction syndrome have a major impact on mortality. Shock patients have low levels of activated protein C and high levels of the endogenous danger signal molecule peroxiredoxin 1; both conditions might represent further therapeutic targets. As major cause of cytopathic hypoxia, mitochondrial dysfunction has also been identified in mitochondria from peripheral blood mononuclear cells in paediatric septic shock. Transcatheter aortic valve endocarditis, a new endocarditis entity after transcatheter aortic valve implantation in old and very old patients, needs our special attention, because immunosenescence may modify the clinical course in a negative sense. Systemic spreading of endocarditis to septic shock adds to the local valve infection the problem of septic shock. Not only in septic shock, but also in classic heart diseases like cardiogenic shock and endocarditis, the detrimental role of inflammatory mediators becomes more and more evident, whereas effective anti-inflammatory treatment concepts are still missing.

Novel Delivery Systems for Anti-Allergic Agents: Allergic Disease and Innovative Treatments

Anti-allergic agents are used to treat a great variety of diseases which usually involve an inflammation reaction. These compounds act by inhibiting the release and the effects of inflammatory mediators (e.g. histamine) in the target tissue. The purpose of anti-allergy therapy is to deliver the drug to its local of action in a therapeutic concentration, minimizing the undesired side effects. In order to solve some of the anti-allergic agents' physicochemical drawbacks and the limitations associated to conventional pharmaceutical formulations (e.g. poor solubility and absorption, skin permeation, stability), novel drug delivery systems, such as cyclodextrins, liposomes, micelles, microemulsions, nano and microparticles, have been developed. Depending on the allergic condition, several administration routes are used to deliver anti-allergic agents, each with its own disadvantages to overcome. In the literature, there are a vast number of papers concerning novel delivery systems for anti-allergic agents, making it difficult to evaluate the information and the promising outcomes. The aim of the present review article is to compile the recent (i.e. in the new millennium) improvements of novel drug delivery technology focusing on the achievement of anti-allergic therapeutic delivery. The potential intrinsic benefits of these systems will reflect an increased therapeutic adherence and better patients' life quality. A critical prospect of future clinical trial directions will also be discussed.

Matrix metalloproteinase 9 polymorphisms and systemic lupus erythematosus: correlation with systemic inflammatory markers and oxidative stress.

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs and is characterized by persistent systemic inflammation. Among the effects of inflammatory mediators, the induction of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) and oxidative stress has been demonstrated to be important in the development of SLE. In this study, the possible association between MMP-9 and MMP-2 functional promoter polymorphism, stress, and inflammatory markers with development of severe cardiovascular disease (CVD), high blood pressure (HBP), and lupus nephropathy (LN) in SLE patients was investigated. The present case-control study consisted of 109 SLE patients with and without CVD, HBP and LN and 101 gender- and age-matched unrelated healthy controls from a population in western Iran. MMP-2 -G1575A and MMP-9 -C1562T polymorphisms were detected by PCR-RFLP, serum MMP-2 and MMP-9, neopterin, malondialdehyde (MDA) and lipid levels were determined by ELISA, HPLC and enzyme assay, respectively. We found that MMP-9 -C1562 T and MMP-2 -G1575A alleles act synergistically to increase the risk of SLE by 2.98 times (p = 0.015). Findings of this study also demonstrated that there is a significant increase in the serum levels of MMP-2, neopterin and MDA and a significant decrease in serum level of MMP-9 in the presence of MMP-9-C1562 T and MMP-2 -G1575A alleles in SLE patients compared to controls. Further, SLE patients with MMP-9 (C/T + T/T) genotype had significantly higher serum concentrations of MMP-2, neopterin, MDA and LDL-C, but lower serum MMP-9 and HDL-C levels than corresponding members of the control group. MMP-9 (C/T + T/T) genotype increased risk of hypertension in SLE patients 2.71-fold. This study for the first time not only suggests that MMP-9 -C1562 T and MMP-2 -G1575A alleles synergistically increase the risk of SLE but also high serum levels of MDA, neopterin, and circulatory levels of MMP-2 and lower MMP-9 in SLE patients. This information may be important in the evaluation of SLE progression and in the elucidation of the mechanisms of the disease pathogenesis.

Does a biological link exist between periodontitis and rheumatoid arthritis?

Periodontitis or Periodontal disease (PD) and Rheumatoid arthritis (RA) are two the most common chronic inflammatory diseases. Periodontitis is a biofilm associ ated destructive inflammatory dise ase of the periodontium caused by specific microorganisms. Rheumatoid arthritis is an autoimmune condition and is identified by elevated serum autoantibody titre directed against citrullinated peptides or rheumatoid factor. Periodontitis may involve some elements of autoimmunity. Recent studies have established that PD and RA show a common pathway and could be closely associated through a common dysregulation and dysfunction in inflamma tory mechanism. The enzyme peptidyl arginine deiminase (PAD), expressed by Porphyromonas gingivalis (P. gingivalis ) is responsible for the enzymatic deimination of arginine residuals to citrulline resulting in protein citrullination and its increased accumulation in RA. Citrullination by PAD may act as a putative biologic link between PD and RA. Association of Human leukocytic antigen-DR4 antigen has been established both with RA and PD. Several interleukins and inflammatory me diators (ILs) and Nuclear factor kappa beta ligand are linked to these common chronic inflammatory diseases. Antibodies directed against heat shock protein (hsp 70 ab) of P. gingivalis , P. melanogenicus and P. intermedia are raised in PD as well as RA. Both the conditions share many pathological and immunological similarities. Bacterial infection, genetic susceptibility, altered immune reaction and inflammatory mediators considered responsible for RA are also associated with PD. So it is plausible that a biological link may exist between PD and RA. Therapies aimed at modifying the expression and effect of inflammatory mediators and effector mol ecules such as matrix metalloproteinases, proinflamma tory cytokines and autoantibodies of structural proteins may probably reduce the severity of both RA and PD.

Effect of low-dose hydrocortisone on gene expression profiles after severe burn injury

The systemic effect of inflammatory mediators released after severe burn is a severe cardiovascular dysfunction called burn shock. Patients need vasopressor infusion to maintain adequate delivery of oxygen but it could have deleterious effects on skin perfusion and worsen the burn depth. This shock could result from the interplay of the initial hypovolemia and the release of multiple inflammatory mediators [1]. It has been shown that a low-dose of hydrocortisone could reduce the shock duration but the mechanisms involved remain unclear. We investigated the systemic genomic response after severe burn injuries and determine whether patterns of gene expression could be associated with a low dose of glucocorticoids.

Mo1940 The Differential Effect of Inflammatory Mediators on Neoplastic and Non-Neoplastic Barrett's Esophagus

Mo1940 The Differential Effect of Inflammatory Mediators on Neoplastic and Non-Neoplastic Barrett's Esophagus

Substance P Stimulates Production of Inflammatory Cytokines in Human Disc Cells

Study design Laboratory study. Objective The aims of this study were as follows: (1) to confirm that Substance P (SP) is expressed by nucleus pulposus (NP) and annulus fibrosus (AF) cells; (2) to determine the effect of SP on expression of inflammatory mediators in human disc cells and the effect of inflammatory mediators on the expression of SP; and (3) to characterize the relative expression of SP receptor isoforms in disc tissue and describe whether exposure to SP changes receptor expression. Summary of background data SP, classically described as a neurotransmitter, acts as an inflammatory regulator in other tissue types, but its role within the intervertebral disc has not been characterized. Methods Human AF and NP cells from 7 individuals were expanded in monolayer and maintained in alginate bead culture. Cells were treated with SP or interleukin (IL)-1β/tumor necrosis factor-α (TNF-α). After treatment, the cells were recovered and then RNA was isolated and transcribed into cDNA. Quantitative reverse-transcriptase polymerase chain reaction was performed to evaluate expression of inflammatory mediators and SP and its receptors. Results Disc cells treated with SP demonstrated significant upregulation of IL-1β, IL-6, and IL-8 in NP and AF cells whereas significant upregulation of RANTES and TNF occurred only in the AF cells. AF and NP cells expressed SP at low levels; expression did not change significantly with SP treatment but was significantly upregulated after treatment with IL-1β/TNF-α. Both SP receptor isoforms were expressed by NP and AF cells. Conclusion SP upregulates inflammatory mediators in disc cells. SP and its receptors were expressed in both NP and AF cells, and expression did not change after treatment with SP but increased after treatment with IL-1β/TNF-α. SP likely acts in an autocrine or paracrine manner in intervertebral disc cells and may be involved in crosstalk between disc cells and neurons, providing a potential mechanism for transmission of painful discogenic stimuli.