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Biomedical subjects

R Bucala

Publications and source records attributed to R Bucala.

At least 19 recordsLinked to original sources
PubMed2006

Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes.

AIMS/HYPOTHESIS: Activation of the receptor for advanced glycation end products (RAGE, also known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs and the severity of nephropathy in type 2 diabetic patients. MATERIALS AND METHODS: We recruited 150 healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-RNase. RESULTS: Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1-1,423.0] interquartile range vs 1,002.6 [726.5-1,345.3], p<0.05) and AGEs (4.07+/-1.13, SD, unit/ml vs 3.39+/-1.05, p<0.01) than controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between the severity of nephropathy and sRAGE (p=0.01). In diabetic subjects, serum log(sRAGE) correlated with AGEs (r=0.27, p<0.001), log(plasma creatinine) (r=0.31, p<0.001), log(urine AER) (r=0.24, p<0.01) and log(triglycerides) (r=0.15, p<0.01). On stepwise linear regression analysis, AGEs and creatinine levels were the main independent determinants of sRAGE concentration. CONCLUSIONS/INTERPRETATION: Serum sRAGE levels and circulating AGEs are associated with the severity of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether endogenous sRAGE potentially influences the development of diabetic vascular complications.

Blood Glucose↗
PubMed2006

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.

Neoplastic cells transport large amounts of glucose in order to produce anabolic precursors and energy within the inhospitable environment of a tumor. The ras signaling pathway is activated in several cancers and has been found to stimulate glycolytic flux to lactate. Glycolysis is regulated by ras via the activity of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFK2/FBPase), which modulate the intracellular concentration of the allosteric glycolytic activator, fructose-2,6-bisphosphate (F2,6BP). We report herein that sequential immortalization and ras-transformation of mouse fibroblasts or human bronchial epithelial cells paradoxically decreases the intracellular concentration of F2,6BP. This marked reduction in the intracellular concentration of F2,6BP sensitizes transformed cells to the antimetabolic effects of PFK2/FBPase inhibition. Moreover, despite co-expression of all four mRNA species (PFKFB1-4), heterozygotic genomic deletion of the inducible PFKFB3 gene in ras-transformed mouse lung fibroblasts suppresses F2,6BP production, glycolytic flux to lactate, and growth as soft agar colonies or tumors in athymic mice. These data indicate that the PFKFB3 protein product may serve as an essential downstream metabolic mediator of oncogenic ras, and we propose that pharmacologic inhibition of this enzyme should selectively suppress the high rate of glycolysis and growth by cancer cells.

Animals↗
PubMed2005

Role for macrophage migration inhibitory factor in asthma.

Macrophage migration inhibitory factor (MIF) is an immunologic regulator that is expressed in inflammatory and autoimmune disorders. We investigated MIF's role in asthma using genetic approaches in a mouse model and in a cohort of asthma patients. Mice genetically deficient in MIF that were primed and aerosol-challenged with ovalbumin showed less pulmonary inflammation and lower airway hyperresponsiveness than genetically matched, wild-type controls. MIF deficiency also resulted in lower titers of specific IgE, IgG(1), and IgG(2a), and decreased pulmonary, T(H)2 cytokine levels. IL-5 concentrations were lower and corresponded to decreased eosinophil numbers in bronchoalveolar lavage fluid. T cell studies also showed a lower level of antigen-specific responses in MIF-KO versus wild-type mice. In an analysis of 151 white patients with mild, moderate, or severe asthma (Global Initiative for Asthma criteria), a significant association was found between mild asthma and the low-expression, 5-CATT MIF allele. Pharmacologic inhibition of MIF may be beneficial and could be guided by the MIF genotype of affected individuals.

Adult↗
PubMed2003

The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting.

Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.

Alleles↗
PubMed2003

Macrophage migration inhibitory factor expression is increased in pituitary adenoma cell nuclei.

Macrophage migration inhibitory factor (MIF) is an essential regulator of the macrophage responses to endotoxin. MIF also has the ability to override the anti-inflammatory actions of glucocorticoids during an immune response, and is thus an important pro-inflammatory factor. The presence of MIF in cells of the anterior pituitary has been described, and high levels of MIF in other rapidly proliferating tIssues have also been demonstrated. It has been hypothesised that MIF release from these cells is influenced by the hypothalamo-pituitary-adrenal axis, and that ACTH and MIF are released simultaneously to exert counter-regulatory effects on cortisol. However, another intracellular role for MIF has also been suggested as it has been shown that MIF exerts an effect on the inhibitory cell cycle control protein p27 through an interaction with Jab1, a protein implicated in p27 degradation. We studied MIF expression in different normal and adenomatous human pituitary samples using immunohistochemistry and RT-PCR. There was evidence of co-immunoprecipitation of MIF with Jab1, suggesting an interaction of the two proteins. Our results showed that there is increased expression of MIF protein in the nuclei of all pituitary adenomas compared with normal tIssue (P=0.0067), but there was no statistically significant difference in nuclear MIF expression between the different adenoma types. Nuclear MIF expression correlated positively with p27 and its phosphorylated form in normal tIssue (P=0.0028 and P<0.0001); however, this relationship was not seen in the adenoma samples. Cytoplasmic expression of MIF was found to be variable both in normal and adenomatous samples, with no consistent pattern. MIF mRNA was demonstrated to be present in all tumour and normal samples studied. Somatotroph tumours showed higher MIF mRNA expression compared with normal pituitary or other types of adenomas. In conclusion, MIF is expressed in cell nuclei in pituitary adenomas to a greater extent than in normal pituitary tIssue. We speculate that it may play a role in the control of the cell cycle, but whether its higher level in adenomas is a cause or a consequence of the tumorigenic process remains to be clarified.

Adenoma↗
PubMed2002

A role for peripheral blood fibrocytes in Lyme disease?

It is proposed that peripheral blood fibrocytes will be a new and important player in the pathogenesis of Lyme disease. Peripheral blood fibrocytes are a circulating leukocyte subpopulation that: (a) express collagen; (b) are an abundant source of cytokines, chemoattractants and growth factors; and (c) are able to recruit and activate naive T-cells and memory T-cells. We predict that peripheral blood fibrocytes will represent a new and important antigen-presenting cell which will play an important role in directing the immune response from the pathogenic Th1 to the protective Th2 response cell in Borrelia infections.

Borrelia burgdorferi↗
PubMed2002

Macrophage migratory inhibitory factor (MIF) expression in acute graft-versus-host disease (GVHD) in allogeneic hemopoietic stem cell transplant recipients.

Graft-versus-host disease (GVHD) is a major complication after hemopoietic stem cell transplantation (HSCT), but its pathogenesis remains uncertain. Macrophage migratory inhibitory factor (MIF) is an important mediator in the allo-immune reaction during renal transplantation, yet its role in hemopoietic stem cell transplantation (HSCT) remains unexplored. This study investigated the potential role of MIF in acute graft-versus-host disease (aGVHD) following allogeneic HSCT. Forty-six randomly selected patients undergoing autologous or allogeneic HSCT were studied. Immunohistochemistry and in situ hybridization were performed to examine tissue MIF mRNA and protein expression on skin and colonic biopsy specimens. The associated T cell and macrophage activation was also studied by immunohistochemical studies. A semi-quantitative method was used to assess MIF staining, as well as T cell and macrophage staining. Serial blood samples were analyzed by ELISA for serum MIF levels. Immunohistochemistry and in situ hybridization performed in 15 skin and 19 colonic biopsies from 17 patients who developed moderate to severe aGVHD showed a significant increase in MIF mRNA and protein expression compared with normal controls (seven skin and five colonic biopsies). MIF was localized within the epidermis and the vascular area of skin, but diffusely expressed in the entire thickness of colon. Macrophage and T lymphocyte infiltration was confined to areas of strong MIF expression. Serial analysis by ELISA showed that only patients who developed aGVHD (n = 19) exhibited an increase (two- to three-fold) in serum MIF during HSCT, but not in the allogeneic HSCT recipients without aGVHD (n = 7) or those who received autologous HSCT (n = 8). In 14 out of 19 patients, serum MIF peaked before the onset of aGVHD. Local and systemic up-regulation of MIF expression is associated with the occurrence of acute GVHD. Its pathogenetic role remains to be further determined.

Acute Disease↗
PubMed2002

A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis.

The macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and regulates the anti-inflammator effects of glucocorticoids. An important role for MIF within the cytokine cascade is to act in concert with endogenous glucocorticoids to control the set-point and magnitude of the inflammatory response. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis. MIF also has been linked to the development of joint damage and disease pathology in experimental animal models. We describe herein a novel CATT-tetranucleotide repeat polymorphism at position -794 of the human Mif gene and show that it functionally affects the activity of the MIF promoter in gene reporter assays. We describe four genotypes which comprise 5, 6, 7, or 8-CATT repeat units and show that the 5-CATT allele has the lowest level of basal and stimulated MIF promoter activity in vitro. The presence of the low expressing, 5-CATT repeat allele correlated with low disease severity in a cohort of rheumatoid arthritis patients.

Arthritis, Rheumatoid↗
PubMed2002

Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations.

OBJECTIVE: Cytokines play an important role in the pathology of rheumatoid arthritis (RA). Macrophage migration inhibitory factor (MIF) is a cytokine with a broad spectrum of actions, including induction of monocyte tumour necrosis factor alpha (TNF-alpha). Evidence of the expression and proinflammatory activity of MIF has recently been demonstrated in RA synovium and in animal models of RA. We wished to assess the relationship between MIF expression in synovium and clinical disease. METHODS: Computer-assisted analysis of the cytokine content of arthroscopically obtained biopsies of RA synovium, using paired samples from eight patients with active and inactive/treated disease, was compared with documented clinical parameters. RESULTS: Synovial MIF immunostaining correlated strongly with disease activity as measured by CRP concentration. Reductions in clinical disease parameters, including CRP, tender and swollen joint counts, were accompanied by significant reductions in synovial MIF. Synovial TNF-alpha, transforming growth factor beta (TGF-beta) and interleukin (IL) 10 also showed a significant reduction in association with reduced disease activity, while IL-1 beta and IL-1 receptor agonist did not. CONCLUSION: The correlation of synovial MIF with disease activity corroborates existing evidence of the role of this cytokine in RA. The demonstration that only MIF and TNF-alpha show significant variation in synovial cytokine content with clinical remission suggests that MIF is an important member of the cytokine hierarchy in RA.

Aged↗
PubMed2002

Response of serum macrophage migration inhibitory factor levels to stimulation or suppression of the hypothalamo-pituitary-adrenal axis in normal subjects and patients with Cushing's disease.

Macrophage migration inhibitory factor (MIF) is a proinflammatory pituitary and immune cell cytokine and a critical mediator of septic shock. It has been reported that MIF is secreted in parallel with ACTH from the pituitary in response to stress or inflammatory stimuli. MIF release from immune cells is also induced rather than inhibited by glucocorticoids. It has therefore been suggested that MIF may be a novel counterregulatory hormone of glucocorticoid action that acts both as a paracrine and endocrine modulator of host responses. We have measured circulating MIF levels, using a human MIF ELISA, in normal subjects and patients under numerous pathophysiological conditions. Serum MIF was measured in normal subjects who underwent stimulation of the hypothalamo-pituitary-adrenal axis with an insulin tolerance test (n = 8), a CRH-stimulation test (n = 5), a short synacthen test (n = 5), and following a low-dose dexamethasone suppression test (n = 6). We also sampled from a peripheral vein and both inferior petrosal sinuses before and after CRH stimulation in four patients with a histologically proven diagnosis of Cushing's disease. Immunostaining of the pituitary tumors for MIF was also performed. In normal subjects serum MIF levels did not rise in parallel with cortisol during the insulin tolerance or CRH test or after administration of synthetic ACTH. In all subjects cortisol levels became undetectable after the low-dose dexamethasone suppression test, and no consistent change was observed in serum MIF levels during the test. In patients with Cushing's disease, there was no basal central-to-peripheral gradient in MIF, and no consistent changes occurred in serum MIF levels in either the left or right inferior petrosal sinus after CRH stimulation; however, immunostaining of the surgically removed pituitary tumors from the same patients showed strong staining for both ACTH and MIF. These results show that in humans acute modulation of the hypothalamo-pituitary-adrenal axis does not significantly alter circulating MIF levels. In addition, ACTH-secreting pituitary tumors that express MIF do not release MIF either spontaneously or in response to CRH stimulation, and there is no gradient for MIF in the venous drainage of the pituitary. Our study suggests that the pituitary gland is not the major contributor to circulating MIF; an autocrine or paracrine role for pituitary-derived MIF is more likely.

Adrenocorticotropic Hormone↗
PubMed2001

Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. AIMS: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). METHODS: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. RESULTS: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group. CONCLUSIONS: These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.

Adult↗
PubMed2001

Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.

Fibrocytes are a distinct population of blood-borne cells that display a unique cell surface phenotype (collagen I+/CD11b+/CD13+/CD34+/CD45RO+/MHC class II+/CD86+) and exhibit potent immunostimulatory activities. Circulating fibrocytes rapidly enter sites of tissue injury, suggesting an important role for these cells in wound repair. However, the regulatory processes that govern the differentiation of blood-borne fibrocytes and the mechanisms that underlie the migration of these cells to wound sites are currently not known. We report herein that ex vivo cultured fibrocytes can differentiate from a CD14+-enriched mononuclear cell population and that this process requires contact with T cells. Furthermore, we demonstrate that TGF-beta1 (1-10 ng/ml), an important fibrogenic and growth-regulating cytokine involved in wound healing, increases the differentiation and functional activity of cultured fibrocytes. Because fibrocytes home to sites of tissue injury, we examined the role of chemokine/chemokine receptor interactions in fibrocyte trafficking. We show that secondary lymphoid chemokine, a ligand of the CCR7 chemokine receptor, acts as a potent stimulus for fibrocyte chemotaxis in vitro and for the homing of injected fibrocytes to sites of cutaneous tissue injury in vivo. Finally, we demonstrate that differentiated, cultured fibrocytes express alpha smooth muscle actin and contract collagen gels in vitro, two characteristic features of wound-healing myofibroblasts. These data provide important insight into the control of fibrocyte differentiation and trafficking during tissue repair and significantly expand their potential role during wound healing.

Animals↗
PubMed2001

Regulation of the CTL response by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) has been shown to be a pivotal cytokine that mediates host inflammatory and immune responses. Recently, immunoneutralization of MIF has been found to inhibit tumor growth in mice; however, the contributing mechanisms underlying this effect have not been well defined. We investigated whether MIF plays a regulatory role in the expression of CTL activity. In a mouse model of the CTL response using the OVA-transfected tumor cell line EL4 (EG.7), we found that cultures of splenocytes obtained from EG.7-primed mice secrete high levels of MIF following Ag stimulation in vitro. Notably, parallel splenocyte cultures treated with neutralizing anti-MIF mAb showed a significant increase in the CTL response directed against EG.7 cells compared with control mAb-treated cultures. This effect was accompanied by elevated expression of IFN-gamma. Histological examination of the EG. 7 tumors from anti-MIF-treated animals showed a prominent increase in both CD4(+) and CD8(+) T cells as well as apoptotic tumor cells, consistent with the observed augmentation of CTL activity in vivo by anti-MIF. This increased CTL activity was associated with enhanced expression of the common gamma(c)-chain of the IL-2R that mediates CD8(+) T cell survival. Finally, CD8(+) T lymphocytes obtained from the spleens of anti-MIF-treated EG.7 tumor-bearing mice, when transferred into recipient tumor-bearing mice, showed increased accumulation in the tumor tissue. These data provide the first evidence of an important role for MIF in the regulation and trafficking of anti-tumor T lymphocytes in vivo.

Adjuvants, Immunologic↗
PubMed2001

Identification and characterization of a homologue of the pro-inflammatory cytokine Macrophage Migration Inhibitory Factor in the tick, Amblyomma americanum.

Studying tick feeding and digestion, we discovered in a cDNA library from partially fed Amblyomma americanum ticks the first known arthropod homologue of a human cytokine, the pro-inflammatory Macrophage Migration Inhibitory Factor (MIF). The tick origin of the MIF cDNA clone was confirmed by sequencing a genomic fragment that contained the full-length tick MIF gene with two introns. Antiserum to a tick MIF-specific peptide as well as antiserum to complete tick MIF revealed the expression of tick MIF in the salivary gland and midgut tissues of A. americanum ticks. In an in vitro functional assay, recombinant tick MIF inhibited the migration of human macrophages to the same extent that recombinant human MIF did.

Amino Acid Sequence↗
PubMed2001

Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids.

(MIF) is a broad-spectrum proinflammatory cytokine implicated in human rheumatoid arthritis. The synthesis of MIF by synovial cells is stimulated by glucocorticoids, and previous studies suggest that MIF antagonizes the anti-inflammatory effects of glucocorticoids. This has not been established in a model of arthritis. We wished to test the hypothesis that MIF can act to reverse the anti-inflammatory effects of glucocorticoids in murine antigen-induced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by intradermal injection and intra-articular injection, respectively, of methylated bovine serum albumin in presensitized mice. Animals were treated with anti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity. Cutaneous DTH to the disease-initiating antigen was significantly inhibited by anti-MIF MoAb treatment (P < 0.001). AIA was also significantly inhibited by anti-MIF MoAb (P < 0.02). DEX treatment induced a dose-dependent inhibition of AIA, which was significant at 0.2 mg/kg (P < 0.05). MIF treatment reversed the effect of therapeutic DEX on AIA (P < 0.001). DEX also significantly inhibited DTH reactions (P < 0.05) but rMIF had no effect on this effect of DEX. DTH and AIA are MIF-dependent models of inflammation and arthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of synovial inflammation. Although DTH was observed to be MIF-dependent and glucocorticoid-sensitive, rMIF had no reversing effect on the suppression of DTH by glucocorticoids. This suggests that inflammatory processes in specific tissues may respond differently to MIF in the presence of glucocorticoids.

Animals↗
PubMed2001

Neuroendocrine properties of macrophage migration inhibitory factor (MIF).

The cytokine macrophage migration inhibitory factor (MIF) is produced by neuroendocrine and immune tissues and possesses several features that allow it to be characterized as a neuroendocrine mediator. Its pro-inflammatory action and its pathogenic role in inflammatory diseases, such as septic shock, arthritis and other diseases, have clearly been demonstrated and may be based in part on neuroendocrine mechanisms. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits. This review summarizes the current state of MIF research and focuses on MIF expression and function in nervous and endocrine tissues.

Animals↗
PubMed2001

Macrophage migration inhibitory factor is an important mediator in the pathogenesis of gastric inflammation in rats.

BACKGROUND & AIMS: Macrophage migration inhibitory factor (MIF) has been shown to play a pivotal role in inflammatory and immune-mediated diseases. This study investigates the role of MIF in gastric inflammation. METHODS: Expression of MIF was examined in a rat gastric ulcer model induced by acetic acid, and the functional role of MIF in acute gastric ulcer was investigated by administration of a neutralizing anti-MIF antibody. RESULTS: MIF messenger RNA and protein were markedly up-regulated in acute gastric ulcer, which correlated with the accumulation of macrophages (P < 0.001) and neutrophils (P < 0.05) at the site of inflammation. Macrophages, like neutrophils, were the major inflammatory cells infiltrating the ulcer base and they strongly expressed inducible nitric oxide synthase. However, macrophages, not neutrophils, were a rich source of MIF production in acute gastric ulcer. In vivo and in vitro blockade of MIF with the neutralizing anti-MIF antibody significantly inhibited the marked up-regulation of MIF, tumor necrosis factor alpha, inducible nitric oxide synthase, and intercellular adhesion molecule-1. This was associated with the marked inhibition of macrophage (70% reduced) and neutrophil (60% reduced) accumulation and activation, thus reducing ulcer sizes and attenuating ulceration. CONCLUSIONS: This study has shown that MIF was markedly up-regulated during acute gastric ulcer. Inhibition of acute gastric ulcer by blockade of MIF indicates that MIF is a key inflammatory mediator and plays a pathogenic role in gastric inflammation.

Acetic Acid↗