Symptoms were assessed by the validated EoE symptom activity index (EEsAI) and the esophageal hypervigilance and anxiety scale (EHAS-7) pre- and post-baked milk introduction. 4 of these patients then ...underwent straight milk introduction, starting with 1 glass (8 oz) of milk per week for 4 weeks, followed by 3 glasses of milk per week for 4 weeks, with symptomatic and histologic assessment after completing each amount as described above. All patients remained in deep histologic and symptomatic remission after regular baked milk and small volume straight milk intake with numerical improvement in quality of life and no deleterious effect on symptoms at 4-6 weeks time. Baseline and median change in eosinophil count and patient questionnaire scores after introduction of baked and straight milk Baseline (Q1, Q3) Change after 6 weeks baked milk (Q1, Q3) P value* Change after 1 glass milk per week (Q1, Q3) P value* Change after 3 glasses milk per week (Q1, Q3) P value* Eosinophils 0.0 (0.0, 0.0) 0.0 (0.0, 1.0) 0.5000 0.5 (0.0, 3.5) 0.500 2.0 (0.0, 3.0) 0.500 EEsAI Score 6.0 (0.0, 12.0) 0.0 (0.0, 0.0) 1.0 0.0 (-6.0, 0.0) 1.0 0.0 (0.0, 0.0) 1.0 EoE-QOL-A Score 99.0 (90.0, 100.0) 3.0 (-3.0, 6.0) 0.4688 5.0 (-7.0, 10.5) 0.8750 6.0 (4.0, 13.0) 0.1250 EHAS-7 Score 10.5 (8.0, 13.0) 0.0 (-2.0, 1.0) 0.7500 * Changes from baseline were assessed for significance, with P values calculated using the Wilcoxon signed rank test (a non-parametric test).
Mast cells leave evidence, a "fingerprint," of their participation in acute and chronic clinical events. That fingerprint is an elevation, either chronic or acute, in levels of their secreted ...mediators or their metabolites. Of these, only serum tryptase is currently one of the diagnostic criteria for systemic mastocytosis or mast cell activation. Combinations of easily obtained and quantified urinary mast cell mediator metabolite levels correlate well with bone marrow findings of systemic mastocytosis. By inhibiting synthesis of or blockading receptors to the elevated mast cell mediator, relief of clinical symptoms can often be achieved.
Matrix metalloproteinases (MMPs) are a family of Zn2+‐dependent extracellular matrix (ECM) degrading endopeptidases that share common functional domains, activation mechanisms, and collectively have ...the capacity to degrade all types of ECM proteins. In addition to playing a central role in ECM turnover, MMPs proteolytically activate or degrade a variety of nonmatrix substrates including chemokines, cytokines, growth factors, and junctional proteins. Thus, they are increasingly recognized as critical players in inflammatory response. Indeed, accumulating data from several studies indicate that they are the predominant proteases involved in the pathogenesis of inflammatory bowel disease (IBD) via their influence on the function and migration of inflammatory cells, mucosal ulceration, as well as matrix deposition and degradation. Some MMPs are constitutively expressed and play a protective role in IBD through their effect on cellular homeostasis, while others are induced during inflammation‐mediated tissue damage. This article focuses on the role of the various MMPs in IBD, discussing their physiologic and pathogenetic role in the context of intestinal defense, mucosal inflammatory response, and immune cell‐epithelial interaction.
(Inflamm Bowel Dis 2007;13:97–107)
Mast cell activation syndrome (MCAS) describes patients with episodes of mast cell mediator release, with negative bone marrow biopsy results, and the failure to meet the criteria for systemic ...mastocytosis.
Identify elevation of mast cell mediators of patients with MCAS.
We performed a retrospective study of 25 patients with MCAS who were evaluated at Mayo Clinic from 2006 to 2012. Patients were reviewed for MCAS symptoms and mast cell mediators, including serum tryptase and 24-hour urine N-methyl histamine (N-MH) and 11β-prostaglandin-F₂α (11β-PGF₂α). The study was approved by the institutional review board.
Urinary 11β-PGF₂α was the most frequently elevated product in MCAS of our 25-patient cohort. Flushing and pruritus had the greatest correlation with elevation of 24-hour urine 11β-PGF₂α value at baseline. The serum tryptase level was elevated in 10 patients, whereas the N-MH level was elevated with 2 patients. Eight of 9 patients with MCAS and with elevated 24-hour urine 11β-PGF₂α who underwent aspirin therapy and follow-up urinary studies had normalization of this mediator (1 patient did not have a follow-up urine study). Six of these 9 patients with MCAS who underwent aspirin therapy had symptomatic improvement.
We recommend measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels of patients with symptoms suggestive of MCAS. Measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice. Given that an elevation of 24-hour urine N-MH level was found only in 2 patients, measurement of this mediator may be less helpful in diagnosing MCAS. We recommend aspirin therapy for patients with MCAS and with elevated 24-hour urine 11β-PGF₂α levels.
Patients with eosinophilic esophagitis (EoE) have a unique esophageal microbiome with increased presence of Haemophilus influenzae, but its role in the disease is unclear.
Microbiome-derived ...bacterial LPS activation of Toll-like receptors (TLR) is a potential mechanism for inducing inflammation in other chronic inflammatory diseases, but it has not been studied in EoE. Our aim was therefore to study microbiome-derived bacterial LPS activation of TLRs in EoE.
We studied 10 patients with active EoE, 9 patients with inactive EoE, and 10 control patients. Esophageal biopsy samples from the controls, patients with active EoE (>15 eosinophils/hpf), and patients with inactive EoE were immunostained for the presence of H influenzae LPS, presence of TLR4, and colocalization of LPS and TLR4. Staining intensity was measured by using confocal laser microscopy and scored on a scale from 0 to 3 as the average score assigned by 2 blinded observers.
H influenzae LPS was detected by positive staining in 20 of the 29 patients (69.0%), including 9 of the 10 patients with active EoE (90.0%), 8 of the 9 patients with inactive EoE (89.9%), and 3 of the 10 controls (30%); its level was greater in the patients with active EoE than in the controls (P = .063). TLR4 was detected by positive staining in 19 of the 29 patients (65.5%), including 9 of the 10 patients with active EoE (90.0%), 4 of the 9 patients with inactive EoE (44.4%), and 6 of the 10 controls (60.0%); its level was higher in the patients with active EoE than in those with inactive EoE (P = .096). The result of testing for colocalization of LPS and TLR4 was positive in 8 of 10 patients with active EoE (80.0%), 1 of 9 patients with inactive EoE (11.1%), and 1 of 10 control patients (10.0%), with greater colocalization of H influenzae LPS and TLR4 staining density in the samples from patients with active EoE than in the controls or the patients with inactive EoE (P = .009 and P = .018, respectively).
Esophageal microbiome–rich H influenzae LPS colocalizes to TLR4 in active EoE. These data lend further support to a role for the esophageal microbiome in modulating the activity of EoE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The matrix metalloproteinases (MMPs), MMP-2 and MMP-9, share structural and substrate similarities and are up-regulated during human as well as animal models of inflammatory bowel disease. We ...recently demonstrated that epithelial-derived MMP-9 is an important mediator of inflammation and tissue damage in colitis. In this study, we examined the role of MMP-2 in acute colitis. Colitis was induced using two models, administration of dextran sodium sulfate (DSS) and Salmonella enterica subsp. serovar Typhimurium (S.T.). Bone marrow chimeras were performed using bone marrow cells from wild-type (WT) and MMP-2(-/-) mice. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, and histology. MMP-2 protein expression and activity were up-regulated in WT mice treated with DSS or S.T. MMP-2(-/-) mice were highly susceptible to the development of colitis induced by DSS (or S.T.) compared with WT. During inflammation, MMP-2 expression was increased in epithelial cells as well as in the infiltrating immune cells. Bone marrow chimera demonstrated that mucosa-derived MMP-2 was required for its protective effects toward colitis. Furthermore, we demonstrate that severe colitis in MMP-2(-/-) is not due to a compensatory increase in MMP-9. Finally, we show that MMP-2 regulates epithelial barrier function. In contrast to MMP-9, mucosa-derived MMP-2 may be a critical host factor that is involved in the prevention or cessation of the host response to luminal pathogens or toxins, an important aspect of healing and tissue resolution. Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis.
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