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1
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Kakehi E, Kotani K. Aspirin-Exacerbated Respiratory Disease Complicated by Eosinophilic Esophagitis: A Case Report. Cureus 2024; 16:e74384. [PMID: 39588529 PMCID: PMC11586787 DOI: 10.7759/cureus.74384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 11/27/2024] Open
Abstract
A 59-year-old woman developed sudden dyspnea after taking non-steroidal anti-inflammatory drugs (NSAIDs) for epigastralgia. She had a history of bronchial asthma after childbirth. Computed tomography showed bilateral peripheral bronchial wall thickening, lumen narrowing, obstruction, and circumferential lower esophageal mucosal edema. The patient was diagnosed with aspirin-exacerbated respiratory disease (AERD), a hypersensitivity reaction. Respiratory symptoms improved with intravenous dexamethasone. Endoscopy confirmed lower esophageal mucosal edema; mucosal biopsy detected eosinophilic infiltration, suggesting eosinophilic esophagitis (EoE). Although EoE is often diagnosed after AERD, the patient was simultaneously diagnosed with AERD and EoE after taking NSAIDs. Thus, EoE should be considered as a potential comorbidity when AERD develops after NSAID administration for abdominal symptoms.
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Affiliation(s)
- Eiichi Kakehi
- Department of General Medicine, Tottori Municipal Hospital, Tottori, JPN
- Division of Community and Family Medicine, Jichi Medical University, Shimotsuke, JPN
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Shimotsuke, JPN
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2
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Underwood B, Troutman TD, Schwartz JT. Breaking down the complex pathophysiology of eosinophilic esophagitis. Ann Allergy Asthma Immunol 2023; 130:28-39. [PMID: 36351516 PMCID: PMC10165615 DOI: 10.1016/j.anai.2022.10.026] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/08/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated disease of the esophagus associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Our understanding of EoE pathophysiology has evolved since its initial recognition more than 20 years ago and has translated into diagnostic and novel therapeutic approaches that are affecting patient care. The mechanisms underlying disease development and progression are influenced by diverse factors, such as genetics, age, allergic comorbidities, and allergen exposures. Central to EoE pathophysiology is a dysregulated feed-forward cycle that develops between the esophageal epithelium and the immune system. Allergen-induced, type 2-biased immune activation by the esophageal epithelium propagates a cycle of impaired mucosal barrier integrity and allergic inflammation, eventually leading to tissue remodeling and progressive organ dysfunction. Herein, we review the current understanding of fundamental pathophysiological mechanisms contributing to EoE pathogenesis.
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Affiliation(s)
- Brynne Underwood
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Ty D Troutman
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Justin T Schwartz
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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3
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Jiang Y, Pan Q, Zhu X, Liu J, Liu Z, Deng Y, Liu W, Liu Y. Knockdown of CCR3 gene inhibits Proliferation, migration and degranulation of eosinophils in mice by downregulating the PI3K/Akt pathway. Int Immunopharmacol 2022; 113:109439. [DOI: 10.1016/j.intimp.2022.109439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/21/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022]
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4
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Tu W, Feng Y, Lai Q, Wang J, Yuan W, Yang J, Jiang S, Wu A, Cheng S, Shao J, Li J, Jiang Z, Tang H, Shi Y, Zhang S. Metabolic Profiling Implicates a Critical Role of Cyclooxygenase-2-Mediated Arachidonic Acid Metabolism in Radiation-Induced Esophageal Injury in Rats. Radiat Res 2022; 197:480-490. [PMID: 35172004 DOI: 10.1667/rade-20-00240.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/05/2022] [Indexed: 11/03/2022]
Abstract
Radiation-induced esophageal injury (RIEL) is a major dose-limiting complication of radiotherapy, especially for esophageal and thoracic cancers. RIEL is a multi-factorial and multi-step process, which is regulated by a complex network of DNA, RNA, protein and metabolite. However, it is unclear which esophageal metabolites are altered by ionizing radiation and how these changes affect RIEL progression. In this work, we established a rat model of RIEL with 0-40 Gy X-ray irradiation. Esophageal irradiation using ≥25 Gy induced significant changes to rats, such as body weight, food intake, water intake and esophageal structure. The metabolic changes and related pathways of rat esophageal metabolites were investigated by liquid chromatography-mass spectrometry (LC-MS). One hundred eighty metabolites showed an up-regulation in a dose-dependent manner (35 Gy ≥ 25 Gy > controls), and 199 metabolites were downregulated with increasing radiation dose (35 Gy ≤ 25 Gy < controls). The KEGG analysis showed that ionizing radiation seriously disrupted multiple metabolic pathways, and arachidonic acid metabolism was the most significantly enriched pathway. 20 metabolites were dysregulated in arachidonic acid metabolism, including up-regulation of five prostaglandins (PGA2, PGJ2, PGD2, PGH2, and PGI2) in 25 or 35 Gy groups. Cyclooxygenase-2 (COX-2), the key enzyme in catalyzing the biosynthesis of prostaglandins from arachidonic acid, was highly expressed in the esophagus of irradiated rats. Additionally, receiver operating characteristic (ROC) curve analysis revealed that PGJ2 may serve as a promising tissue biomarker for RIEL diagnosis. Taken together, these findings indicate that ionizing radiation induces esophageal metabolic alterations, which advance our understanding of the pathophysiology of RIEL from the perspective of metabolism.
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Affiliation(s)
- Wenling Tu
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.,School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Yahui Feng
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Qian Lai
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Jinlong Wang
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Weijun Yuan
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Jingxuan Yang
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Sheng Jiang
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Ailing Wu
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Shuanghua Cheng
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Jichun Shao
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Jingyi Li
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.,School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, China
| | - Zhiqiang Jiang
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Hui Tang
- West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yuhong Shi
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Shuyu Zhang
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.,West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
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5
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Racca F, Pellegatta G, Cataldo G, Vespa E, Carlani E, Pelaia C, Paoletti G, Messina MR, Nappi E, Canonica GW, Repici A, Heffler E. Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets. Front Physiol 2022; 12:815842. [PMID: 35095572 PMCID: PMC8790151 DOI: 10.3389/fphys.2021.815842] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/09/2021] [Indexed: 12/11/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.
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Affiliation(s)
- Francesca Racca
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- *Correspondence: Francesca Racca,
| | - Gaia Pellegatta
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Giuseppe Cataldo
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Edoardo Vespa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Elisa Carlani
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Corrado Pelaia
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Giovanni Paoletti
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Maria Rita Messina
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Emanuele Nappi
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Giorgio Walter Canonica
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Digestive Endoscopy Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Enrico Heffler
- Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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6
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Chiang KC, Imig JD, Kalantar-Zadeh K, Gupta A. Kidney in the net of acute and long-haul coronavirus disease 2019: a potential role for lipid mediators in causing renal injury and fibrosis. Curr Opin Nephrol Hypertens 2022; 31:36-46. [PMID: 34846312 DOI: 10.1097/mnh.0000000000000750] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.
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Affiliation(s)
| | - John D Imig
- Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, California, USA
| | - Ajay Gupta
- KARE Biosciences, Orange, California
- Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, California, USA
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7
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Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in Eosinophilic Esophagitis: The Road to Fibrostenosis is Paved With Good Intentions. Front Immunol 2020; 11:603295. [PMID: 33335531 PMCID: PMC7736408 DOI: 10.3389/fimmu.2020.603295] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/03/2020] [Indexed: 12/15/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an antigen-driven disease associated with epithelial barrier dysfunction and chronic type 2 inflammation. Eosinophils are the defining feature of EoE histopathology but relatively little is known about their role in disease onset and progression. Classically defined as destructive, end-stage effector cells, eosinophils (a resident leukocyte in most of the GI tract) are increasingly understood to play roles in local immunity, tissue homeostasis, remodeling, and repair. Indeed, asymptomatic esophageal eosinophilia is observed in IgE-mediated food allergy. Interestingly, EoE is a potential complication of oral immunotherapy (OIT) for food allergy. However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects. This is seemingly at odds with multiple studies which have shown that EoE disease severity correlates with tissue eosinophilia. Herein, we review the potential role of eosinophils in EoE at different stages of disease pathogenesis. Based on current literature we suggest the following: (1) eosinophils are recruited to the esophagus as a homeostatic response to epithelial barrier disruption; (2) eosinophils mediate barrier-protective activities including local antibody production, mucus production and epithelial turnover; and (3) when type 2 inflammation persists, eosinophils promote fibrosis.
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Affiliation(s)
- Alfred D Doyle
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Mia Y Masuda
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Hirohito Kita
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, United States
| | - Benjamin L Wright
- Division of Allergy, Asthma, and Clinical Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States.,Division of Pulmonology, Phoenix Children's Hospital, Phoenix, AZ, United States
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8
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Ryu S, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Effenberger M, Shin JI, Kronbichler A. Pathogenesis of Eosinophilic Esophagitis: A Comprehensive Review of the Genetic and Molecular Aspects. Int J Mol Sci 2020; 21:ijms21197253. [PMID: 33008138 PMCID: PMC7582808 DOI: 10.3390/ijms21197253] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 01/21/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14. We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-β1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.
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Affiliation(s)
- Seohyun Ryu
- Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Kalthoum Tizaoui
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, 1068 Tunis, Tunisia;
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (S.C.)
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (S.C.)
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Correspondence: ; Tel.: +82-2-2228-2050
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria;
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9
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Therapeutic Potential of Hematopoietic Prostaglandin D 2 Synthase in Allergic Inflammation. Cells 2019; 8:cells8060619. [PMID: 31226822 PMCID: PMC6628301 DOI: 10.3390/cells8060619] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/12/2019] [Accepted: 06/19/2019] [Indexed: 12/15/2022] Open
Abstract
Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D2 (PGD2) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and survival of leukocytes in various allergy-associated disorders. In the periphery, the hematopoietic PGD synthase (hPGDS) acts downstream of the arachidonic acid/COX pathway catalysing the isomerisation of PGH2 to PGD2, which makes it an interesting target to treat allergic inflammation. Although much effort has been put into developing efficient hPGDS inhibitors, no compound has made it to the market yet, which indicates that more light needs to be shed on potential PGD2 sources and targets to determine which particular condition and patient will benefit most and thereby improve therapeutic efficacy. In this review, we want to revisit current knowledge about hPGDS function, expression in allergy-associated cell types and their contribution to PGD2 levels as well as beneficial effects of hPGDS inhibition in allergic asthma, rhinitis, atopic dermatitis, food allergy, gastrointestinal allergic disorders and anaphylaxis.
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10
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Durchschein F, Eherer A, Grill M, Sturm EM, Pommer V, Langner C, Högenauer C, Schicho R. Involvement of EP2 and EP4 Receptors in Eosinophilic Esophagitis: A Pilot Study. Dig Dis Sci 2019; 64:2806-2814. [PMID: 30989466 PMCID: PMC6744386 DOI: 10.1007/s10620-019-05623-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/08/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND The prostaglandin D2 receptor DP2 has been implicated in eosinophil infiltration and the development of eosinophilic esophagitis (EoE). AIMS AND METHODS In this study, we investigated an involvement of PGE2 (EP1-EP4) and PGD2 (DP1) receptors in EoE by measuring their expression in peripheral blood eosinophils and esophageal mucosal biopsies of EoE patients and by performing migration and adhesion assays with eosinophils from healthy donors. RESULTS Expression of EP2 and EP4, but not EP1 and EP3, was decreased in blood eosinophils of patients with EoE vs. control subjects. Adhesion of eosinophils to esophageal epithelial cells was decreased by EP2 receptor agonist butaprost and EP4 agonist ONO-AE1-329, whereas DP1 agonist BW245C increased adhesion. In chemotaxis assays with supernatant from human esophageal epithelial cells, only ONO-AE1-329 but not butaprost or BW245C inhibited the migration of eosinophils. Expression of EP and DP receptors in epithelial cells and eosinophils was detected in sections of esophageal biopsies from EoE patients by immunohistochemistry. qPCR of biopsies from EoE patients revealed that gene expression of EP4 and DP1 was the highest among PGE2 and PGD2 receptors. Esophageal epithelial cells in culture showed high gene expression for EP2 and EP4. Activation of EP2 and EP4 receptors decreased barrier integrity of esophageal epithelial cells in impedance assays. CONCLUSIONS Activation of EP2 and EP4 receptors may inhibit eosinophil recruitment to the esophageal mucosa. However, their activation could negatively affect esophageal barrier integrity suggesting that eosinophilic rather than epithelial EP2 and EP4 have a protective role in EoE.
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Affiliation(s)
- Franziska Durchschein
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Eherer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Magdalena Grill
- Otto Loewi Research Center, Divison of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Eva M. Sturm
- Otto Loewi Research Center, Divison of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Veronika Pommer
- Otto Loewi Research Center, Divison of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria
| | - Cord Langner
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Christoph Högenauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria ,BioTechMed, Graz, Austria
| | - Rudolf Schicho
- Otto Loewi Research Center, Divison of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria ,BioTechMed, Graz, Austria
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11
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Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with an atopic predisposition which appears to be increasing in prevalence over the last few decades. Symptoms stem from fibrosis, swelling, and smooth muscle dysfunction. In the past two decades, the etiology of EoE has been and is continuing to be revealed. This review provides an overview of the effects of genetics, environment, and immune function including discussions that touch on microbiome, the role of diet, food allergy, and aeroallergy. The review further concentrates on the pathophysiology of the disease with particular focus on the important concepts of the molecular etiology of EoE including barrier dysfunction and allergic hypersensitivity.
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Affiliation(s)
- Benjamin P Davis
- Department of Internal Medicine, Division of Immunology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52246, USA.
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12
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Peinhaupt M, Roula D, Theiler A, Sedej M, Schicho R, Marsche G, Sturm EM, Sabroe I, Rothenberg ME, Heinemann A. DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator. J Leukoc Biol 2018; 104:159-171. [PMID: 29607536 PMCID: PMC6032830 DOI: 10.1002/jlb.3ma1017-404r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 02/15/2018] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
Prostaglandin (PG) D2 is the ligand for the G-protein coupled receptors DP1 (D-type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro-inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor-mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which-as a consequence-sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti-apoptotic gene BCL-XL , but also induced pro-inflammatory genes, such as VLA-4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti-apoptotic, early-response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro-inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti-inflammatory therapy in eosinophilic diseases.
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Affiliation(s)
- Miriam Peinhaupt
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - David Roula
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Anna Theiler
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Miriam Sedej
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Rudolf Schicho
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Gunther Marsche
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Eva M Sturm
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Ian Sabroe
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, England
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Akos Heinemann
- Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
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13
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Hart KM, Fabre T, Sciurba JC, Gieseck RL, Borthwick LA, Vannella KM, Acciani TH, de Queiroz Prado R, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci Transl Med 2018; 9:9/396/eaal3694. [PMID: 28659437 DOI: 10.1126/scitranslmed.aal3694] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/07/2017] [Accepted: 05/17/2017] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-γ (IFN-γ) signature. Conversely, IFN-γ-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-β (TGF-β) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-β and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-β alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLD collaboratively with TGF-β in the liver.
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Affiliation(s)
- Kevin M Hart
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas Fabre
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec, Canada
| | - Joshua C Sciurba
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard L Gieseck
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lee A Borthwick
- Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Kevin M Vannella
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas H Acciani
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Rafael de Queiroz Prado
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Robert W Thompson
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sandra White
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Genevieve Soucy
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada
| | - Marc Bilodeau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Thirumalai R Ramalingam
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Thomas A Wynn
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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14
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Samuchiwal SK, Boyce JA. Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology. J Allergy Clin Immunol 2018; 141:1182-1190. [PMID: 29477727 DOI: 10.1016/j.jaci.2018.02.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/08/2018] [Accepted: 02/09/2018] [Indexed: 12/11/2022]
Abstract
Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology.
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Affiliation(s)
- Sachin K Samuchiwal
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass
| | - Joshua A Boyce
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass.
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15
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Blanchard C, Simon D, Schoepfer A, Straumann A, Simon HU. Eosinophilic esophagitis: unclear roles of IgE and eosinophils. J Intern Med 2017; 281:448-457. [PMID: 28425585 DOI: 10.1111/joim.12568] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the oesophagus. Recognized as a distinct entity only two decades ago, the emergence of the disease along with the availability of new technologies has rapidly opened new research avenues and outlined the main features of the pathogenesis of EoE. Yet, each advance in our understanding of the disease has raised new questions about the previous consensus. Currently, new subsets of the disease challenge our diagnostic criteria. For instance, it was believed that EoE did not respond to proton pump inhibitor (PPI) therapy; however, it has now been shown that a substantial proportion of EoE patients indeed respond to PPIs. In addition, a new subset of patients not even presenting eosinophil infiltrates in the oesophagus has also been described. Moreover, approaches for better understanding the heritability of the disease bring into question the dogma of predominant genetic involvement. Furthermore, the specificity and sensitivity of allergy testing for targeted food avoidance is highly controversial, and the production of specific antibodies in EoE now includes IgG4 in addition to IgE. In conclusion, EoE is perceived as 'a moving target' and the aim of this review was to summarize the current understanding of EoE pathogenesis.
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Affiliation(s)
- C Blanchard
- Nestlé Research Center, Lausanne, Switzerland
| | - D Simon
- Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - A Schoepfer
- Division of Gastroenterology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - A Straumann
- Swiss EoE Clinic and EoE Research Network, Olten, Switzerland
| | - H-U Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
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16
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Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets. Curr Allergy Asthma Rep 2017; 16:48. [PMID: 27333777 DOI: 10.1007/s11882-016-0628-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy. Lipids are critical participants in cell signaling events which influence key physiologic (bronchoconstriction) and immune phenomena (degranulation, chemotaxis, sensitization). Lipid-mediated cellular mechanisms including: (1) formation of structural support platforms (lipid rafts) for receptor signaling complexes, (2) activation of a diverse family of G-protein coupled receptors, and (3) mediating intracellular signaling cascades by acting as second messengers. Here, we review four classes of bioactive lipids (platelet activating factor, the leukotrienes, the prostanoids, and the sphingolipids) with special emphasis on lipid synthesis pathways and signaling, atopic disease pathology, and the ongoing development of atopy treatments targeting lipid mediator pathways.
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17
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Ridolo E, Melli V, De’ Angelis G, Martignago I. Eosinophilic disorders of the gastro-intestinal tract: an update. Clin Mol Allergy 2016; 14:17. [PMID: 27956893 PMCID: PMC5131414 DOI: 10.1186/s12948-016-0055-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 11/10/2016] [Indexed: 02/06/2023] Open
Abstract
Eosinophilic diseases of the gastrointestinal tract, including eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), are rare chronic pathologies of the digestive system, with an immuno-mediated pathogenesis. Recent data suggest that, together with the "classic" IgE-response to allergens, also a delayed hypersensitivity mechanism could be involved in the development of eosinophilic disorders. EoE and EGE were studied only in the latest decades and as a consequence accurate data are not yet available, concerning not only pathogenesis, but also epidemiology, treatment and outcomes. The diagnosis of EoE is centered on endoscopic findings but the certainty is obtained by histological examination from biopsy samples, that has a sensitivity of 100% when based on five samples. The currently available treatments include topical corticosteroids, specific diets and endoscopic treatment. Concerning EGE, three subtypes (mucosal, muscular, and serosal) were identified. The diagnosis is based, as for EoE, on endoscopic and histological assessment, and the treatment includes pharmacological and dietetic approaches. Further studies are warranted in order to better define the etiology and pathogenesis of eosinophilic diseases of the gastrointestinal tract, and thus to develop more appropriate and specific therapies.
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Affiliation(s)
- Erminia Ridolo
- Department of Clinical and Experimental Medicine, University of Parma, via Gramsci, 14, 43100 Parma, Italy
| | - Valerie Melli
- Department of Clinical and Experimental Medicine, University of Parma, via Gramsci, 14, 43100 Parma, Italy
| | - Gianluigi De’ Angelis
- Department of Clinical and Experimental Medicine, University of Parma, via Gramsci, 14, 43100 Parma, Italy
| | - Irene Martignago
- Department of Clinical and Experimental Medicine, University of Parma, via Gramsci, 14, 43100 Parma, Italy
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18
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Pelletier T, Tamayev R, Iammatteo M, Nautsch D, Hudes G, Lukin D, Jerschow E. Eosinophilic esophagitis as possible complication of aspirin treatment in patient with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2016; 118:120-122. [PMID: 27865717 DOI: 10.1016/j.anai.2016.10.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/13/2016] [Accepted: 10/20/2016] [Indexed: 10/20/2022]
Affiliation(s)
- Teresa Pelletier
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Robert Tamayev
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Melissa Iammatteo
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Deborah Nautsch
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Golda Hudes
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Dana Lukin
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Elina Jerschow
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
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19
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Moawad FJ, Cheng E, Schoepfer A, Al-Haddad S, Bellizzi AM, Dawson H, El-Zimaity H, Guindi M, Penagini R, Safrooneva E, Chehade M. Eosinophilic esophagitis: current perspectives from diagnosis to management. Ann N Y Acad Sci 2016; 1380:204-217. [DOI: 10.1111/nyas.13164] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/01/2016] [Accepted: 06/03/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Fouad J. Moawad
- Gastroenterology Service, Department of Medicine; Walter Reed National Military Medical Center; Bethesda Maryland
| | - Edaire Cheng
- Pediatric Gastroenterology, Hepatology & Nutrition Division; University of Texas Southwestern Medical Center; Dallas Texas
| | - Alain Schoepfer
- Division of Gastroenterology and Hepatology; Centre Hospitalier Universitaire; Vaudois/CHUV Lausanne Switzerland
| | - Sahar Al-Haddad
- Department of Laboratory Medicine; St. Michael's Hospital; Hamilton Ontario Canada
| | - Andrew M. Bellizzi
- Department of Pathology; University of Iowa Hospitals and Clinics, University of Iowa Carver College of Medicine; Iowa City Iowa
| | - Heather Dawson
- Institute of Pathology; University of Bern; Bern Switzerland
| | | | - Maha Guindi
- Department of Pathology and Laboratory Medicine; Cedars-Sinai Medical Center; Los Angeles California
| | - Roberto Penagini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation; Università degli Studi; Milan Italy
| | - Ekaterina Safrooneva
- Institute of Social and Preventive Medicine; University of Bern; Bern Switzerland
| | - Mirna Chehade
- Department of Pediatrics and Medicine, Mount Sinai Center for Eosinophilic Disorders; Icahn School of Medicine at Mount Sinai; New York New York
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20
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Hill DA, Spergel JM. The Immunologic Mechanisms of Eosinophilic Esophagitis. Curr Allergy Asthma Rep 2016; 16:9. [PMID: 26758862 DOI: 10.1007/s11882-015-0592-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease that is triggered by food and/or environmental allergens and is characterized by a clinical and pathologic phenotype of progressive esophageal dysfunction due to tissue inflammation and fibrosis. EoE is suspected in patients with painful swallowing, among other symptoms, and is diagnosed by the presence of 15 or more eosinophils per high-power field in one or more of at least four esophageal biopsy specimens. The prevalence of EoE is increasing and has now reached rates similar to those of other chronic gastrointestinal disorders such as Crohn's disease. In recent years, our understanding of the immunologic mechanisms underlying this condition has grown considerably. Thanks to new genetic, molecular, cellular, animal, and translational studies, we can now postulate a detailed pathway by which exposure to allergens results in a complex and coordinated type 2 inflammatory cascade that, if not intervened upon, can result in pain on swallowing, esophageal strictures, and food impaction. Here, we review the most recent research in this field to synthesize and summarize our current understanding of this complex and important disease.
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Affiliation(s)
- David A Hill
- Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.,Division of Allergy and Immunology, The Children's Hospital of Philadelphia, 3550 Market St., Philadelphia, PA, 19104, USA
| | - Jonathan M Spergel
- Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. .,Division of Allergy and Immunology, The Children's Hospital of Philadelphia, 3550 Market St., Philadelphia, PA, 19104, USA.
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21
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Davis BP, Rothenberg ME. Mechanisms of Disease of Eosinophilic Esophagitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 11:365-93. [PMID: 26925500 DOI: 10.1146/annurev-pathol-012615-044241] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.
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Affiliation(s)
- Benjamin P Davis
- Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242;
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229;
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22
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Goyal A, Cheng E. Recent discoveries and emerging therapeutics in eosinophilic esophagitis. World J Gastrointest Pharmacol Ther 2016; 7:21-32. [PMID: 26855809 PMCID: PMC4734951 DOI: 10.4292/wjgpt.v7.i1.21] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 10/13/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Eosinophilic esophagitis (EoE) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease (GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor - responsive esophageal eosinophilia (PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for EoE rather than a diagnostic screen to differentiate GERD, PPI-REE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.
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23
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Leung J, Beukema KR, Shen AH. Allergic mechanisms of Eosinophilic oesophagitis. Best Pract Res Clin Gastroenterol 2015; 29:709-720. [PMID: 26552770 PMCID: PMC4919901 DOI: 10.1016/j.bpg.2015.09.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 06/25/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023]
Abstract
Eosinophilic oesophagitis (EoE) is characterized by oesophageal dysfunction and oesophageal eosinophilia refractory to proton-pump-inhibitor treatment. EoE is a food allergy, as elimination of food trigger(s) abrogates the disease, while trigger reintroduction causes recurrence. The allergic mechanism of EoE involves both IgE and non-IgE processes. There is a break in oral tolerance, the immune mechanism allowing enteric exposure to food and micro-organisms without causing deleterious immune responses. Changes in life-style, alterations in gut flora and use of antibiotics may be increasing disease prevalence. Mouse models of EoE and human studies revealed the role of regulatory T-cells and iNKT-cells in the pathogenesis. Th2-cytokines like IL-4, IL-5 and IL-13, and other cytokines like TGFβ and TSLP are involved, but perhaps no one cytokine is critically important for driving the disease. Control of EoE may require a pharmaceutical approach that blocks more than one target in the Th2-inflammatory pathway.
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24
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Martin LJ, Franciosi JP, Collins MH, Abonia JP, Lee JJ, Hommel KA, Varni JW, Grotjan JT, Eby M, He H, Marsolo K, Putnam PE, Garza JM, Kaul A, Wen T, Rothenberg ME. Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease. J Allergy Clin Immunol 2015; 135:1519-28.e8. [PMID: 26051952 DOI: 10.1016/j.jaci.2015.03.004] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 02/18/2015] [Accepted: 03/05/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS v2.0) measures patient-relevant outcomes. However, whether patient-identified domains (dysphagia, gastroesophageal reflux disease [GERD], nausea/vomiting, and pain) align with clinical symptomology and histopathologic and molecular features of eosinophilic esophagitis (EoE) is unclear. OBJECTIVE The purpose of this study was to determine whether clinical features of EoE, measured through PEESS v2.0, associate with histopathologic and molecular features of EoE. This represents a novel approach for analysis of allergic diseases, given the availability of allergic tissue biopsy specimens. METHODS We systematically recruited treated and untreated pediatric patients with EoE (aged 2-18 years) and examined parent proxy-reported symptoms using the PEESS v2.0. Clinical symptomology was collected by questionnaire. Esophageal biopsy samples were quantified for levels of eosinophils, eosinophil peroxidase (EPX) immunohistochemical staining, and mast cells. Molecular features were assessed by using the EoE Diagnostic Panel (94 EoE-related gene transcripts). Associations between domain scores and clinical symptoms and biological features were analyzed with Wilcoxon rank sum and Spearman correlation. RESULTS The PEESS v2.0 domains correlated to specific parent-reported symptoms: dysphagia (P = .0012), GERD (P = .0001), and nausea/vomiting (P < .0001). Pain correlated with multiple symptoms (P < .0005). Dysphagia correlated most strongly with overall histopathology, particularly in the proximal esophagus (P ≤ .0049). Markers of esophageal activity (EPX) were significantly associated with dysphagia (strongest r = 0.37, P = .02). Eosinophil levels were more associated with pain (r = 0.27, P = .06) than dysphagia (r = 0.24, P = .13). The dysphagia domain correlated most with esophageal gene transcript levels, predominantly with mast cell-specific genes. CONCLUSION We have (1) established a validated, parent proxy-reported measure for pediatric EoE, the PEESS v2.0; (2) verified that the parent proxy effectively captures symptoms; (3) determined that the dysphagia domain most closely aligns with symptoms and tissue-based molecular biomarkers; (4) established that symptoms correlate with EPX staining; and (5) observed association between mast cells and dysphagia.
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Affiliation(s)
- Lisa J Martin
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio
| | - James P Franciosi
- Division of Gastroenterology, Department of Pediatrics, Nemours Children's Health System, Orlando, Fla
| | - Margaret H Collins
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - J Pablo Abonia
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - James J Lee
- Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz
| | - Kevin A Hommel
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - James W Varni
- Department of Pediatrics, College of Medicine, Department of Landscape Architecture and Urban Planning, College of Architecture, Texas A&M University, College Station, Tex
| | - J Tommie Grotjan
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Michael Eby
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Hua He
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Keith Marsolo
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Philip E Putnam
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jose M Garza
- Children's Center for Digestive Health Care, Atlanta, Ga
| | - Ajay Kaul
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ting Wen
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Marc E Rothenberg
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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25
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Abstract
PURPOSE OF REVIEW Eosinophilic esophagitis (EoE) is an esophageal disease characterized by an accumulation of eosinophils in the esophagus, which is normally devoid of eosinophils. The interest of the scientific community in EoE has grown considerably over the past two decades, and understanding of the molecular mechanisms involved in this disease has increased greatly in the last 2 years. RECENT FINDINGS Important new insights into the pathogenesis of EoE recently have been achieved. Recent evaluations considering genetic and the environmental risk factors have led to the concept that some still-unknown environmental factors influence the risk of developing EoE more than the genetic predisposition. New molecules (in addition to interleukin-13, eotaxin-3, transforming growth factor-β1, thymic stromal lymphopoietin, filaggrin, or interleukin-5) also have been shown to be involved in the disease pathogenesis. SUMMARY The present review describes recent advances in the understanding of the molecular mechanisms underlying EoE, and how these new findings have enhanced understanding of the pathogenesis of this new esophageal disorder.
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26
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Cheng E. Translating new developments in eosinophilic esophagitis pathogenesis into clinical practice. ACTA ACUST UNITED AC 2015; 13:30-46. [PMID: 25598233 DOI: 10.1007/s11938-014-0041-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OPINION STATEMENT New developments in eosinophilic esophagitis (EoE) pathogenesis are shaping our current therapeutic and management strategies. EoE is a chronic allergic inflammatory disease with progression to fibrostenotic disease. The disease warrants early diagnosis and long-term maintenance therapy. The diagnosis of EoE should be based on the concept of an allergy-mediated disease with esophageal dysfunction and esophageal eosinophilia. Recent findings suggest that proton pump inhibitor (PPI)-responsive esophageal eosinophilia (PPI-REE) is likely a continuum of EoE or a similar T-helper 2 (Th2)-mediated allergic process. PPIs have therapeutic properties that can benefit both gastroesophageal reflux disease (GERD) and EoE. Therefore, PPIs should be considered not a diagnostic tool but, rather, a therapeutic option for EoE. If patients are PPI nonresponsive, then dietary therapy or steroid therapy should be considered. Dilation can be reserved as adjuvant therapy for severe fibrostenotic lesions.
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Affiliation(s)
- Edaire Cheng
- Esophageal Diseases Center, Pediatric Gastroenterology, Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA,
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27
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Abstract
Eosinophilic esophagitis is rapidly increasing in incidence. It is associated with food antigen-triggered, eosinophil-predominant inflammation, and the pathogenic mechanisms have many similarities to other chronic atopic diseases. Studies in animal models and from patients have suggested that allergic sensitization leads to food-specific IgE and T-helper lymphocyte type 2 cells, both of which seem to contribute to the pathogenesis along with basophils, mast cells, and antigen-presenting cells. In this review our current understandings of the allergic mechanisms that drive eosinophilic esophagitis are outlined, drawing from clinical and translational studies in humans as well as experimental animal models.
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