A Novel Histologic Scoring System to Evaluate Mucosal Biopsies From Patients With Eosinophilic Esophagitis

Protheroe, Cheryl; Woodruff, Samantha A.; Petris, Giovanni De; Mukkada, Vincent A.; Ochkur, Sergei I.; Janarthanan, Sailajah; Lewis, Jason; Pasha, Shabana F.; Lunsford, Tisha; Harris, Lucinda A.; Sharma, Virender K.; McGarry, Michael P.; Lee, Nancy A.; Furuta, Glenn T.; Lee, James J.

doi:10.1016/j.cgh.2009.03.022

Cited by 177 publications

(166 citation statements)

References 19 publications

(18 reference statements)

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“…The extent of eosinophil degranulation associated with the I5/hE2 model is not a function of pulmonary leukotriene-mediated events. Immunohistochemistry of lung sections using a monoclonal antibody that specifically recognizes eosinophil peroxidase (EPX [12]) demonstrated that the induced tissue eosinophilia of the parental I5/hE2 model remained unchanged in I5/hE2 mice devoid of all leukotrienes (5-LO 2/2 /I5/hE2), LTB 4 activities (BLT-1 2/2 /I5/hE2), or the blockade of cys-leukotriene-mediated events (MK/I5/hE2). Moreover, assessments of extracellular matrix-associated EPX deposition in the lungs of these animals showed that the extensive eosinophil degranulation (i.e., increased EPX) linked with the I5/hE2 model was not a function of leukotriene-mediated activities.…”

Section: Discussionmentioning

confidence: 99%

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Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation

Ochkur

Protheroe

et al. 2013

Am J Respir Cell Mol Biol

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Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2-driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B 4 (LTB 4 ) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase-deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-b in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB 4 receptor (BLT-1 2/2 /I5/ hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene-mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cysleukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene-mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-b.Keywords: 5-lipoxygenase; asthma; eosinophils; montelukast; lung Leukotrienes represent a biologically active group of low molecular weight lipid mediators (i.e., eicosanoids) formed from arachidonic acid that is derived from membrane phospholipids (1). 5-Lipoxygenase (5-LO) is a primary component to this process, initiating the oxidation of arachidonic acid (1) and the subsequent production of intermediate metabolites (e.g., 5-oxe-eicosatetraenoic acid (2), promoting proinflammatory cell recruitment as well as the eventual formation of the prominent leukotriene subtypes (reviewed in Ref. 1).5-LO activities and the production of leukotrienes are linked with a variety of leukocytes that are both resident and recruited in response to allergen provocation, including neutrophils, eosinophils, mast cells, macrophages, and basophils (3 2/2 (6)]), offer ideal models of drug approaches targeting these pathways in human subjects.We have previously reported the creation of a transgenic mouse model of chronic T helper (Th) 2-polarized inflammation (I5/hE2) that is characterized by pathological changes that are abolished in the absence of the induced eosinop...

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Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical identification of eosinophils and evidence of degranulation was performed using a monoclonal antibody recognizing EPX (12).…”

Section: Identification Of Lung-infiltrating Eosinophils and Evidencementioning

confidence: 99%

Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation

Ochkur

Protheroe

et al. 2013

Am J Respir Cell Mol Biol

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“…For example, we have demonstrated, through the use of a novel anti-eosinophil peroxidase monoclonal antibody (EPX-mAb), that this detection method was capable of identifying tissue infiltrating eosinophils in patient biopsies, as well as evidence of degranulation, that was significantly beyond the ability to do so through conventional evaluations of hematoxylin and eosin-stained slides. 83,117 In addition, biochemical assays of eosinophil activities 118 and eosinophil granule proteins have been used as novel assays to link eosinophil activities to disease severity and/or patient outcomes as is true of unique ELISA assays of eosinophil granule proteins (eg, EPX 119 ). The availability of these novel methodologies is of particular interest moving forward as the roles of eosinophils expand from the "classic" eosinophil-associated diseases of asthma and helminth infection to the myriad of diseases and pathologies linked with eosinophils.…”

Section: Eosinophils: Biomarkers In Translational Strategies Of Patiementioning

confidence: 99%

The expanding role(s) of eosinophils in health and disease

Jacobsen¹,

Helmers

Lee³

et al. 2012

Blood

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Surprisingly, the role(s) of eosinophils in health and disease is often summarized by clinicians and basic research scientists as a pervasive consensus opinion first learned in medical/graduate school. Eosinophils are rare white blood cells whose activities are primarily destructive and are only relevant in parasitic infections and asthma. However, is this consensus correct? This review argues that the wealth of available studies investigating the role(s) of eosinophils in both health and disease demonstrates that the activities of these granulocytes are far more expansive and complex than previously appreciated. In turn, this greater understanding has led to the realization that eosinophils have significant contributory roles in a wide range of diseases. Furthermore, published studies even implicate eosinophil-mediated activities in otherwise healthy persons. We suggest that the collective reports in the literature showing a role for eosinophils in an everincreasing number of novel settings highlight the true complexity and importance of this granulocyte. Indeed, discussions of eosinophils are no longer simple and more often than not now begin with the question/statement "Did you know . . .?" (Blood. 2012;120(19):3882-3890)

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“…These findings suggest that quantification of eosinophil infiltration based on H&E staining is likely to be an underrepresentation of the magnitude of inflammation. Previous studies using esophageal tissue sections from human patients with eosinophilic esophagitis have shown that Epx mAb ‐ based IHC detects a 4‐fold higher number of eosinophils compared with H&E staining and potentially enables differentiation of difficult‐to‐diagnose eosinophilic esophagitis and gastroesophageal reflux disease 20. In another study using lung biopsy specimens from patients with acute lung injury, a >40‐fold higher sensitivity in the detection of eosinophils was achieved by IHC with Epx mAb relative to H&E‐stained sections, resulting in the identification of higher numbers of eosinophils in these patients compared with controls in whom differences using H&E staining alone were not significant 18.…”

Section: Discussionmentioning

confidence: 99%

Assessment of eosinophils in gastrointestinal inflammatory disease of dogs

Baştan

Seelig

Day

et al. 2018

Veterinary Internal Medicne

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BackgroundAccurate identification of eosinophils in the gastrointestinal (GI) tract of dogs with eosinophilic GI disease (EGID) by histological evaluation is challenging. The currently used hematoxylin and eosin (H&E) staining method detects intact eosinophils but does not detect degranulated eosinophils, thus potentially underrepresenting the number of infiltrating eosinophils.ObjectiveTo develop a more sensitive method for identifying and quantifying both intact and degranulated eosinophils to diagnose EGID more accurately.MethodsEndoscopically obtained paraffin‐embedded intestinal biopsy specimens from dogs with GI signs were examined. The study groups were dogs with eosinophilic enteritis (EE), lymphoplasmacytic and mixed enteritis, and control dogs with GI signs but no histologic changes on tissue sections. Consecutive sections were immunolabeled with monoclonal antibodies (mAbs) against the eosinophil granule protein eosinophil peroxidase (Epx) and stained by H&E, respectively. The number of eosinophils was manually quantified and classified as intact or degranulated.ResultsThe number of intact eosinophils detected in Epx mAb‐labeled duodenal sections was significantly higher compared with that in H&E‐stained sections, with a similar relationship noted in the colon and stomach. The Epx mAb allowed the unique assessment of eosinophil degranulation. The number of intact and degranulated eosinophils was significantly higher in duodenal lamina propria of the EE and mixed group compared to the control group.ConclusionImmunohistochemical detection of Epx provides a more precise method to detect GI tract eosinophils compared to H&E staining and could be used as an alternative and reliable diagnostic tool for assessment of biopsy tissues from dogs with EGID.

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A Novel Histologic Scoring System to Evaluate Mucosal Biopsies From Patients With Eosinophilic Esophagitis

Cited by 177 publications

References 19 publications

Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation

Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation

The expanding role(s) of eosinophils in health and disease

Assessment of eosinophils in gastrointestinal inflammatory disease of dogs

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