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Biomedical subjects

Glenn T Furuta

Publications and source records attributed to Glenn T Furuta.

At least 19 recordsLinked to original sources
PubMed2006

Eosinophils in the gastrointestinal tract.

Although we know that eosinophils reside in the normal gastrointestinal tract and increase during inflammatory states, their exact role in gut homeostasis and in the pathogenesis of inflammatory processes is not certain. An increasing number of clinical reports suggest that eosinophils participate in the pathogenesis of mucosal inflammation, and emerging literature is beginning to define these mechanisms. For example, homing of eosinophils to the gastrointestinal tract is better understood with respect to the roles of specific eosinophilic attractants, such as the eotaxins and interleukin-5. As mechanisms of eosinophil recruitment, activation, and functional responses are further elucidated, novel targets for treatment strategies in specific diseases will likely follow. We review recent developments in eosinophil immunobiology as they relate to gastrointestinal inflammation and provide an update on clinical aspects of eosinophilic esophagitis as they relate to eosoinophilic diseases of the gastrointestinal tract.

Animals↗
PubMed2006

Upper gastrointestinal tract eosinophilic disorders: pathobiology and management.

Patients with eosinophilic esophagitis present with symptoms similar to those from gastroesophageal reflux disease along with dense esophageal eosinophilia (normal gastric and duodenal biopsies) that persist despite aggressive acid blockade. The dramatic increase in prevalence of eosinophilic esophagitis over the past several years provides clinicians with a new explanation for previously unexplained dysphagia, food impaction, vomiting, and abdominal pain. As a product of this recognition, an increasing number of basic and translational studies are building a new understanding of the pathogenesis of esophageal eosinophilia. This review addresses recent studies that define clinical features, genetic predisposition, pathogenetic mechanisms, and treatment options for eosinophilic esophagitis.

Biopsy↗
PubMed2006

Emerging questions regarding eosinophil's role in the esophago-gastrointestinal tract.

PURPOSE OF REVIEW: Eosinophilic inflammation of the gastrointestinal tract is either increasing in frequency or being better recognized. Whichever is the case, clinical needs to meet this new challenge include establishing diagnostic criteria, identifying the natural history and determining effective, tolerable treatments. RECENT FINDINGS: During the last 5 years, the emergence of eosinophilic esophagitis stimulated many case series; the new frontiers relate to understanding disease pathogenesis and maintenance treatments. Eosinophilic gastrointestinal diseases involving the rest of the gastrointestinal tract pose new challenges in understanding the role of eosinophils in intestinal dysmotility and protein loss. SUMMARY: This review will focus on new clinical developments in the field of eosinophilic gastrointestinal diseases and the contribution of basic studies in understanding eosinophils impact on gastrointestinal inflammation.

Animals↗
PubMed2006

Eosinophils in the esophagus--peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia.

OBJECTIVES: Scattered eosinophils in the distal esophagus traditionally provide the hallmark for peptic esophagitis, but the upper limit of eosinophils and the longitudinal extent of peptic inflammation along the esophagus are unknown. Recently, adults and children with upper intestinal symptoms and >20 eosinophils/high-power field (eos/HPF) have been given the diagnosis of allergic esophagitis. Standardized diagnostic criteria for allergic esophagitis are lacking and the isolated finding of large numbers of eosinophils in the squamous epithelium has been used as the defining feature. We cared for three patients with symptoms and endoscopic features of esophagitis with >20 eos/HPF in their esophageal mucosa. Symptoms, endoscopic features, and histologic findings resolved after 2 months of proton pump inhibitor (PPI) treatment. The aim of this case series is to demonstrate that features thought to be consistent with a diagnosis of allergic esophagitis are also observed in peptic esophagitis. METHODS: A retrospective chart review of three patients with esophagitis (>20 eos/HPF) whose symptoms and eosinophilia resolved with PPI treatment was performed. Esophageal biopsies were reviewed in a blinded manner by one pathologist. RESULTS: Patients (aged 14, 25, and 5 yr) presented with dysphagia, food impaction, and vomiting. Endoscopic features included white exudates and linear furrows. None of the patients received antiallergic treatments or dietary eliminations prior to endoscopy. Following treatment with PPIs alone, all patients became asymptomatic and endoscopic findings reverted to normal. In all three patients, pre- and post-PPI treatment eosinophil numbers/HPF decreased to normal/near normal (37 to 1, 21 to 3, and 52 to 0 eosinophils/HPF in patients 1, 2, and 3, respectively). CONCLUSION: Large numbers of eosinophils can be seen in peptic esophagitis. This histologic finding must be interpreted in the context of the clinical setting in which it is obtained.

Adolescent↗
PubMed2006

Collagen gel contraction assay.

Mucosal tissues undergo contraction and relaxation on a continuous basis. In its normal state, the pliable intestinal tract is characterized by a rhythmic pattern of contractions controlled by its intrinsic neuronal innvervation. In chronic inflammatory diseases such as Crohn's disease, the intestine can become stiff and fibrotic, losing much of its normal motility. Although muscle fiber contraction accounts for much of this activity, contraction of nonmuscle tissue is constantly occurring in events associated with chronic inflammation, such as wound healing, scar formation, and tissue remodeling. However, the physiological and pathological mechanisms defining these events are not well defined. Tissue contraction is a dynamic event characterized by both intracellular and extracellular events. A number of cells, such as fibroblasts, epithelial cells, lymphocytes, and eosinophils, normally reside within the gastrointestinal tract. Additionally, the extracellular matrix is composed of a complex infrastructure that includes collagen and other molecules. The manner in which these two components interact is not certain, but the use of recent model systems has provided insights into these processes. The collagen lattice contraction assay provides a model for tissue contraction that takes advantage of the finding that cell-populated collagen hydrogels contract over time in a predictable, consistent manner. This model allows for investigation of the influence of specific agonists on the rate and extent of matrix contraction.

Biological Assay↗
PubMed2005

Treatment of eosinophilic esophagitis in children.

Eosinophilic esophagitis (EE) is an increasingly recognized disease of the esophagus with distinct clinicopathologic features. Adult and pediatric patients experience upper intestinal symptoms including food impaction, vomiting, abdominal pain, or dysphagia. Histopathologic analysis of the distal and proximal esophageal mucosa demonstrates dense eosinophilic infiltration despite proton pump inhibition. Few studies document the long-term outcomes of EE but current evidence suggests that EE is a chronic condition that can sometimes lead to esophageal strictures. Although the incidence of this complication is not yet known, it has sparked significant interest in defining safe, effective treatments. Once a diagnosis of EE is made, patients should seek the consultation of the allergist in an effort to identify possible food sensitivities. This is particularly important because the etiologic agent(s) that drive the eosinophilia are likely different for each patient. If the allergic evaluation identifies a specific food, this food should be strictly avoided as a first-line treatment. If a food is not identified, an elemental formula should be used to induce a remission. If an elemental diet cannot be used, topical steroids are effective in inducing a remission. The side effects associated with long-term steroid administration limit their use as a maintenance medication. Given the lack of prognostic data, the use of systemic corticosteroids should be reserved for severe cases when dietary elimination or topical steroids are ineffective. Most importantly, patients should remain under the care of a physician so that long-term outcomes can be identified. To date, diet restriction has been identified as the only effective maintenance treatment, but montelukast and topical cromolyn may also offer benefit. Anti-interleukin-5 antibody represents an emerging form of targeted therapy.

Journal Article↗
PubMed2005

Association of eosinophilic inflammation with esophageal food impaction in adults.

INTRODUCTION: Esophageal food impaction is a common presentation of eosinophilic esophagitis. The prevalence of eosinophilic esophagitis among patients with food impaction is unknown. To address this, we evaluated clinicopathologic features of adults with food impaction. METHODS: For a 3-year period, patients from a single, adult, community-based gastroenterology practice with esophageal food impaction were evaluated. Histories were assessed and esophageal biopsy specimens were evaluated by routine and immunohistochemical techniques. RESULTS: Thirty-one patients with food impaction were evaluated. Seventeen of 31 patients had >20 eosinophils/high power field (HPF) without gender predilection. Thirteen of these 17 patients had been treated with proton pump inhibitors at the time biopsy specimens were obtained. Patients with >20 eosinophils/HPF were significantly younger (mean age 42 +/- 4 years) than patients with <20 eosinophils/HPF (mean age 70 + 3 years). Superficial white exudates and eosinophilic microabscesses in the squamous epithelium were features observed only in patients with >20 eosinophils/HPF. Immunopathologic analysis demonstrated increased CD8 lymphocytes and major basic protein deposition in their squamous epithelium. CONCLUSIONS: More than half of patients with esophageal food impaction in a primary gastroenterology practice have >20 eosinophils/HPF. Based on clinicopathologic features, a significant number likely have eosinophilic esophagitis.

Abscess↗
PubMed2005

Allergic eosinophilic esophagitis: a primer for pathologists.

Allergic eosinophilic esophagitis is a recently described clinical-pathologic entity that is being increasingly recognized in children and adults. In this review, we evaluate current information on the clinical, endoscopic, and pathologic features of this condition and summarize the most useful parameters that support its diagnosis.

Adult↗
PubMed2005

Eosinophils alter colonic epithelial barrier function: role for major basic protein.

Mucosal eosinophils increase in a number of gastrointestinal diseases that are often associated with altered epithelial barrier function, including food allergic enteropathies and inflammatory bowel diseases. Although eosinophils are known to secrete biologically active mediators including granule proteins, their role in gastrointestinal diseases is uncertain. The aim of this study was to determine the impact of eosinophils on intestinal barrier function. Epithelial barrier function was determined in a coculture of eosinophils and T84 epithelial cells and in a murine model of T helper (Th) type 2-mediated colitis. Coculture conditions resulted in decreased transepithelial resistance (TER) and increased transepithelial flux. Cell-free coculture supernatants contained a > or =5-kDa soluble factor that also diminished TER; these supernatants contained the eosinophil-granule proteins major basic protein (MBP) and eosinophil-derived neurotoxin (EDN). T84 barrier function decreased significantly when basolateral surfaces were exposed to native human MBP but not EDN. Additional studies identified downregulation of the tight junctional molecule occludin as at least one mechanism for MBP action. MBP-null mice were protected from inflammation associated with oxazolone colitis compared with wild-type mice. In conclusion, MBP decreases epithelial barrier function and in this manner contributes to the pathogenesis of inflammatory bowel diseases.

Animals↗
PubMed2004

Association of Schatzki ring with eosinophilic esophagitis in children.

OBJECTIVE: To describe the clinicopathologic characteristics of children with Schatzki ring and to determine if Schatzki ring is associated with eosinophilic esophagitis. METHODS: The authors report 18 adolescents with radiographically diagnosed Schatzki ring (SR). Their clinical and histologic characteristics were reviewed in a blinded fashion. RESULTS: The mean age of the patients was 15.8 +/- 0.8 years and mean duration of symptoms was 2.6 +/- 0.4 years. By histologic criteria, two groups of patients were defined. Eight had clinical and histologic criteria of eosinophilic esophagitis (EE) and 10 of peptic esophagitis. There were no differences in the symptoms or radiographic findings in the two groups. The SR was not identified by endoscopy in any EE patient and was identified in 70% of peptic esophagitis patients. Grossly apparent mucosal features associated with EE were significantly more common in those with EE. Those with peptic esophagitis had a significantly higher acid exposure than did those with EE (12.6 +/- 2.9 v 2.0 +/- 1.1%; P < 0.01) by esophageal pH probe. Patients with peptic esophagitis responded to proton pump inhibitors and/or dilatation, whereas those with EE did not have good response and required specific therapy for EE. CONCLUSIONS: EE may play a role in the pathogenesis of some patients with SR.

Adolescent↗
PubMed2004

Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.

Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium-targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1-regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

Animals↗
PubMed2003

Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.

Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (>60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (>20-and >12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A2B receptor (AdoRA2B) is selectively up-regulated by hypoxia (>5-fold increase in mRNA), and that AdoRA2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia.

Adenine Nucleotides↗