Eosinophils; Esophagitis; Symptoms; Therapy
Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. As such, therapies aimed at eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, and diseases not primarily associated with eosinophils such as autoimmunity and malignancy. Recently, eosinophil-targeted therapeutic agents aimed at blocking specific steps involved in eosinophil development, migration and activation have entered clinical testing and have produced encouraging results and insights into the role of eosinophils. Herein, we describe recent advances in the development of first generation eosinophil-targeted therapies and highlight strategies for using personalized medicine approaches for eosinophilic disorders.
We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13–driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. Herein, we compared epithelial responses between normal (NL) and EE patients aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained up to 5 passages, with 67% and 62% of cell lines reaching confluence in NL and EE, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 ± 1.98 ng/mL vs. 12.46 ± 2.90 ng/mL at pH 7.4 and 4 respectively, p<0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin, and SPRR3 were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies compared to NL. While the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared to control individuals (6.1% vs. 1.3% respectively, p=0.0172), the decreased filaggrin expression was uniformly seen in all EE patients in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.
CD22 is currently recognized as a B cell-specific Siglec and has been exploited therapeutically with humanized anti-CD22 monoclonal antibody having been used against B cell leukemia. Herein, tissue-specific eosinophil mRNA microarray analysis identified that CD22 transcript levels of murine gastrointestinal (GI) eosinophils are 10-fold higher than those of lung eosinophils. In order to confirm the mRNA data at the protein level, we developed a FACS-based protocol designed to phenotype live GI eosinophils isolated from the murine lamina propria. Indeed, we found that jejunum eosinophils expressed remarkably high levels of surface CD22, similar to levels found in B cells across multiple mouse strains. In contrast, CD22 was undetectable on eosinophils from the colon, blood, thymus, spleen, uterus, peritoneal cavity and allergen-challenged lung. Eosinophils isolated from newborn mice did not express CD22 but subsequently upregulated CD22 expression to adult levels within the first 10 days after birth. The GI lamina propria from CD22 gene-targeted mice harbored more eosinophils than wild-type control mice, while the GI eosinophil turnover rate was unaltered in the absence of CD22. Our findings identify a novel expression pattern and tissue eosinophilia-regulating function for the “B cell-specific” inhibitory molecule CD22 on GI eosinophils.
Eosinophils; mucosa; Siglec; CD22
Eosinophilic esophagitis (EE) is an emerging disease associated with both food and respiratory allergy characterized by extensive esophageal tissue remodeling and abnormal esophageal gene expression including increased IL-13. We investigated the ability of increased airway IL-13 to induce EE-like changes. Mice that overexpress an IL-13 transgene in the lung (but not esophagus) accumulated esophageal IL-13 and developed prominent esophageal remodeling with epithelial hyperplasia, angiogenesis, collagen deposition and increased circumference. IL-13-induced marked changes in esophageal transcripts overlapped with the human EE esophageal transcriptome. IL-13-induced esophageal eosinophilia was eotaxin-1 (but not eotaxin-2) dependent but remodeling occurred independent of eosinophils, as demonstrated by studying eosinophil lineage-deficient IL-13 transgenic mice. IL-13-induced remodeling was significantly enhanced by IL-13Rα2 gene deletion, indicating an inhibitory effect of IL-13Rα2. In the murine system, there was partial overlap between IL-13-induced genes in the lung and esophagus, yet the transcriptomes were also divergent at the tissue level. In human esophagus, IL-13 levels correlated with the magnitude of the EE transcriptome. In conclusion, inducible airway expression of IL-13 results in an esophageal gene expression and extensive tissue remodeling pattern that resembles human EE. Notably, we have identified a pathway for inducing EE-like changes that is IL-13-driven, eosinophil-independent and suppressed by IL-13Rα2.
Eosinophilic esophagitis (EoE) is a polygenic disorder characterized by the accumulation of eosinophils in the esophagus. We carried out a genome-wide association study on clinically and biopsy confirmed EoE patients to identify common variants associated with the disease risk. One hundred and eighty one EoE samples from Cincinnati Children’s Hospital (CCHMC) and 170 EoE samples and ~3100 controls from Children’s Hospital of Philadelphia (CHOP) were genotyped on the Illumina 550K BeadChip. All patients and controls were of European ancestry. Following standard quality control filtering of the genotype data we carried out Cochran-Armitage trend tests at each SNP using the CCHMC samples as a discovery cohort. We detected genome-wide association with variants on chr5q22 that mapped to a single LD block encompassing the TSLP and WDR36 genes. The most significantly associated SNP at that locus which maps upstream of the TSLP gene remained wide significant after Bonferroni correction (rs3806932, uncorrected P-value = 7.18×10−8, OR = 0.54). Eleven other SNPs in LD with rs3806932 were also significantly associated with EoE and mapped to the same LD block on 5q22. We subsequently replicated the association in the independent CHOP cohort (170 cases, 1130 controls) with rs3806932 P-value = 8×10−3 OR = 0.73; combined P-value for rs3806932 across CCHMC and CHOP cohorts = 3.19×10−9). In addition, TSLP was overexpressed in the esophagus of EoE patients compared with control individuals with no differences observed in the expression of WDR36. In conclusion, we have identified the first genetic association with EoE predisposition at 5q22 implicating TSLP and/or WDR36 as genes potentially involved in the pathogenesis of EoE.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is compounded by both genetic predisposition and aberrant responses to environmental antigens, particularly those that are food-derived. Data have indicated a unique transcriptional response in vivo that defines EoE and which is partially attributable to the Th2 cytokine interleukin 13 (IL-13). Moreover, a number of genetic risk variants in pro-inflammatory and epithelial cell genes associate with EoE susceptibility, demonstrating novel heritable mechanisms that contribute to disease risk. Here, we discuss recent advances in our understanding of the intrinsic (genetic) and extrinsic (environmental) components that illustrate the complex nature of EoE.
Eosinophilic esophagitis; genetics; candidate gene; genome-wide association; polymorphism
Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disorder that responds to dietary therapy; however, data evaluating the effectiveness of dietary therapeutic strategies is limited.
This study compared the effectiveness of three frequently prescribed dietary therapies [elemental, six-food elimination, and skin prick and atopy patch-directed elimination] and assessed the remission predictability of skin tests and their utility in directing dietary planning.
A retrospective cohort of proton-pump inhibitor-unresponsive, non-glucocorticoid-treated eosinophilic esophagitis patients who had two consecutive endoscopic biopsies associated with dietary intervention was identified. Biopsy histology and remissions (< 15 eosinophils/high-power field) following dietary therapy and food reintroductions were evaluated.
Ninety-eight of 513 patients met eligibility criteria. Of these 98, 50% (49), 27% (26), and 23% (23) received elemental, six-food elimination, and directed diets, respectively. Remission occurred in 96%, 81%, and 65% of patients on elemental, six-food elimination, and directed diets, respectively. The odds of post-diet remission vs. non-remission were 5.6-fold higher (P=0.05) on elemental vs. six-food elimination, 12.5-fold higher (P=0.003) on elemental vs. directed, and were not significantly different (P=0.22) on six-food elimination vs. directed diets. Following 116 single-food reintroductions, the negative predictive value of skin testing for remission was 40%–67% (milk 40%, egg 56%, soy 64%, and wheat 67%).
All three dietary therapies are effective; however, an elemental diet is superior at inducing histologic remission compared with six-food elimination and skin test-directed diets. Notably, an empiric six-food elimination diet is as effective as a skin test-directed diet. The negative predictive values of foods most commonly reintroduced in single-food challenges are not sufficient to support the development of dietary advancement plans solely based on skin tests.
Eosinophilic esophagitis; eosinophils; histologic remission; pediatric; dietary therapy; food allergy; negative predictive values; elemental diet; six-food elimination diet; skin test-directed elimination diet
Mast Cells; Eosinophilic Esophagitis; Human
Resistin-like molecule α (Relm-α) is one of the most up-regulated gene products in allergen- and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-α was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-α production, and the role of Relm-α after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-α was secreted into the airway lumen, dependent on both the IL-13 receptor–α1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene–targeted mice demonstrate that Relm-α was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-α in the lungs. The differential regulation of Relm-α expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-α in acute experimental models of allergen-associated Th2 immune responses.
resistin-like molecule–α; asthma; IL-4; IL-13Rα1
Eosinophils are multifunctional leukocytes that increase in various tissues in a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse inflammatory responses. In this review, the clinical association of eosinophils with diseases of the skin, lung and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, etiology and treatment are discussed.
asthma; cutaneous; dermatitis; eosinophilia; esophagitis; intestine; lung; respiratory; skin
eosinophil disorders; hypereosinophilic syndrome (HES); global consensus; classification
Gastrointestinal eosinophilia, as a broad term for abnormal eosinophil accumulation in the GI tract, involves many different disease identities. These diseases include primary eosinophil associated gastrointestinal diseases, gastrointestinal eosinophilia in HES and all gastrointestinal eosinophilic states associated with known causes. Each of these diseases has its unique features but there is no absolute boundary between them. All three groups of GI eosinophila are described in this chapter although the focus is on primary gastrointestinal eosinophilia, i.e. EGID.
Eosinophil; gastrointestinal; inflammation; pathogenesis; therapy
Interleukin (IL)-13 and IL-4 are hallmark cytokines of Th2-associated diseases including asthma. Recent studies revealed that IL-13Rα1 regulates asthma pathogenesis by mediating both IL-4 and IL-13-mediated responses. Nonetheless, the relative contribution of each cytokine in response to aeroallergen challenge and the degree of functional dichotomy between IL-4 and IL-13 in asthma remains unclear. Consistent with prior publications, we demonstrate that IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production but not IgE and Th2 cytokine production. We demonstrate that aeroallergen-induced eosinophil recruitment and chemokine production were largely dependent of IL-13Rα1 following Aspergillus (Asp) but not house dust mite (HDM) challenges. Notably, Asp-challenged mice displayed increased IL-13Rα1-dependent accumulation of dendritic cell subsets into lung draining lymph nodes in comparison with HDM. Comparison of IL-4 and IL-13 levels in the different experimental models revealed increased IL-4:IL-13 ratios following HDM challenge, likely explaining the IL-13Rα1-independent eosinophilia and chemokine production. Consistently, eosinophil adoptive-transfer experiments revealed near ablation of lung eosinophilia in response to Asp in Il13ra1−/− mice, suggesting that Asp-induced lung eosinophil recruitment is regulated by IL-13-induced chemokine production, rather than altered IL-13 signaling in eosinophils. Furthermore, the near complete protection observed in Il13ra1−/− mice in response to Asp-challenge was dependent on mucosal sensitization since Alum/Asp-sensitized mice that were re-challenged with Asp developed IL-13Rα1-independent eosinophilia although other asthma parameters remained IL-13Rα1-dependent. These results establish that IL-13Rα1 is required for aeroallergen-induced airway resistance and that allergen-induced chemokine production and consequent eosinophilia is dictated by the balance between IL-4 and IL-13 production in situ.
Allergy; Lung; Cytokines; Chemokines; Cytokine receptors; Eosinophils
IL-13 overexpression in the lung induces inflammatory and remodeling responses that are prominent features of asthma. Whereas most studies have concentrated on the development of IL-13–induced disease, far fewer studies have focused on the reversibility of IL-13–induced pathologies. This is particularly important because current asthma therapy appears to be poor at reversing lung remodeling. In this manuscript, we used an externally regulatable transgenic system that targets expression of IL-13 to the lung with the aim of characterizing the reversibility process. After 4 wk of doxycycline (dox) exposure, IL-13 expression resulted in mixed inflammatory cell infiltration, mucus cell metaplasia, lung fibrosis, and airspace enlargement (emphysema). After withdrawal of dox, IL-13 protein levels were profoundly reduced by 7 d and below baseline by 14 d. During this time frame, the level of lung eosinophils returned to near normal, whereas macrophages, lymphocytes, and neutrophils remained markedly elevated. IL-13–induced mucus cell metaplasia significantly decreased (91%) 3 wk after withdrawal of dox, showing strong correlation with reduced eosinophil levels. In contrast, IL-13–induced lung fibrosis did not significantly decline 4 wk after dox withdrawal. Importantly, IL-13–induced emphysema persisted, but modestly declined 4 wk after dox. Examination of transcript expression profiles identified a subset of genes that remained increased weeks after transgene expression was no longer detected. Notably, numerous IL-13–induced cytokines and enzymes were reversible (IL-6 and cathepsins), whereas others were sustained (CCL6 and chitinases) after IL-13 withdrawal, respectively. Thus, several hallmark features of IL-13–induced lung pathology persist and are dissociated from eosinophilia after IL-13 overexpression ceases.
asthma; cytokines; eosinophils; inflammation; lung
An altered balance between Th1 and Th2 cytokines is responsible for a variety of immuno-inflammatory disorders such as asthma, yet the role of post-transcriptional mechanisms, such as those mediated by microRNAs, in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. Here we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to antigens. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome, and significantly increased levels of the Th1 cytokine IFNγ. Biological network-based transcriptome analysis of OVA-challenged miR-21-/-mice identified an unexpected prominent dysregulation of IL-12/IFNγ pathways as the most significantly affected in the lungs with a key role for miR-21 in IFNγ signaling and T-cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation, and OVA-challenged CD4+ T lymphocytes to produce increased IFNγ and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 vs. Th2 responses, defining a new mechanism for regulating polarized immuno-inflammatory responses.
Tissue recruitment and activation of eosinophils contribute to allergic symptoms by causing airway hyperresponsiveness and inflammation. Shape changes and mediator release in eosinophils may be regulated by mammalian Rho-related guanosine triphosphatases. Of these, Rac2 is essential for F-actin formation as a central process underlying cell motility, exocytosis, and respiratory burst in neutrophils, while the role of Rac2 in eosinophils is unknown. We set out to determine the role of Rac2 in eosinophil mediator release and F-actin-dependent shape change in response to chemotactic stimuli.
Rac2-deficient eosinophils from CD2-IL-5 transgenic mice crossed with rac2 gene knockout animals were examined for their ability to release superoxide through respiratory burst or eosinophil peroxidase by degranulation. Eosinophil shape change and actin polymerization were also assessed by flow cytometry and confocal microscopy following stimulation with eotaxin-2 or platelet-activating factor.
Eosinophils from wild-type mice displayed inducible superoxide release, but at a small fraction (4–5%) of human eosinophils. Rac2-deficient eosinophils showed significantly less superoxide release (p < 0.05, 26% less than wild type). Eosinophils lacking Rac2 had diminished degranulation (p < 0.05, 62% less eosinophil peroxidase) and shape changes in response to eotaxin-2 or platelet-activating factor (with 68 and 49% less F-actin formation, respectively; p < 0.02) compared with wild-type cells.
These results demonstrate that Rac2 is an important regulator of eosinophil function by contributing to superoxide production, granule protein release, and eosinophil shape change. Our findings suggest that Rho guanosine triphosphatases are key regulators of cellular inflammation in allergy and asthma.
Superoxide; Eosinophil peroxidase; Exocytosis; Calcium ionophore; Eotaxin-2; Platelet-activating factor
Recent genome-wide association studies of pediatric IBD have implicated the 17q12 loci, which contains the eosinophil specific chemokine gene CCL11, with early-onset IBD susceptibility. In the present study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that DSS treatment promotes the recruitment of F4/80+CD11b+CCR2+Ly6Chigh inflammatory monocytes into the colon. F4/80+CD11b+CCR2+Ly6Chigh monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6Chigh intestinal inflammatory MΦs revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4 and Cxcl2, and Arg1, Chi3l3, Ccl11 and IL-10, respectively. Attenuation of DSS-induced F4/80+CD11b+CCR2+Ly6Chigh monocyte recruitment to the colon in CCR2−/− mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6ChighCCR2+ inflammatory monocyte/MΦ-derived CCL11.
Background & Aims
Innate and adaptive immune responses are regulated by crosstalk between activation and inhibitory signals. Dysregulation of the inhibitory signal can lead to aberrant chronic inflammatory diseases such as the inflammatory bowel diseases (IBD). Little is known about negative regulation of innate intestinal immune activation. We examined the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of macrophage function in innate intestinal immunity.
We examined the susceptibility of Pirb-/- and wild-type (WT) mice to dextran sodium sulfate (DSS)-induced colitis. We assessed proinflammatory cytokine release and MAPK and NFκB activation in Pirb-/- and WT macrophages following E. coli stimulation. Macrophage transfer experiments were performed to define the role of PIR-B in the negative regulation of macrophage function in DSS-induced colitis. We also assessed expression of PIR-B human homologs (ILT-2 and ILT-3) in colon biopsy samples from healthy individuals (controls) and patients with IBD.
Pirb-/- mice had increased susceptibility to DSS-induced colitis. In vitro analysis demonstrated increased production of proinflammatory cytokines (IL-6, IL-1β and TNF-α) and activation of MAPK and NFκB in Pirb-/- macrophages following bacterial activation. Adoptive transfer of bone marrow-derived Pirb-/- macrophages into WT mice was sufficient to increase disease susceptibility. ILT-2 and ILT-3 were expressed on CD68+ and CD68- mononuclear cells and intestinal epithelium in colon biopsy samples from patients and controls.
PIR-B negatively regulates macrophage functions in response to pathogenic bacteria and chronic intestinal inflammatory responses. Inhibitory receptors such as PIR-B might be used as therapeutic targets for treatment of patients with IBD.
Inhibitory receptors; macrophages; IBD
Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition.
Definition; eosinophilia; eosinophilic leukemia; hypereosinophilic syndromes
Eosinophil infiltration into the esophagus is observed in diverse diseases including gastroesophageal reflux and allergic gastroenteritis, but the processes involved are largely unknown. We now report an original model of experimental esophagitis induced by exposure of mice to respiratory allergen. Allergen-challenged mice develop marked levels of esophageal eosinophils, free eosinophil granules, and epithelial cell hyperplasia, features that mimic the human disorders. Interestingly, exposure of mice to oral or intragastric allergen does not promote eosinophilic esophagitis, indicating that hypersensitivity in the esophagus occurs with simultaneous development of pulmonary inflammation. Furthermore, in the absence of eotaxin, eosinophil recruitment is attenuated, whereas in the absence of IL-5, eosinophil accumulation and epithelial hyperplasia are ablated. These results establish a pathophysiological connection between allergic hypersensitivity responses in the lung and esophagus and demonstrate an etiologic role for inhaled allergens and eosinophils in gastrointestinal inflammation.
The histological identification of increased eosinophils in the gastrointestinal tract occurs in numerous clinical disorders; however, there is a limited understanding of the mechanisms regulating eosinophil trafficking into this mucosal surface. The results presented in this study characterize the processes regulating eosinophil homing into the gastrointestinal tract at baseline. Eosinophils were found to be present in the lamina propria of 19-day-old embryos and germ-free adult mice at concentrations comparable to those present in non–germ-free adult mice. Furthermore, eosinophil gastrointestinal levels were not altered by increasing circulating eosinophils after pulmonary allergen challenge. Gastrointestinal eosinophil levels were partially reduced in mice deficient in recombinase activating gene-1 (RAG-1), IL-5, or the β common chain (βc), but these reductions paralleled reductions in circulating eosinophils. In contrast, mice deficient in eotaxin had a marked reduction in gastrointestinal eosinophils but normal levels of eosinophils in the hematopoietic compartments. Furthermore, eotaxin was important for regulating eosinophil levels, even in the presence of high levels of IL-5. These investigations demonstrate eosinophil homing into the gastrointestinal tract during embryonic development occurring independently of viable intestinal flora. Furthermore, eotaxin is identified as the primary regulator of eosinophil gastrointestinal homing under homeostatic states, and may therefore have a fundamental role in innate immune responses.
J. Clin. Invest. 103:1719–1727 (1999).
Genome-wide screening and positional cloning have linked neuropeptide S receptor 1 (NPSR1) with asthma and airway hyperresponsiveness. However, the mechanism by which NPSR1 regulates pulmonary responses remains elusive. Because neuropeptide S and its receptor NPSR1 are expressed in brain regions that regulate respiratory rhythm, and Npsr1-deficient mice have impaired stress and anxiety responses, we aimed to investigate whether neuropeptide S and NPSR1 regulate respiratory function through a central-mediated pathway. After neuropeptide S intracerebroventricular administration, respiratory responses of wildtype and Npsr1-deficient mice were monitored by whole-body or invasive plethysmography with or without serial methacholine inhalation. Airway inflammatory and hyperresponsiveness were assessed in allergen-challenged (ovalbumin or Aspergillus fumigatus) Npsr1-deficient mice. Analysis of breathing patterns by whole-body plethysmography revealed that intracerebroventricular neuropeptide S, as compared with the artificial cerebral spinal fluid control, increased respiratory frequency and decreased tidal volume in an NPSR1-dependent manner but did not affect enhanced pause. Following serial methacholine inhalation, intracerebroventricular neuropeptide S increased respiratory frequency in wildtype mice, but not Npsr1-deficient mice, and had no effect on tidal volume. Intracerebroventricular neuropeptide S significantly reduced airway responsiveness to methacholine as measured by whole-body plethysmography. Npsr1 deletion had no impact on airway inflammation or hyperresponsiveness in ovalbumin- or Aspergillus fumigatus-induced experimental asthma. Our results demonstrate that neuropeptide S and NPSR1 regulate respiratory function through a central nervous system-mediated pathway.
Respiration; brain; neuropeptide S; neuropeptide S receptor 1; panting; stress
This study examined health-related quality of life and adjustment among children with eosinophil- associated gastrointestinal disorders (EGID) compared with an age-matched sample without acute or chronic illness. Participants were youth ages 2 to 18 years. Children and caregivers completed measures of psychological symptoms and health-related quality of life (HRQOL). Significant group differences were found for child report of depressive, as well as anxiety symptoms. Significant group differences were also found for caregiver report of psychological symptoms and social skills. Finally, based on parent and youth report, HRQOL and greater school absenteeism were associated with EGID diagnosis.