Citations
167 citation(s) found for "Kita, H".
Airway epithelial anion secretion and barrier function following exposure to fungal aeroallergens: role of oxidative stress
Zaidman, Nathan A. , O’Grady, Kelly E., Patil, Nandadevi, Milavetz, Francesca, Maniak, Peter J., Kita, Hirohito , O’Grady, Scott M. , Kita, H
American Journal of Physiology-Cell Physiology | April 27, 2017 | Volume: 313 | Issue: 1 | Pages: C68-C79
10.1152/ajpcell.00043.2017
| PMID 28446427
Aeroallergens produced by Alternaria alternata can elicit life-threatening exacerbations of asthma in patients sensitized to this fungus. In this study, the effect of Alternaria on ion transport mechanisms underlying mucociliary clearance and airway epithelial barrier function was investigated in human airway epithelial cells. Apical exposure to Alternaria induced an increase in anion secretion that was inhibited by blockers of CFTR and Ca2+-activated Cl− channels. Stimulation of anion secretion was dependent on Ca2+ uptake from the apical solution. Alternaria exposure also produced an increase in reactive oxygen species (ROS) that was blocked by pretreatment with the oxidant scavenger glutathione (GSH). GSH and the NADPH oxidase inhibitor/complex 1 electron transport inhibitor diphenylene iodonium chloride (DPI) blocked ATP release and the increase in intracellular [Ca2+] evoked by Alternaria. Alternaria also decreased transepithelial resistance, and a portion of this effect was dependent on the increase in ROS. However, the Alternaria-induced increase in unidirectional dextran (molecular mass = 4,000 Da) flux across the epithelium could not be accounted for by increased oxidative stress. These results support the conclusion that oxidative stress induced by Alternaria was responsible for regulating Ca2+-dependent anion secretion and tight junction electrical resistance that would be expected to affect mucociliary clearance.
Correlation of Symptoms, Clinical Signs, and Biomarkers of Inflammation in Postsurgical Chronic Rhinosinusitis
Racette, Samuel D. , Wijewickrama, Rohan C., Jayaprakash, Vijayvel , Sherris, David A., Kita, Hirohito , O’Donnell, Frank E., Ponikau, Jens U., Santos, Carlos Henrique Marques dos , Kita, H
Annals of Otology, Rhinology & Laryngology | April 5, 2017 | Volume: 126 | Issue: 6 | Pages: 455-462
10.1177/0003489417701939
| PMID 28376637
Objective: The study aimed to evaluate symptoms described by patients with chronic rhinosinusitis with polypoid changes/nasal polyps and their correlation with computed tomography (CT), nasal endoscopy, and intranasal biomarkers. Study Design: Prospective multicenter study symptom data from postsurgical adult chronic rhinosinusitis study participants with recurrent disease refractory to medical therapy were analyzed in comparison with objective data. Methods: Using logistic regression analysis, participant-rated 16-question surveys from 258 participants were assessed for correlation with nasal endoscopy scores, CT percentage of sinus occlusion, and intranasal biomarkers of fungal antigens (Alternaria and Aspergillus), eosinophilic inflammation (eosinophil-derived neurotoxin [EDN] and major basic protein [MBP]), and inflammatory cytokines (interleukins 5 and 13). Results: Study participant assessments revealed increased CT occlusion in participants presenting with greater inability to smell ( P < .019). Mucosal inflammation identified on nasal endoscopy was positively correlated with congestion ( P < .028), runny nose ( P < .002), and ear pain ( P < .007). Elevated EDN was positively correlated in patients with bothersome congestion ( P < .031) and runny nose ( P < .011). Sneezing was positively correlated with multiple markers: Alternaria ( P < .024), interleukin-13 ( P < .027), MBP ( P < .034), and interleukin-5 ( P < .019). Conclusion: Nasal endoscopy, not CT imaging, has the strongest correlation with the 2 cardinal symptoms of congestion and runny nose in CRS patients; these correlate with biomarkers of eosinophilic inflammation.
Application of a Natural Language Processing Algorithm to Asthma Ascertainment. An Automated Chart Review
Sohn, Sunghwan , Rolfes, Mary , Seabright, Alicia, Ryu, Euijung , Voge, Gretchen A., Bachman, Kay, Park, Miguel A., Kita, Hirohito , Croghan, Ivana T. , Liu, Hongfang , Juhn, Young J. , Bachman, Kay A, Wi, Chung‐Il , Kita, H
American Journal of Respiratory and Critical Care Medicine | April 4, 2017 | Volume: 196 | Issue: 4 | Pages: 430-437
10.1164/rccm.201610-2006oc
| PMID 28375665
Abstract Rationale Difficulty of asthma ascertainment and its associated methodologic heterogeneity have created significant barriers to asthma care and research. Objectives We evaluated the validity of an existing natural language processing (NLP) algorithm for asthma criteria to enable an automated chart review using electronic medical records (EMRs). Methods The study was designed as a retrospective birth cohort study using a random sample of 500 subjects from the 1997–2007 Mayo Birth Cohort who were born at Mayo Clinic and enrolled in primary pediatric care at Mayo Clinic Rochester. Performance of NLP-based asthma ascertainment using predetermined asthma criteria was assessed by determining both criterion validity (chart review of EMRs by abstractor as a gold standard) and construct validity (association with known risk factors for asthma, such as allergic rhinitis). Measurements and Main Results After excluding three subjects whose respiratory symptoms could be attributed to other conditions (e.g., tracheomalacia), among the remaining eligible 497 subjects, 51% were male, 77% white persons, and the median age at last follow-up date was 11.5 years. The asthma prevalence was 31% in the study cohort. Sensitivity, specificity, positive predictive value, and negative predictive value for NLP algorithm in predicting asthma status were 97%, 95%, 90%, and 98%, respectively. The risk factors for asthma (e.g., allergic rhinitis) that were identified either by NLP or the abstractor were the same. Conclusions Asthma ascertainment through NLP should be considered in the era of EMRs because it can enable large-scale clinical studies in a more time-efficient manner and improve the recognition and care of childhood asthma in practice.
Kita, Hirohito
Nihon Shoni Arerugi Gakkaishi. The Japanese Journal of Pediatric Allergy and Clinical Immunology | March 18, 2017 | Volume: 14 | Issue: 3 | Pages: 303-303
Oxidative stress serves as a key checkpoint for IL‐33 release by airway epithelium
Uchida, Masaru , Anderson, Elizabeth , Squillace, Diane L., Patil, Nikita , Maniak, Peter J., Iijima, Koji, Kita, Hirohito , Kita, H , O’Grady, Scott M.
Allergy | March 8, 2017 | Volume: 72 | Issue: 10 | Pages: 1521-1531
10.1111/all.13158
| PMID 28273344
AbstractBackgroundInterleukin (IL)‐33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL‐33 release is controlled. The transcription factor nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) plays a key role in antioxidant response regulation.ObjectiveThe goal of this project was to investigate the role of cellular oxidative stress in controlling IL‐33 release in airway epithelium.MethodsComplementary approaches were used that included human bronchial epithelial cells and mouse models of airway type‐2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2‐cyano‐3,12‐dioxooleana‐1,9‐dien‐28‐oic acid methyl ester (CDDO‐Me) was used to evaluate the role of Nrf2‐induced antioxidant molecules.ResultsHuman bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N‐acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL‐33 release. Administration of CDDO‐Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO‐Me treatment reduced allergen‐induced ATP secretion and IL‐33 release by airway epithelial cells in vitro and protected mice from IL‐33 release and asthma‐like pathological changes in the lungs.ConclusionsThe balance between oxidative stress and antioxidant responses plays a key role in controlling IL‐33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.
Unsupervised network mapping of commercially available immunoassay yields three distinct chronic rhinosinusitis endotypes
Divekar, Rohit , Rank, Matthew A. , Squillace, Diane L., Kita, Hirohito , Rank, Matthew, Squillace, Diane, Lal, Devyani , Kita, H
International Forum of Allergy & Rhinology | January 2, 2017 | Volume: 7 | Issue: 4 | Pages: 373-379
10.1002/alr.21904
| PMID 28042687
Background Endotyping chronic rhinosinusitis (CRS) through simplified cytokine assays may help direct individualized therapy such as corticosteroids, antibiotics, or biologics. We performed an unsupervised network analysis to endotype CRS and control subjects using a commercially available cytokine‐chemokine immunoassay. Methods A 41‐plex cytokine‐chemokine array along with major basic protein (MBP) assay was performed on sinonasal surgical tissue of 32 adults. Subjects were defined as non‐CRS controls (n = 6), CRS with nasal polyps (CRSwNP; n = 13), and CRS without nasal polyps (CRSsNP; n = 13). Unsupervised network modeling was performed to reveal association cytokine‐chemokine (“analyte”) clusters and “subject” groups. Results Network mapping and unsupervised clustering revealed 3 analyte clusters and 3 subject groups. Analyte cluster‐1 was composed of T helper 1 (Th1)/Th17 type markers, analyte cluster‐2 Th2 markers, and analyte cluster‐3 chemokines (CC) and growth factors (GF). Subject group‐1 was devoid of CRSwNP, had fewer asthmatics, and was associated most strongly with analyte cluster‐3 (CC/GF) ( p < 0.001). Subject group‐2 was characterized with the most asthmatics (86%) and CRSwNP (100%) patients, and was associated with analyte cluster‐2 (Th2; p < 0.001). Subject group‐3 was associated with both analyte cluster‐1 (Th1/Th17) and analyte cluster‐3 (CC/GF) ( p < 0.001), and had the highest proportion of CRSsNP patients (62.5%). Tissue levels of MBP, eosinophilia, and computed tomography (CT) scores were significantly higher in subject group‐2 vs other groups ( p ≤ 0.05). Conclusion An unbiased network‐mapping approach using a commercially available immunoassay kit reveals 3 distinct tissue cytokine‐chemokine signatures that endotype CRS patients and controls. These signatures are prominent even in a limited number of patients, and may help formulate individualized therapy and optimize outcomes.
Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis
Kouzaki, Hideaki , Matsumoto, Koji , Kikuoka, Hirotaka , Shimizu, Shino , Kita, Hirohito , Shimizu, Takeshi , Shimizu, Shino , Shimizu, Takeshi , Kato, Tomohisa , Tojima, Ichiro , Kita, H
American Journal of Respiratory and Critical Care Medicine | October 25, 2016 | Volume: 195 | Issue: 6 | Pages: 737-747
10.1164/rccm.201603-0529oc
| PMID 27779422
Abstract Rationale Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function. Objectives To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS). Methods We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined. Measurements and Main Results Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology. Conclusions Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.
Influence of HLA‐DR polymorphism and allergic sensitization on humoral immune responses to intact pneumococcus in a transgenic mouse model
Sheen, Youn Ho, Rajagopalan, Govindarajan , Snapper, Clifford M. , Kita, Hirohito , Juhn, Young J. , Wi, Chung‐Il , Umaretiya, Puja J. , Kita, H
HLA | August 10, 2016 | Volume: 88 | Issue: 1-2 | Pages: 25-34
10.1111/tan.12851
| PMID 27506953
AbstractAsthma is independently associated with HLA‐DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA‐DR polymorphism (HLA‐DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti‐pneumococcal polysaccharide and anti‐surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA‐DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat‐killed Pn14 at day 24. Serum titers of anti‐phosphorylcholine (PC) IgM and IgG, anti‐pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti‐pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM‐sensitized and 22 control mice). HDM‐sensitized mice, irrespective of HLA‐DR polymorphism, had significantly lower humoral immune responses. HLA‐DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti‐PC IgG response. In contrast, the anti‐PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti‐PPS14 IgG and anti‐PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA‐DR polymorphism.
Group 2 Innate Lymphoid Cells Promote an Early Antibody Response to a Respiratory Antigen in Mice
Iijima, Koji, Bartemes, Kathleen R. , Kita, Hirohito , Drake, Li Yin, Drake, Li Y. , Kita, H
The Journal of Immunology | July 16, 2016 | Volume: 197 | Issue: 4 | Pages: 1335-1342
10.4049/jimmunol.1502669
| PMID 27421480
Abstract Innate lymphoid cells (ILCs) are a new family of immune cells that play important roles in innate immunity in mucosal tissues, and in the maintenance of tissue and metabolic homeostasis. Recently, group 2 ILCs (ILC2s) were found to promote the development and effector functions of Th2-type CD4+ T cells by interacting directly with T cells or by activating dendritic cells, suggesting a role for ILC2s in regulating adaptive immunity. However, our current knowledge on the role of ILCs in humoral immunity is limited. In this study, we found that ILC2s isolated from the lungs of naive BALB/c mice enhanced the proliferation of B1- as well as B2-type B cells and promoted the production of IgM, IgG1, IgA, and IgE by these cells in vitro. Soluble factors secreted by ILC2s were sufficient to enhance B cell Ig production. By using blocking Abs and ILC2s isolated from IL-5–deficient mice, we found that ILC2-derived IL-5 is critically involved in the enhanced production of IgM. Furthermore, when adoptively transferred to Il7r−/− mice, which lack ILC2s and mature T cells, lung ILC2s promoted the production of IgM Abs to a polysaccharide Ag, 4-hydroxy-3-nitrophenylacetyl Ficoll, within 7 d of airway exposure in vivo. These findings add to the growing body of literature regarding the regulatory functions of ILCs in adaptive immunity, and suggest that lung ILC2s promote B cell production of early Abs to a respiratory Ag even in the absence of T cells.
IL‐33 mediates reactive eosinophilopoiesis in response to airborne allergen exposure
Anderson, Élizabeth , Iijima, Koji, Bartemes, Kathleen R. , Chen, C.‐C. , Kita, H., Kita, Hirohito , Kobayashi, Takao , Kita, H
Allergy | February 11, 2016 | Volume: 71 | Issue: 7 | Pages: 977-988
10.1111/all.12861
| PMID 26864308
AbstractBackgroundExposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues.MethodsTo investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene‐deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms.ResultsNaïve BALB/c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata. Expression of IL‐5 and IL‐33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen‐exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti‐IL‐5 antibody. Mice deficient in the IL‐33 receptor ST2 (i.e., Il1rl1−/− mice) were unable to increase their serum levels of IL‐5 and allergen‐induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells (ILC2s) in the lungs showed robust expression of IL‐5 after Alternaria exposure.ConclusionsThese finding suggests that lung IL‐33, through innate activation of ILC2s and their production of IL‐5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions.