Publications by authors named "Koichi Tomoda"

73 Publications

Case Report: Various Abnormalities in Lipid and Glucose Metabolism Induced by Capecitabine.

Front Oncol 2021 4;11:664475. Epub 2021 May 4.

Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan.

Capecitabine has been used for the treatment of various types of tumors. The rare side effects induced by capecitabine have been reported as hypertriglyceridemia, acute pancreatitis associated with hypertriglyceridemia and hypertriglyceridemia complicated with hyperglycemia. The mechanisms of capecitabine-induced hypertriglyceridemia are unclear. In this report, we present a subject with sigmoid colon cancer and capecitabine-induced dyslipidemia. LDL-cholesterol level was markedly elevated throughout the long period of treatment with capecitabine. In addition, triglyceride level was high and not stable during the treatment period. Her dyslipidemia was ameliorated by the treatment with 5 mg of rosuvastatin, which is one of the HMG-CoA reductase inhibitors.
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http://dx.doi.org/10.3389/fonc.2021.664475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130559PMC
May 2021

Primary Epstein-Barr virus infection shortly after primary Cytomegalovirus infection: a case report.

J Med Case Rep 2021 May 3;15(1):257. Epub 2021 May 3.

Department of General Internal Medicine 1, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.

Background: Infectious mononucleosis (IM) and mononucleosis-like illnesses are common viral infectious diseases which are often accompanied by a high fever, pharyngitis and lymphadenopathy in adults, although such infection in childhood is generally subclinical. Most cases of IM are caused by the Epstein-Barr virus (EBV) or Cytomegalovirus (CMV). However, it is difficult to diagnose IM only with subjective symptoms, and thus EBV and CMV are nearly indistinguishable in clinical practice.

Case Presentation: A 20-year-old healthy Japanese woman had a 2-day history of high fever and consulted us. She had sex for the first time 6 months earlier. Her virus antibodies showed that she was infected with primary CMV. About 5 months later, she again experienced high fever and lymph node enlargement at the posterior cervical region. Her virus antibodies showed that she was infected with primary EBV at that time.

Conclusion: Herein, we report a healthy adult Japanese woman with primary EBV infection relatively soon after primary CMV infection. It is very interesting to compare the symptoms and/or clinical data after EBV and CMV infection in the same patient within a short period of time. Our patient was diagnosed based only on subjective symptoms, physical examination and laboratory data, without tests of such virus-related antibodies. Therefore, clinicians should bear in mind that primary EBV infection and/or primary CMV infection is possible when patients have symptoms such as high fever, pharyngitis and lymphadenopathy, even in healthy adults.
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http://dx.doi.org/10.1186/s13256-021-02817-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091641PMC
May 2021

Case Report: Emphysematous Cystitis and Pyelonephritis Induced by Uterine Prolapse in a Subject With Untreated Diabetes Mellitus.

Front Med (Lausanne) 2021 9;8:658682. Epub 2021 Apr 9.

Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kawasaki, Japan.

Type 2 diabetes mellitus (T2DM) is often accompanied by a lot of complications due to chronic hyperglycemia and inflammation. Emphysematous cystitis and pyelonephritis are rare types of urinary tract infections and are often complicated with DM. Herein, we report a case of emphysematous cystitis and pyelonephritis complicated with untreated DM. In addition, this case was very rare and interesting in that her emphysematous cystitis and pyelonephritis were induced by severe uterine prolapse, obstructive uropathy and urination disorders. Both uterine prolapse and DM should be appropriately treated because both can lead to the development of emphysematous cystitis and pyelonephritis.
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http://dx.doi.org/10.3389/fmed.2021.658682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083874PMC
April 2021

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis.

Auris Nasus Larynx 2021 Aug 29;48(4):646-652. Epub 2021 Jan 29.

Department of Otorhinolaryngology, Kansai Medical University, shinmachi 2-5-1, Hirakata, Osaka, Japan.

Objective: Japanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed.

Methods: This study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients' nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices.

Results: From the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment.

Conclusion: The efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.
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http://dx.doi.org/10.1016/j.anl.2021.01.003DOI Listing
August 2021

Pyogenic psoas abscess on the dorsal side, and bacterial meningitis and spinal epidural abscess on the ventral side, both of which were induced by spontaneous discitis in a patient with diabetes mellitus: A case report.

J Diabetes Investig 2021 Jul 5;12(7):1301-1305. Epub 2020 Dec 5.

Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan.

Type 2 diabetes mellitus patients are immunocompromised, particularly under poorly controlled conditions, and thereby they could develop rare inflammatory diseases, such as spontaneous discitis, pyogenic psoas abscess, spinal epidural abscess and bacterial meningitis. Herein we report a pyogenic psoas abscess on the dorsal side, and bacterial meningitis and spinal epidural abscess on the ventral side, both of which were induced by spontaneous discitis in a patient with poorly controlled type 2 diabetes mellitus. This case was very rare and interesting, because we successfully treated various infections with antibiotics over a long period of time, complicated by hyperglycemic crises, although the patient suffered severe bone destruction and required rehabilitation for a long time.
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http://dx.doi.org/10.1111/jdi.13461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264412PMC
July 2021

Rapidly Exacerbating Autoimmune Hemolytic Anemia Together With Marked Cytokine Storm Triggered by Pneumonia Infection: A Case Report.

Front Immunol 2020 15;11:574540. Epub 2020 Sep 15.

Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan.

Autoimmune hemolytic anemia (AIHA) is caused by hemolysis induced by the reaction of autoantibodies with red blood cells. AIHA is usually classified as either warm antibody or cold antibody-mediated AIHA. In addition, AIHA caused by infection is classified as secondary AIHA. It is well-known that alteration of various cytokine levels is closely associated with a variety of disorders such as infectious diseases. In addition, it is known that IL-10/ IL-12 imbalance is an indicator of Th2-dominat conditions and a progressive marker of AIHA. A 82-year-old Japanese man was brought to the emergency room with pneumonia and heart failure. After admission, we started antibiotics therapy. Next day, he had symptoms of jaundice and his total bilirubin level was elevated. Five days after admission, his inflammation markers were further elevated and he had hemolytic anemia. We finally diagnosed him as severe warm-type AIHA associated with pneumoniae infection. Seven days after admission, his severe leucocytosis was further aggravated, and then he suddenly had cardiac arrest and respiratory failure, and finally died of multiple organ failure. Unfortunately, we failed to rescue him from severe AIHA induced by pneumonia infection. Herein, we report a subject with pneumonia-triggered warm-type AIHA together with marked cytokine storm. IL-18 levels were markedly elevated without elevation of IL-12 levels. In addition, IL-10/IL-12 imbalance was observed. These data suggest that once marked cytokine storm is induced, infection-induced AIHA is exacerbated very rapidly.
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http://dx.doi.org/10.3389/fimmu.2020.574540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522505PMC
June 2021

Early voice therapy for unilateral vocal fold paralysis improves subglottal pressure and glottal closure.

Am J Otolaryngol 2020 Nov - Dec;41(6):102727. Epub 2020 Sep 13.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010, Japan.

Purpose: In cases of unilateral vocal fold paralysis (UVFP), voice disorders caused by glottic insufficiency can lead to a considerable reduction in the patient's quality of life. Voice therapy (VT) is an effective treatment that must be started early after the onset of vocal fold paralysis. This study examined the effect of early VT for patients with UVFP occurring after esophagectomy.

Materials And Methods: Patients who had residual UVFP at 1 month postoperatively after esophagectomy for esophageal cancer between November 2014 and March 2017 were evaluated. Seventeen patients were divided into the VT group (n = 6) and non-VT group (n = 11). We compared these two groups and retrospectively examined the effect of early VT. The study endpoints included aerodynamic tests, laryngeal endoscopy, laryngeal stroboscopy, and glottal closure. All of these evaluations were performed at preoperatively and at 1 and 3 months postoperatively.

Results: Subglottal pressure reduced notably in the VT group, and both the mean flow rate and maximum phonation time tended to improve after VT. Conversely, there were no significant differences in MFR and MPT in the non-VT group. Furthermore, although UVFP remained after VT, we achieved glottal closure for all three patients. Conversely, only two of the six patients with glottic insufficiency in the non-VT group achieved glottal closure.

Conclusion: VT may be effective for improving impaired vocal function in patients with UVFP. It is reasonable to expect that VT can be initiated 1 month after the onset of vocal fold paralysis.
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http://dx.doi.org/10.1016/j.amjoto.2020.102727DOI Listing
December 2020

Basedow's disease with associated features of Hashimoto's thyroiditis based on histopathological findings.

BMC Endocr Disord 2020 Aug 5;20(1):120. Epub 2020 Aug 5.

Department of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, 701-0192, Japan.

Background: Basedow's disease and Hashimoto's thyroiditis are autoimmune thyroid disorders and usually diagnosed with elevation of serum autoimmune antibodies. Thyrotropin receptor antibodies (TRAb) and/or thyroid-stimulating antibody (TSAb) are usually used for diagnosis of Basedow's disease, and thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb) are for diagnosis of Hashimoto's thyroiditis. However, it is difficult to diagnose a subject as Basedow's disease with associated features of Hashimoto's thyroiditis only with elevation of such autoimmune antibodies.

Case Presentation: A 44-year-old woman with 5-year history of Basedow's disease underwent a total thyroidectomy. She did not have a goiter. TRAb, TSAb, TPOAg and TgAb were all positive before a total thyroidectomy. In histopathological macroscopic examination, diffuse hyperplasia of the thyroid gland was observed. Furthermore, in histopathological microscopic examination, both characteristics of Basedow's disease and Hashimoto's thyroiditis were observed. After a total thyroidectomy, titers of all thyroid-associated autoimmune antibodies were markedly reduced.

Conclusion: Herein, we report a subject with Basedow's disease without a goiter whose TPOAb and TgAb were relatively high at the onset of Basedow's disease. In addition, interestingly, the histopathological findings of this subject showed direct signs of Basedow's disease and Hashimoto's thyroiditis in the same thyroid gland. Considering from such findings, she seemed to have Basedow's disease with associated features of Hashimoto's thyroiditis. In conclusion, we should bear in mind the possibility of Basedow's disease with associated features of Hashimoto's thyroiditis in subjects with Basedow's disease, particularly when TPOAb and TgAb as well as TRAb and TSAb are positive.
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http://dx.doi.org/10.1186/s12902-020-00602-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405338PMC
August 2020

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

Allergol Int 2020 Apr 10;69(2):232-238. Epub 2020 Jan 10.

Department of Otorhinolaryngology, Head & Neck Surgery, Kansai Medical University, Osaka, Japan.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear.

Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69.

Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking.

Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma.
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http://dx.doi.org/10.1016/j.alit.2019.11.002DOI Listing
April 2020

A Novel Approach for Investigating Upper Airway Hyperresponsiveness Using Micro-CT in Eosinophilic Upper Airway Inflammation such as Allergic Rhinitis Model.

Biomolecules 2019 06 27;9(7). Epub 2019 Jun 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Airway hyperresponsiveness (AHR) has been proposed as a feature of pathogenesis of eosinophilic upper airway inflammation such as allergic rhinitis (AR). The measurement system for upper AHR (AHR) in rodents is poorly developed, although measurements of nasal resistance have been reported. Here we assessed UAHR by direct measurement of swelling of the nasal mucosa induced by intranasal methacholine (MCh) using micro-computed tomography (micro-CT). Micro-CT analysis was performed in both naïve and ovalbumin-induced AR mice following intranasal administration of MCh. The nasal cavity was segmented into two-dimensional horizontal and axial planes, and the data for nasal mucosa were acquired for the region of interest threshold. Then, a ratio between the nasal mucosa area and nasal cavity area was calculated as nasal mucosa index. Using our novel method, nasal cavity structure was clearly identified on micro-CT, and dose-dependent increased swelling of the nasal mucosa was observed upon MCh treatment. Moreover, the nasal mucosa index was significantly increased in AR mice compared to controls following MCh treatment, while ovalbumin administration did not affect swelling of the nasal mucosa in either group. This UAHR following MCh treatment was completely reversed by pretreatment with glucocorticoids. This novel approach using micro-CT for investigating UAHR reflects a precise assessment system for swelling of the nasal mucosa following MCh treatment; it not only sheds light on the mechanism of AR but also contributes to the development of new therapeutic drugs in AR patients.
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http://dx.doi.org/10.3390/biom9070252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681309PMC
June 2019

Critical role of CCL4 in eosinophil recruitment into the airway.

Clin Exp Allergy 2019 06 29;49(6):853-860. Epub 2019 Mar 29.

Department of General Medical Practice and Laboratory Diagnostic Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Background: Excessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1β (MIP-1β or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships between eosinophils and CCL4, have not been fully elucidated.

Objective: To examine the involvement of CCL4 in eosinophilic airway inflammation.

Methods: We analysed supernatants of activated eosinophils and BALF from 16 patients with eosinophilic pneumonia (EP). Further, we examined the effects of CCL4 on eosinophil functions in vitro and those of anti-CCL4 neutralizing antibody in an in vivo model.

Results: We found that purified human eosinophils stimulated with IL-5 predominantly secreted CCL4 and that patients with EP had elevated CCL11 and CCL4 levels in BALF compared with samples from individuals without EP. Because CCL4 levels were more strongly correlated with eosinophil count and expression of eosinophil granule proteins than CCL11, in vitro experiments using purified eosinophils concentrated on the former chemokine. Interestingly, CCL4 acted as a chemoattractant for eosinophils. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness.

Conclusions And Clinical Relevance: Overall, these findings highlight an important role of CCL4 in the mechanisms underlying eosinophil recruitment into the airway and may provide a novel insight into this potential therapeutic target.
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http://dx.doi.org/10.1111/cea.13382DOI Listing
June 2019

Eosinophilic Upper Airway Inflammation in a Murine Model Using an Adoptive Transfer System Induces Hyposmia and Epithelial Layer Injury with Convex Lesions.

Med Sci (Basel) 2019 Feb 5;7(2). Epub 2019 Feb 5.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory upper airway disease, accompanied mainly by eosinophilia and/or asthma. In addition, the disease correlates with a high rate of hyposmia, following a marked infiltration of eosinophils into the inflamed site, the paranasal sinus. Although eosinophils are known to contribute to the development of hyposmia and CRSwNP pathology, the underlying mechanisms remain unclear. This study aimed to investigate whether eosinophilic upper airway inflammation induces hyposmia and CRSwNP in a murine model using an adoptive transfer system.

Methods: To induce eosinophilic rhinosinusitis, splenocytes, including a high proportion (over 50%) of activated eosinophils (SPLhEos), were collected from interleukin-5 transgenic mice following double intraperitoneal injections of antigens, such as ovalbumin, house dust mite, or fungus. Activated SPLhEos with corresponding antigens were then transferred into the nasal cavity of recipient mice, which were sensitized and challenged by the corresponding antigen four times per week. Olfactory function, histopathological, and computed tomography (CT) analyses were performed 2 days after the final transfer of eosinophils.

Results: Hyposmia was induced significantly in mice that received SPLhEos transfer compared with healthy and allergic mice, but it did not promote morphological alteration of the paranasal sinus. Pathological analysis revealed that epithelial layer injury and metaplasia similar to polyps, with prominent eosinophil infiltration, was induced in recipient tissue. However, there was no nasal polyp development with interstitial edema that was similar to those recognized in human chronic rhinosinusitis.

Conclusions: This study supports the previously unsuspected contribution of eosinophils to CRS development in the murine model and suggests that murine-activated eosinophilic splenocytes contribute to the development of hyposmia due to more mucosal inflammation than physical airway obstruction and epithelial layer injury with convex lesions.
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http://dx.doi.org/10.3390/medsci7020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409781PMC
February 2019

Regulation of Interaction between the Upper and Lower Airways in United Airway Disease.

Med Sci (Basel) 2019 Feb 11;7(2). Epub 2019 Feb 11.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, 573-1010, Japan.

The concept of united airway disease comprises allergic rhinitis (AR) with asthma, and eosinophilic chronic rhinosinusitis (ECRS) with asthma. It embodies a comprehensive approach to the treatment of upper and lower airway inflammation. The treatment of upper airway inflammation reduces asthma symptoms and decreases the dose of inhaled corticosteroids (ICS) necessary to treat asthma. However, little is known about the mechanisms of interaction between upper and lower airway inflammation. Here we review these mechanisms, focusing on neural modulation and introduce a novel therapeutic approach to united airway disease using a fine-particle ICS. Our understanding of the relationship between the upper and lower airways and its contribution to T helper 2 (Th2)-skewed disease, such as AR and/or ECRS with asthma, has led us to this novel therapeutic strategy for a comprehensive approach to the treatment of upper airway inflammation with asthma.
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http://dx.doi.org/10.3390/medsci7020027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410259PMC
February 2019

HFA-BDP Metered-Dose Inhaler Exhaled Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial Asthma: A Blinded, Placebo-Controlled Study.

Front Immunol 2018 25;9:2192. Epub 2018 Sep 25.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka, Japan.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma. Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN ( = 11) or placebo MDI ETN ( = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity. HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10-30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance. Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).
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http://dx.doi.org/10.3389/fimmu.2018.02192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178134PMC
October 2019

Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.

Am J Nephrol 2018 18;47(5):325-332. Epub 2018 May 18.

Department of Nephrology, Wakayama Medical University, Wakayama, Japan.

Background: Recent studies suggest that prebiotic and/or probiotic treatments ameliorate kidney function in humans and animals by improving the gut environment. However, the gut microbiota and kidney disease interactions remain to be determined. This study investigated whether synbiotics modulate the gut microbiota and ameliorate kidney function using a rat model of chronic kidney disease (CKD). As uremic toxins are associated with CKD-related mineral and bone disorder, the secondary aim was to evaluate the relationship between synbiotics and secondary hyperparathyroidism (SHPT).

Methods: 5/6 nephrectomy (Nx) rats were developed as the CKD model. Sham-operated (sham) rats were used as the control. To investigate the effectiveness of prebiotics (glutamine, dietary fiber, and oligosaccharide) and probiotics (Bifidobacterium longum strain; GFOB diet), rats were randomly assigned to 4 groups: Nx group fed the GFOB diet (n = 10); Nx group fed the control (CON) diet (n = 10); sham group fed the GFOB diet (n = 5); and sham group fed the control diet (n = 5). Blood, feces, and kidney samples were collected and analyzed.

Results: Serum creatinine (Cre) and blood urea nitrogen in the Nx GFOB group were significantly lower than those in the Nx CON group. Serum indoxyl sulfate in the Nx GFOB group was lower than that in the Nx CON group, and significantly correlated with serum Cre. Inorganic phosphorus and intact parathyroid hormone in the Nx GFOB group were significantly lower than those in the Nx CON group.

Conclusion: Improving the gut environment using synbiotics ameliorated kidney function and might be a pharmacological treatment for SHPT without any serious adverse events.
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http://dx.doi.org/10.1159/000488947DOI Listing
December 2019

Persimmon-derived tannin has bacteriostatic and anti-inflammatory activity in a murine model of Mycobacterium avium complex (MAC) disease.

PLoS One 2017 21;12(8):e0183489. Epub 2017 Aug 21.

Department of Immunology, Nara Medical University, Kashihara, Nara, Japan.

Nontuberculous mycobacteria (NTM), including Mycobacterium avium complex (MAC), cause opportunistic chronic pulmonary infections. Notably, MAC susceptibility is regulated by various factors, including the host immune system. Persimmon (Ebenaceae Diospyros kaki Thunb.) tannin is a condensed tannin composed of a polymer of catechin groups. It is well known that condensed tannins have high antioxidant activity and bacteriostatic properties. However, it is hypothesized that condensed tannins might need to be digested and/or fermented into smaller molecules in vivo prior to being absorbed into the body to perform beneficial functions. In this study, we evaluated the effects of soluble persimmon-derived tannins on opportunistic MAC disease. Soluble tannins were hydrolyzed and evaluated by the oxygen radical absorbance capacity (ORAC) method. The ORAC value of soluble tannin hydrolysate was approximately five times greater than that of soluble tannin powder. In addition, soluble tannin hydrolysate exhibited high bacteriostatic activity against MAC in vitro. Furthermore, in an in vivo study, MAC infected mice fed a soluble tannin-containing diet showed significantly higher anti-bacterial activity against MAC and less pulmonary granuloma formation compared with those fed a control diet. Tumor necrosis factor α and inducible nitric oxide synthase levels were significantly lower in lungs of the soluble tannin diet group compared with the control diet group. Moreover, proinflammatory cytokines induced by MAC stimulation of bone marrow-derived macrophages were significantly decreased by addition of soluble tannin hydrolysate. These data suggest that soluble tannin from persimmons might attenuate the pathogenesis of pulmonary NTM infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565117PMC
October 2017

Cells Expressing Prominin-1 in Neonatal Murine Inferior Colliculus Differentiate into Neurons and Glia.

Mol Neurobiol 2018 Jun 9;55(6):4998-5005. Epub 2017 Aug 9.

Department of Public Health, Kansai Medical University, Osaka, Japan.

Inferior colliculus (IC) is a major center for the integration and processing of acoustic information from ascending auditory pathways. Damage to the IC as well as normal aging can impair auditory function. Novel strategies such as stem cell (SC)-based regenerative therapy are required for functional recovery because mature neural cells have a minimal regenerative capacity after an injury. However, it is not known if there are neural stem cells (NSCs) in the IC. Herein, we screened for NSCs by surface marker analysis using flow cytometry. Isolated IC cells expressing prominin-1 (CD133) exhibited the cardinal NSC properties self-renewal capacity, expression of known NSC markers (SOX2 and nestin), and multipotency. Prominin-1-expressing cells from neonatal IC generated neurospheres, and culture of these neurospheres in differentiation-conditioned medium gave rise to gamma-aminobutyric acid-ergic (GABAergic) neurons, astrocytes, and oligodendrocytes. The presence of NSC-like cells in the IC has important implications for understanding IC development and for potential regenerative therapy.
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http://dx.doi.org/10.1007/s12035-017-0701-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948249PMC
June 2018

Prevalence of chronic obstructive pulmonary disease in independent community-dwelling older adults: The Fujiwara-kyo study.

Geriatr Gerontol Int 2017 Dec 16;17(12):2421-2426. Epub 2017 Jun 16.

Second Department of Internal Medicine, Nara Medical University, Nara, Japan.

Aim: As the Japanese population ages, the number of older patients with chronic obstructive pulmonary disease (COPD) is expected to increase, but the prevalence of COPD in patients aged ≥80 years remains unclear. The purpose of the present study was to determine the prevalence of COPD in independent community-dwelling older adults aged ≥80 years.

Methods: We investigated the prevalence of COPD in 2862 independent community-dwelling older adults (1504 men, 1358 women, mean age 77.7 ± 7.0 years) who underwent spirometry in the Fujiwara-kyo study, a study of successful aging in older adults. Those participants with airflow limitation (forced expiratory volume in 1 s/forced vital capacity <0.7) who indicated on a self-administered questionnaire that they had a history of smoking and did not have bronchial asthma were considered to have COPD.

Results: The prevalence of COPD was 16.9% among all participants and 37.4% among smokers. The prevalence among individuals aged ≥80 years (19.7%) was significantly higher than that among those aged <80 years (16.0%; P < 0.05). When forced expiratory volume in 1 s/forced vital capacity lower limit of normal was used as the criterion for airflow limitation, the prevalence fell to 11.0%. Patients with mild-to-moderate airflow limitation (stage I/stage II) accounted for the great majority (91.2%) of COPD patients aged ≥80 years.

Conclusions: A high prevalence of mild-to-moderate COPD was observed even in the independent community-dwelling older adults aged ≥80 years. However, the benefits of the spirometric screening and treatment for these patients needs to be determined. Geriatr Gerontol Int 2017; 17: 2421-2426.
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http://dx.doi.org/10.1111/ggi.13091DOI Listing
December 2017

Residual Recurrent Nerve Paralysis After Esophagectomy is Associated with Preoperative Lower Serum Albumin.

Dysphagia 2017 08 24;32(4):520-525. Epub 2017 Apr 24.

Department of Otolaryngology Head & Neck Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.

Esophagectomy for esophageal cancer is invasive thoracic surgery with a high incidence rate of postoperative complications and prolongation of hospitalization, even if the standardized clinical pathway improves the outcome (mortality and morbidity). Postoperative recurrent nerve paralysis (RNP) is related to respiratory complications concomitant with prolonged hospitalization. However, it has not been elucidated which factors affect the incidence and recovery of RNP. To detect the predictive factor for postoperative RNP, we focused on preoperative serum albumin. Patients who had esophageal cancer with standard esophagectomy were evaluated. In total, 94 patients were divided into three groups depending on the presence of RNP (46 in patients without RNP, 29 in those with transient RNP who recovered within 6 months follow-up and 19 in those with residual RNP). We retrospectively investigated factors associated with residual RNP. Preoperative lower serum albumin was associated with residual RNP. In addition, days to the resumption of oral intake and duration of stay in the hospita postoperatively were delayed in the group of residual RNP. Multiple regression analysis indicated that preoperative serum albumin was a predictive factor for residual RNP. Preoperative lower serum albumin level might be linked to residual RNP which could prolong the resumption of postoperative oral intake and shorten the period of stay at the hospital after esophagectomy, leading to unfavorable outcomes for patients.
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http://dx.doi.org/10.1007/s00455-017-9793-3DOI Listing
August 2017

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development.

Mol Ther Nucleic Acids 2017 Mar 31;6:163-172. Epub 2016 Dec 31.

Second Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan.

Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E. CS-E augments cell contraction and CHST15 siRNA inhibits collagen production. We found that bleomycin treatment increased CHST15 expression in interstitial fibroblasts at day 14. CHST15 siRNA was injected intranasally on days 1, 4, 8, and 11, and CHST15 mRNA was significantly suppressed by day 14. CHST15 siRNA reduced lung CSPG and the grade of fibrosis. CHST15 siRNA repressed the activation of fibroblasts, as evidenced by suppressed expression of α smooth muscle actin (αSMA), connective tissue growth factor (CTGF), lysyl oxidase like 2 (LOXL2), and CC-chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). Inflammatory infiltrates in the bronchoalveolar lavage fluid (BALF) and interstitium were diminished by CHST15 siRNA. These results indicate a pivotal role for CHST15 in fibroblast-mediated lung fibrosis and suggest a possible new therapeutic role for CHST15 siRNA in pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.omtn.2016.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363499PMC
March 2017

Primary Malignant Lymphoma Originating from the Chest Wall without Preceding Pleural Disease.

Intern Med 2017 17;56(6):681-686. Epub 2017 Mar 17.

Department of Respiratory Medicine, Saiseikai Suita Hospital, Japan.

An 84-year-old woman presented to our hospital with dyspnea on exertion and left back pain. Chest X-ray and chest computed tomography (CT) revealed an irregular pleural mass invading her left chest wall with rib destruction and pleural effusion. CT-guided needle biopsy revealed diffuse large B-cell lymphoma. Low-dose oral etoposide produced a complete response, and she continued oral chemotherapy for one year after the diagnosis and maintained good performance status. We herein report a very rare case of non-pyothorax-associated lymphoma that nonetheless resulted in great recovery.
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http://dx.doi.org/10.2169/internalmedicine.56.7053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410480PMC
May 2017

Acute Bilateral Renal and Splenic Infarctions Occurring during Chemotherapy for Lung Cancer.

Intern Med 2016;55(24):3635-3639. Epub 2016 Dec 15.

The Second Department of Internal Medicine, Nara Medical University, Japan.

We herein report a rare case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer. A 60-year-old man presented with acute and intensive upper abdominal and back pain during chemotherapy with cisplatin and etoposide for lung cancer. Contrast-enhanced computed tomography (CT) revealed bilateral renal and splenic infarctions. After the administration of unfractionated heparin his pain was relieved with a clearance of the infarctions in the CT findings and a recovery of renal dysfunction. Enhanced coagulation by lung cancer and arterial ischemia by chemotherapy may therefore contribute to the development of these infarctions.
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http://dx.doi.org/10.2169/internalmedicine.55.6891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283965PMC
April 2017

Replacement of SFC-DPI with SFC-MDI exhaled through the nose improves eosinophilic chronic rhinosinusitis in patients with bronchial asthma.

Int J Clin Pharmacol Ther 2017 Jan;55(1):89-94

Objective: Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is a refractory disease closely associated with bronchial asthma. We recently reported on the efficacy of ultra-fine particle inhaled corticosteroids (ICS) (hydrofluoroalkane-134a-beclomethasone dipropionate: HFA-BDP) exhalation through the nose (ETN) treatment for mild-to-moderate asthmatics with ECRS. However, the effect of HFA-BDP ETN was found to be transient in some cases with severe ECRS and asthma, requiring treatment with higher-dose ICS and long-acting β2-agonists (LABA). Here, we present a case of refractory ECRS with severe asthma treated with a combination of high-dose ICS and LABA ETN, and we discuss the mechanisms for its effectiveness.

Methods: A 57-year-old man was treated with the combined regimen of HFA-BDP ETN and salmeterol/fluticasone combination (SFC) dry powder inhaler (DPI) for his refractory ECRS with severe asthma. For better control, we replaced SFC-DPI with SFC metered-dose inhaler (MDI) ETN and evaluated the clinical effect and corticosteroid sensitivity. We also examined the flow and deposition of fine particles released by SFC-MDI ETN.

Results: After switching to SFC-MDI ETN, the patient's conditions markedly resolved with the restoration of corticosteroid sensitivity and PP2A activity. The fine particles released by SFC-MDI ETN at least partially flowed out through the external nares and seemed to be deposited on the ethmoid sinus.

Conclusion: Fine particle ICS/LABA ETN might be an additional therapeutic option for refractory ECRS with severe asthma and corticosteroid insensitivity.
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http://dx.doi.org/10.5414/CP202633DOI Listing
January 2017

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression.

Allergol Int 2017 Jan 5;66(1):42-51. Epub 2016 Aug 5.

Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP).

Methods: IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined.

Results: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs.

Conclusions: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.
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http://dx.doi.org/10.1016/j.alit.2016.04.017DOI Listing
January 2017

Reexamination of Etiology and Surgical Outcome in Patient With Advanced External Auditory Canal Cholesteatoma.

Otol Neurotol 2016 07;37(6):728-34

Department of Otolaryngology-Head and Neck Surgery, Kansai Medical University, Osaka, Japan.

Objective: To describe the etiology of advanced cases of external auditory canal (EAC) cholesteatoma (EACC), and to report the surgical management and outcomes based on canalplasty depending on the extent of adjacent structures involvement around the EAC.

Study Design: Retrospective case review.

Setting: University hospital.

Patients: Participants comprised 28 patients (12 males, 16 females) ranging in age from 9 to 86 years old. All patients presented with advanced-stage EACC (Naim's classification: stage III/IV).

Intervention: Surgery ranged from simple bony meatoplasty with cartilage graft repair to more enlarged EAC canalplasty combined with tympanoplasty.

Result: EACC was categorized as idiopathic in 22 patients and secondary EACC in six patients. Six patients with idiopathic EACC were receiving hemodialysis, one of whom showed bilateral pathology. Particularly in cases with epithelial invasion into the hypotympanum immediately adjacent to the jugular bulb, multi-layered repair including bone paste, post-auricular pedicled musculo-periosteal flap, auto cartilage, and temporalis muscle fascia were required. Five patients required revision surgery (17%), including one case of recurrent (reconstructed) cholesteatoma and three cases of perforation of the tympanic membrane.

Conclusion: In the majority of our series, underlying diseases followed with microangiopathy and angiogenesis could be possible candidates in the etiology of EACC. Enlarged bony meatoplasty and multilayered reconstruction surgery brought about self-cleaning and dried the EAC in advanced-stage EACC.
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http://dx.doi.org/10.1097/MAO.0000000000001079DOI Listing
July 2016

Concomitant Systemic Sclerosis and Sarcoidosis with Combined Pulmonary Fibrosis and Emphysema.

Intern Med 2016 15;55(10):1331-5. Epub 2016 May 15.

Department of Respiratory Medicine, Saiseikai Suita Hospital, Japan.

A 75-year-old woman was referred to our hospital with the chief symptom of dyspnea. Chest computed tomography revealed lymphadenopathy, emphysema, and honeycombing. Sarcoidosis was diagnosed due to an elevated serum ACE level and the findings of a lymph-node biopsy. Her smoking history, radiography findings, and impaired gas exchange indicated combined pulmonary fibrosis and emphysema (CPFE). Raynaud's phenomenon gradually appeared, and we also diagnosed her with systemic sclerosis (SSc). Right heart catheterization revealed pulmonary hypertension (PH). Smoking was assumed to be the chief cause, but SSc may also induce the development of CPFE. Severe PH induced by CPFE or SSc was present, but the influence of sarcoidosis also could not be ignored.
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http://dx.doi.org/10.2169/internalmedicine.55.5903DOI Listing
March 2017

Hypertrophic Pachymeningitis as a Delayed Complication of Granulomatosis with Polyangiitis.

Intern Med 2016 15;55(4):413-7. Epub 2016 Feb 15.

Second Department of Internal Medicine, Nara Medical University, Japan.

A 69-year-old man presented with upper airway symptoms, multiple lung nodules and masses, proteinuria and hematuria, and an increased level of proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA). Granulomatosis with polyangiitis (GPA) was diagnosed by a transbronchial lung biopsy. All of these symptoms were ameliorated and the level of PR3-ANCA declined following treatment with prednisolone and cyclophosphamide. The patient developed a headache 16 months after the onset of symptoms, and contrast-enhanced magnetic resonance imaging showed the thickening of the dura mater, which suggested that hypertrophic pachymeningitis (HP) had developed as a complication of GPA. HP can be a unique complication of GPA at recurrence, and can occur without the relapse of other lesions or an increase in PR3-ANCA level.
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http://dx.doi.org/10.2169/internalmedicine.55.5434DOI Listing
August 2016

Establishment of mesenchymal stem cell lines derived from the bone marrow of green fluorescent protein-transgenic mice exhibiting a diversity in intracellular transforming growth factor-β and bone morphogenetic protein signaling.

Mol Med Rep 2016 Mar 18;13(3):2023-31. Epub 2016 Jan 18.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan.

Cytokines and their intercellular signals regulate the multipotency of mesenchymal stem cells (MSCs). The present study established the MSC lines SG‑2, ‑3, and ‑5 from the bone marrow of green fluorescent protein (GFP)‑transgenic mice. These cell lines clearly expressed mouse MSC markers Sca‑1 and CD44, and SG‑2 and ‑5 cells retained the potential for osteogenic and adipogenic differentiation in the absence of members of the transforming growth factor (TGF)‑β superfamily. By contrast, SG‑3 cells only retained adipogenic differentiation potential. Analysis of cytokine and cytokine receptor expression in these SG cell lines showed that bone morphogenetic protein (BMP) receptor 1B was most highly expressed in the SG‑3 cells, which underwent osteogenesis in response to BMP, while TGF‑β receptor II was most highly expressed in SG‑3 and ‑5 cells. However, it was unexpectedly noted that phosphorylation of Smad 2, a major transcription factor, was induced by TGF‑β1 in SG‑2 cells but not in SG‑3 or ‑5 cells. Furthermore, TGF‑β1 clearly induced the expression of Smad‑interacting transcription factor CCAAT/enhancer binding protein‑β in SG‑2 but not in SG‑3 or ‑5 cells. These results demonstrated the establishment of TGF‑β‑responsive SG‑2 MSCs, BMP‑responsive SG‑3 MSCs and TGF‑β/BMP‑unresponsive SG‑5 MSCs, each of which was able to be traced by GFP fluorescence after transplantation into in vivo experimental models. In conclusion, the present study suggested that these cell lines may be used to explore how the TGF‑β superfamily affects the proliferation and differentiation status of MSCs in vivo.
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http://dx.doi.org/10.3892/mmr.2016.4794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768972PMC
March 2016

RNA interference targeting carbohydrate sulfotransferase 3 diminishes macrophage accumulation, inhibits MMP-9 expression and promotes lung recovery in murine pulmonary emphysema.

Respir Res 2015 Dec 9;16:146. Epub 2015 Dec 9.

Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara, 634-8521, Japan.

Background: Chondroitin sulfate proteoglycans are an important mediators in inflammation and leukocyte trafficking. However, their roles in pulmonary emphysema have not been explored. In a murine model of elastase-induced pulmonary emphysema, we found increased carbohydrate sulfotransferase 3 (CHST3), a specific enzyme that synthesizes chondroitin 6-sulfate proteoglycan (C6SPG). To elucidate the role of C6SPG, we investigated the effect of small interfering RNA (siRNA) targeting CHST3 that inhibits C6SPG-synthesis on the pathogenesis of pulmonary emphysema.

Methods: Mice were intraperitoneally injected with CHST3 siRNA or negative control siRNA on day0 and 7 after intratracheal instillation of elastase. Histology, respiratory function, glycosaminoglycans (GAGs) content, bronchoalveolar lavage (BAL), elastin staining and gene expressions of tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9 mRNA were evaluated on day7 and/or day21.

Results: CHST3 mRNA increased at day 7 and decreased thereafter in lung. CHST3 siRNA successfully inhibited the expression of CHST3 mRNA throughout the study and this was associated with significant reduction of GAGs and C6SPG. Airway destruction and respiratory function were improved by the treatment with CHST3 siRNA. CHST3 siRNA reduced the number of macrophages both in BAL and lung parenchyma and also suppressed the increased expressions of TNF-α and MMP-9 mRNA. Futhermore, CHST3 siRNA improved the reduction of the elastin in the alveolar walls.

Conclusions: CHST3 siRNA diminishes accumulation of excessive macrophages and the mediators, leading to accelerate the functional recovery from airway damage by repair of the elastin network associated with pulmonary emphysema.
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http://dx.doi.org/10.1186/s12931-015-0310-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673861PMC
December 2015

A Hypopharyngeal Lipoma Resulting in Obstructive Sleep Apnea.

Intern Med 2015 1;54(21):2789-90. Epub 2015 Nov 1.

Second Department of Internal Medicine, Nara Medical University, Japan.

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http://dx.doi.org/10.2169/internalmedicine.54.4287DOI Listing
May 2016
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