Masayuki Nakayama

Physical activity in patients with idiopathic pulmonary fibrosis

Physical activity is an important parameter in patients with chronic obstructive pulmonary disease, but has not been studied in detail in patients with interstitial lung disease. This study aimed to evaluate physical activity in patients with idiopathic pulmonary fibrosis (IPF).

Clinical Significance of Interleukin 33 (IL-33) in Patients with Eosinophilic Pneumonia

BACKGROUND Interleukin 33 (IL-33) works as a functional mediator in allergic disease by enhancing the activity of eosinophils and inducing expression of T helper 2 (Th2)-associated cytokines. However, the role of IL-33 in pulmonary eosinophilia has not been elucidated. We investigated the levels of IL-33 in eosinophilic pneumonia (EP) together with associated cytokines, and discussed the clinical significance of IL-33 in EP. METHODS Sera and bronchoalveolar lavage fluid (BALF) were obtained from 16 patients with EP, including acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP). Twelve patients with acute respiratory distress syndrome (ARDS) were also included for comparison. The concentration of IL-33 and Th2 cytokines (IL-4, IL-5, IL-13) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS The concentration of serum IL-33 was significantly higher in patients with AEP than in CEP. In CEP, only patients with atopic factors showed mild increase of serum IL-33. The concentration of BALF IL-33 was also significantly elevated in AEP, however, it remained quite low in CEP. Among Th2 cytokines, IL-5 was significantly increased in both serum and BALF in AEP, and the level of IL-5 was positively correlated with that of IL-33. ARDS showed no increase of serum and BALF IL-33. CONCLUSIONS The remarkable increase of BALF IL-33 in AEP indicated the local production of IL-33 in lungs. IL-33 is considered to be a local key molecule for triggering pulmonary eosinophilia, together with IL-5. BALF IL-33 appears to be a useful marker for discriminating AEP from CEP and ARDS.

Impaired inflammatory responses to multiple Toll-like receptor ligands in alveolar macrophages of streptozotocin-induced diabetic mice

ObjectiveTo investigate the effect of hyperglycemic state on the activation of alveolar macrophages (AMs) mediated via Toll-like receptors (TLRs) typically associated with bacterial infection.MethodsAMs obtained from normoglycemic control mice and streptozotocin-induced diabetic mice were stimulated ex vivo with the following: a TLR2 ligand, peptidoglycan (PGN); a TLR4 ligand, lipopolysaccharide (LPS); or a TLR5 ligand, flagellin (FLG). Cytokine production and mRNA expression were measured by ELISA and real-time PCR, respectively. TLR expression was assessed by real-time PCR and flow cytometry.ResultsAMs from diabetic mice produced significantly less TNF-α after PGN or FLG stimulation, and less IL-6 after FLG stimulation, compared with AMs from control mice. The decrease in the production of these cytokines was associated with reduced mRNA expression of the corresponding cytokines. In contrast, production of TNF-α and IL-6 after LPS stimulation did not differ between groups. Furthermore, there was no substantial difference in the expression of TLR2, TLR4, and TLR5 in AMs between the groups. The increased JNK phosphorylation induced by PGN or FLG stimulation was downregulated in AMs from diabetic mice.ConclusionsHyperglycemic state impairs the reactivity of AMs to multiple TLR ligands. This effect might result from hyperglycemia-induced alteration of intracellular signaling and is unlikely due to the modulation of TLR expression.

Effect of hochuekkito on alveolar macrophage inflammatory responses in hyperglycemic mice.

Diabetes mellitus reduces immunological activity and increases susceptibility to various infections. Hochuekkito (TJ-41) has been reported to improve the weakened physical condition of various chronic diseases. BALB/c mice were divided into three groups; groups A and B were fed a standard diet, and group C, a TJ-41 diet. Two weeks after starting these diets, hyperglycemia was induced in groups B and C by injection with streptozotocin. Two weeks later, bronchoalveolar lavage was performed. Toll-like receptor (TLR) ligands (TLR2: peptidoglycan, PGN; TLR4: lipopolysaccharide, LPS; TLR5: flagellin, FLG) were used to stimulate alveolar macrophages (AMs), and TNF-α production was measured. Under hyperglycemic conditions and PGN or FLG stimulation, TNF-α production from AMs was significantly reduced in group B compared with group A. However, treatment with TJ-41 (group C) significantly improved the impaired production of TNF-α. These results suggest that, under hyperglycemic conditions, TJ-41 can improve the inflammatory responses of AMs with stimulation of TLR ligands.

Serum Torque Teno Virus DNA Titer in Idiopathic Pulmonary Fibrosis Patients with Acute Respiratory Worsening

OBJECTIVE Acute respiratory worsening is defined as the unexpected rapid deterioration of idiopathic pulmonary fibrosis (IPF), and idiopathic acute respiratory worsening is known as an acute exacerbation of IPF. Torque teno virus (TTV) is a circular single-stranded DNA virus whose pathological significance remains unclear. The aim of the present study was to investigate the prevalence and titer of TTV DNA in IPF patients with acute respiratory worsening. METHODS The serum TTV DNA titer was measured using real-time PCR in nine IPF patients (two treated with steroids and immunosuppressants; seven treated without steroids or immunosuppressants) who developed acute worsening, including five patients with acute exacerbation. The serum TTV DNA titer was also measured in eight stable IPF cases and four IPF cases of lung cancer. In addition, in order to examine time course changes in the TTV DNA titer, the titer was measured more than once, with an interval of four weeks or longer, in eight patients. RESULTS Among the nine IPF patients with acute worsening, the TTV DNA titer was above 1×10(6) copies/mL in two subjects without acute exacerbation who had been continuously treated with steroids and immunosuppressants. Meanwhile, the mean TTV DNA titer was 2.4±2.6 (×10(4) copies/mL) in the five patients with acute exacerbation and 3.1±3.4 (×10(4) copies/mL) in the eight patients with stable IPF. Moreover, the TTV DNA titers were increased in all three IPF patients who started treatment with steroids and immunosuppressants. CONCLUSION Our results suggest that it is unlikely that TTV is directly involved in the onset of acute exacerbation of IPF and that the serum TTV DNA titer potentially reflects the immunosuppressive state of the host due to treatment.

Age-related differences in chest radiographic staging of sarcoidosis in Japan

To the Editor: Sarcoidosis is generally thought to occur more frequently in adults 50 years of age [2, 3]. When comparing the results of national epidemiological surveys conducted in Japan between 1960 and 2004, the incidence rate in females >50 years of age can be seen to have gradually increased while that for bilateral hilar lymphadenopathy (BHL) has decreased [3]. However, whether there is any association between these trends in Japan remains to be elucidated. An earlier study conducted in Europe suggested that older patients are less likely to present with stage 1 sarcoidosis at diagnosis [2]. Against this background, in this study, we aimed to identify the age-related differences in chest radiographic staging of sarcoidosis in Japan. We reviewed 588 consecutive Japanese patients newly diagnosed with sarcoidosis (431 biopsy proven and 157 clinically proven) who were admitted to or underwent bronchoscopy between April 1974 and July 2012 at Jichi Medical University Hospital (Tochigi, Japan). The diagnosis was made based on the diagnostic criteria and guidelines for sarcoidosis developed by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2007 [4]. We compared chest radiographic staging between subgroups differentiated by sex and age at diagnosis (younger diagnosis group <45 years of age, older …

Memory-type ST2 + CD4 + T cells participate in the steroid-resistant pathology of eosinophilic pneumonia

The lung develops an unique epithelial barrier system to protect host from continuous invasion of various harmful particles. Interleukin (IL-)33 released from epithelial cells in the lung drives the type 2 immune response by activating ST2− expressed immune cells in various allergic diseases. However, the involvement of memory-type ST2+CD4+ T cells in such lung inflammation remains unclear. Here we demonstrated that intratracheal administration of IL-33 resulted in the substantial increase of numbers of tissue-resident memory-type ST2+CD4+ T cells in the lung. Following enhanced production of IL-5 and IL-13, eosinophilic lung inflammation sequentially developed. IL-33-mediated eosinophilic lung inflammation was not fully developed in T cell-deficient Foxn1nu mice and NSG mice. Dexamethasone treatment showed limited effects on both the cell number and function of memory-type ST2+CD4+ T cells. Thus our study provides novel insight into the pathogenesis of eosinophilic lung disease, showing that memory-type ST2+CD4+ T cells are involved in IL-33-induced eosinophilic inflammation and elicited steroid-resistance.

The Relationship between the Incidence of Summer-type Hypersensitivity Pneumonitis and Environmental Factors in Southern Tochigi Prefecture

Objective Environmental and climatic changes have been occurring throughout the past 20 years in Japan. Correspondingly, the antigens that cause hypersensitivity pneumonitis might be changing. In an epidemiological survey of Japan in the 1980s, summer-type hypersensitivity pneumonitis (SHP) accounted for 74.4% of the cases of hypersensitivity pneumonitis. The epidemiological characteristics of this disease have not been reported since then. We investigated the annual changes in the number of cases of SHP and the factors affecting the results. Methods Cases that were diagnosed as SHP were retrieved from the medical records of our institute between 1990 and 2015. The diagnostic criteria proposed by the Japanese Ministry of Health, Labour and Welfare in 1990 were applied to obtain the definite diagnosis. Patients The study population included 25 diagnosed patients, including one intrafamilial case. The subjects were predominantly non-smoking women in their 50s and all lived in wooden houses that had been constructed more than 10 years previously. Results The number of cases that were diagnosed as SHP tended to decrease during the study period. However, temporal increases tended to occur in years with increased rainfall and decreased daylight hours. No relationship appeared to exist between the number of cases and high temperatures or humidity levels. Conclusion The incidence of SHP currently appears to be decreasing; however, the weather conditions in any given year might cause a temporal increase in the incidence rate.

A patient with sarcoidosis who developed heterochronic involvements in different organs from initial organs during 7 years

A 59-year-old woman, who was given a diagnosis of sarcoidosis by supraclavicular lymph node biopsy 5 years previously, was admitted for further examination following abnormal radiologic findings. Nodular pulmonary and abdominal lesions were observed by computed tomography, and liver biopsy was performed and showed epithelioid cell granulomas. She was asymptomatic and was followed up with no therapy. At 1 year follow-up, the pulmonary and abdominal lesions had nearly complete resolution. Nodular pulmonary and abdominal lesions in patients with sarcoidosis can mimic metastatic disease, lymphoma, and infection, and can reappear during disease activity. Therefore, differential diagnosis and continual follow-up are important.

Use of low-cost three-dimensional printer to simulate grasping of bronchial foreign body: Foreign body simulated with 3D printer

An 89‐year‐old man was hospitalized with severe pneumonia. Chest computed tomography showed a foreign body in the left main bronchus. We moulded a three‐dimensional (3D) model of the foreign body with a low‐cost 3D printer and found it had the shape of a tooth. We simulated grasping the model with several forceps and succeeded in grasping it with a retrieval net and shark‐tooth forceps. Bronchoscopy was performed after his respiratory condition improved. We found a dental foreign body that had accidentally moved and become stuck in the right upper bronchus. We scraped it out with a retrieval net and grasped the recess site of the foreign body with a shark‐tooth forceps as performed in the simulation. Removal was successful, and the total bronchoscopy time was 9 min. The bronchial foreign body was safely grasped and removed in a short time after simulation with several forceps using a low‐cost 3D printer.