Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention

IL-33 and RANTES( Regulated on Activation, Normal T Cell Expressed and Secreted) in BAL Fluid in Asthma Patients Without Cigarette Smoking

Background:Inflammatory cytokines and chemokines have been reported to play important roles in thepathogenesis of bronchial asthma. However, no criteria for the classification of `smoker\u27 and `atopic\u27 in bronchialasthma have been defined. In this study, we compared the levels of several cytokines found in thebronchoalveolar lavage( BAL) fluid of patients classified as having bronchial asthma.Methods:Cell subpopulations in BAL fluid were counted. BAL fluid levels of interleukin( IL)-4, -5, -13,-17, and -33 and RANTES (regulated on activation, normal T cell expressed and secreted were measuredusing a bead suspension array in 36 asthma patients (13 males, 23 females;mean age, 39.5±92.8 years)who were non-smokers, 18 asthma patients( 11 males, 7 females;mean age, 30.7±2.7 years) who were exor current smokers( Brinkman index( BI):1&#8722;399), and 10 asthma patients( 9 males, 1 female;mean age,50.2±5.5 years) who were current heavy smokers( BI:&#8805; 400). Relationships were assessed by Spearman\u27srank correlation analysis.Results:The number of lymphocytes in BAL cell subpopulations of non-smokers( 25±7×103/ml) weresignificantly (p<0.05) higher than those of heavy smokers (12±3×103 /ml). The number of neutrophilswas significantly( p<0.05) higher in heavy smokers( 18±9×103/ml) than in non-smokers( 4±2×103/ml).Levels of IL-33 and RANTES were significantly (P<0.05) higher in non-smokers (26.1±7.3 pg/ml and42.8±10.3 pg/ml, respectively) than in heavy smokers (13.7±4.5 pg/ml and 27.4±5.4 pg/ml, respectively).In addition, the levels of IL-33 and RANTES in non-smokers were significantly( P<0.05) higher in atopicasthma patients (33.0±9.8 pg/ml and 47.8±14.0 pg/ml, respectively) than in non-atopic asthma patients(9.1±3.8 pg/ml and 29.5±7.8 pg/ml, respectively). A good correlation was noted between RANTES andlymphocytes (R=0.365, P<0.05) or IL-33 (R=0.561, P<0.05) in atopic asthma patients who were nonsmokers.Conclusions:Differences in the cell types of BAL fluid, as well as in the levels of IL-33 and RANTES inasthma patients with or without smoking, might reflect pathogenesis

Involvement of Bird-related IgG Antibodies in Interstitial Pneumonia

Background and Objective:Chronic interstitial pneumonia (IP) might include chronic hypersensitivity pneumonitis (HP) and chronic bird-related hypersensitivity pneumonitis (BRHP). A specific antigen is difficult to identify in these diseases, and such evidence would provide important clues suggesting a diagnosis of HP. In this study, we used an ImmunoCAP analysis system to measure specific IgG antibodies against pigeons and budgerigars in the sera of patients with IP and investigated the involvement of bird-related IgG antibodies in IP.Methods:The study group comprised 22 patients with idiopathic pulmonary fibrosis (IPF), 8 with chronic IP, 7 with subacute HP, 7 with chronic HP, and 10 with control diseases. All cases were diagnosed from 2000 through 2011 at the Institute of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University. Clinical features, results of laboratory examinations, and levels of serum IgG antibodies against pigeons and budgerigars were compared.Results:There were no significant differences among the disease groups in C-reactive protein, leukocyte count, lactate dehydrogenase, and the results of blood gas analysis. KL-6 and surfactant protein D were significantly higher in subacute HP and chronic HP. The levels of anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies in each disease group were respectively as follows:IPF, 11.02±5.97&#8200;mg/l, 5.03±3.97&#8200;mg/l;chronic IP, 10.04±8.55&#8200;mg/l, 3.30±1.47&#8200;mg/l;subacute HP, 14.39±9.13&#8200;mg/l, 7.96±6.47&#8200;mg/l;chronic HP, 24.97±16.19&#8200;mg/l, 11.50±13.80&#8200;mg/l;and control diseases, 8.66±3.15&#8200;mg/l, 3.77±1.05&#8200;mg/l. The mean levels of anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies were significantly higher in chronic HP. There was a positive correlation between anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies (R2 = 0.715, p<0.001). Conclusions:In patients with clinically diagnosed chronic HP, high levels of anti-pigeon IgG antibodies or anti-budgerigar IgG antibodies were confirmed using an ImmunoCAP analysis system. In general, HP (especially chronic HP) is difficult to diagnose definitively, and this analysis system is expected to facilitate diagnosis

Clinical Characteristics of Acute Exacerbations of Idiopathic Pulmonary Fibrosis and Involvement of Viral, Mycoplasma pneumoniae, and Chlamydophila pneumoniae Infections

Background and Objective:To clarify the clinical characteristics of acute exacerbation of idiopathic pulmonaryfibrosis (IPF) and the involvement of infections with pathogenic microorganisms and viruses inacute exacerbation.Methods:During the 12 years from 2000 through 2011, we studied 50 patients who were admitted andreceived treatment for acute exacerbation of IPF in our department. Demographic characteristics, imagingfindings, laboratory findings, changes in antibody titers against bacteria, Mycoplasma pneumoniae, Chlamydophilapneumoniae, and known viruses, and outcomes were studied.Results:Among the 50 patients with acute exacerbation of IPF( 41 men and 9 women) 29 patients died(mortality rate, 58.0%). Computed tomography showed subpleural peripheral ground-glass opacities( GGO)in 5 patients, multiple patchy GGO in 19, and diffuse GGO in 26. Only the PaO2/FiO2 ratio was significantlylower in the non-survivors compared with survivors. Three patients had high titers of IgM antibodiesagainst C. pneumoniae, but acute infection was ruled out by the changes in IgA and IgG antibodies in pairedserum samples. Antibody titers against known viruses significantly increased in 2 patients( respiratory syncytialvirus in 1 and adenovirus 11 in 1). In acute-phase serum samples, 7 patients had increased antibodytiters against parainfluenza virus 3, resulted in no significant change in paired serum samples.Conclusions:Our results suggest that known pathogens do not play a role in acute exacerbation of IPF.The outcomes of IPF remain poor, and the elucidation of the causes and pathological features of acute exacerbationof IPF, including the identification of unknown pathogens, is awaited

Clinical Significance of Propionibacterium acnes in the Formation of Noncaseating Epithelioid-Cell Granulomas of the Mediastinal Lymph Nodes and Lung in Patients with Lung Cancer:Differential Diagnosis Between Sarcoid Reactions and Sarcoidosis

Objectives:Sarcoidosis is a systemic noncaseating epithelioid-cell granulomatous disease of unknown origin.Granulomas occurring around malignant tumors and regional lymph nodes can be caused by sarcoid reactions.The mechanisms underlying sarcoidosis and sarcoid reactions remain unclear. Whether increaseduptake of fluorodeoxyglucose( FDG) in lymph nodes on positron emission tomography( PET) is caused bytumor metastasis, the concurrent presence of sarcoidosis, or sarcoid reactions must be determined to ensureproper disease staging and selection of treatment policy. We studied patients who underwent surgery forlung cancer and had no histopathological evidence of lymph-node metastasis in whom concurrent sarcoidosisor sarcoid reactions were diagnosed.Methods:In six patients who underwent surgery for primary lung cancer, granulomatous lesions werehistopathologically studied in dissected lymph nodes and lung. Tissue sections were stained with monoclonalantibodies against Propionibacterium acnes( PAB antibodies).Results:The six patients had noncaseating epithelioid-cell granulomas in mediastinal lymph nodes andlung. Clinically, concurrent sarcoidosis was suspected, but the results of staining the tissue specimens withPAB antibodies( in granulomas, alveolar macrophages, Hamazaki-Wesenberg bodies, and lymphatic sinuses)suggested sarcoid reactions in 5 patients. In one patient in whom granulomas stained positive with PAB antibodies,concurrent sarcoidosis was diagnosed.Conclusions:In patients with lung cancer who have no distinct systemic evidence of sarcoidosis, thepresence of noncaseating epithelioid-cell granulomas in the lung hilum or mediastinum is usually caused bysarcoid reactions

Exogenous S100A4 Protein Attenuates Bleomycin-induced Pulmonary Fibrosis in Mice by Reducing the Levels of Fibroblast Growth Factors

Background and objective:The calcium-binding protein S100A4 belongs to the S100 family and is involved in fibrotic and inflammatory processes, in which tissue remodeling, cell motility, and epithelialmesenchymal transition play major roles. Cytoplasmic S100A4 is a marker of lung fibroblasts in pulmonary fibrosis;however, the effects of exogenous S100A4 on fibrotic and inflammatory processes in pulmonary fibrosis are unclear. This study examined the effects of exogenous S100A4 protein in mice with bleomycin-induced pulmonary fibrosis.Methods:Bleomycin was administered to mice by intratracheal instillation on day 1. Intratracheal S100A4 protein was administered 4 times after bleomycin treatment. Bronchoalveolar lavage fluid was obtained and lung histological examinations were performed on day 14 after bleomycin administration. Lung tissue was homogenized on the same day to assess the mRNA expression of cytokines, fibroblast growth factors, and S100A4.Results:Unexpectedly, we observed that the administration of exogenous S100A4 protein apparently reduced lung fibrosis in bleomycin-treated mice. In addition, the levels of lymphocyte accumulation and insulin-like growth factor-1 mRNA were significantly reduced in bleomycin-treated lung by S100A4 administration.Conclusions:Exogenous S100A4 protein attenuates bleomycin-induced pulmonary fibrosis in mice by reducing lymphocyte function and the levels of fibroblast growth factors

CD4^+ -Central Memory and Effector Memory T Cells in Patients with Asthma

Asthma is associated with chronic airway inflammation, suggesting that its pathogenesis is driven by type 2 helper T (Th2) cells among memory/effector CD4^+ T, cells. CCR4, a chemokine receptor, is considered a preferential marker for Th2 cells. Another chemokine receptor, CCR7, is regarded to be a suitable molecule for T-cell homing to lymph nodes. Recent studies have demonstrated that memory T cells are subdivided into central memory T cells (TCMs) and effector memory T cell (TEMs), designated as CCR7^+ CD62L^+ CD45RA^- and CCR7^- CD62L^- CD45RA^-, respectively. Nevertheless, the properties of TCMs and TEMs in allergic diseases remains unknown. This study focused on the cytokine production and the populations and survival of CD4^+ TCMs and CD4^+ TEMs in patients with asthma (n=3-5), as compared with those in healthy controls (n=4-5). We found that the population of TEMs in asthma was greater than that in healthy control. IL-4-producing cells among both activated TCMs and TEMs and IFN-γ-producing cells among TEMs were more abundant in asthma than in healthy control. Apoptotic cells stained with annexin V and propidium iodide (PI) were more numerous among both TCMs and TEMs in asthma than in healthy control after stimulation with both phorbol myristate acetate and ionomycin. Although CCR4^+ cell populations among TCMs and TEMs were similar in patients with asthma and healthy controls, cytokine-production profiles differed significantly. Namely, CCR4^+ (but not CCR4^-) TCMs and TEMs produced IL-4 and CCR4^+(but not CCR4^-) TCMs produced IFN-γ in both asthma and healthy control. In contrast, both CCR4^+ and CCR4^- TEMs produced IFN-γ. The production levels of IL-4 and IFN-γ by each subpopulation were greater in asthma than in healthy control. Our results suggest that increased CCR4^+-TEMs in peripheral blood accumulate in the lung and to play an important role in the development and maintenance of airway inflammation in asthma. To our knowledge, this is the first study to investigate CCR4^+ TCMs and TEMs in bronchial asthma and healthy controls

A Case of Inflammatory Lung Disease and Retroperitoneal Fibrosis Attributed to Systemic IgG4-related Disease

Recently, immunoglobulin (Ig) G4-related diseases such as autoimmune pancreatitis (AIP), sclerosingsialadenitis, retroperitoneal fibrosis, and sclerosing cholangitis have been reported. IgG4-related diseases arecharacterized by high serum IgG4 concentrations, sclerosing inflammation with numerous IgG4-positiveplasma cells, and steroid sensitivity, irrespective of their organ of origin. We describe a case of inflammatorylung disease and retroperitoneal fibrosis, suggested to involve IgG4. The patient was a 76-year-old man. Acomputed tomographic scan of the chest showed nodular air-space consolidation in the left upper lobe. Theserum IgG4 concentration was abnormally elevated, but there was no evidence of AIP. Bilateral hydronephrosisassociated with thickened soft tissue around the abdominal aorta had been diagnosed previously. Hehad undergone surgery, and retroperitoneal fibrosis was diagnosed histologically (hematoxylin and eosinstain). Histological examination of bronchoscopic specimens taken from the left S3 region showed mononuclear-cell infiltration of the fibrotic bronchial wall, including many IgG4-positive plasma cells. Specimens ofthe region affected by retroperitoneal fibrosis were retrospectively reanalyzed, and the cells were positivefor IgG4 on immunostaining, similar to the lung tissue. The patient responded to treatment with corticosteroids.In conclusion, the present case shared many clinical and clinicopathological similarities with systemicIgG4-related autoimmune disease. To our knowledge, however, this is the first reported case of inflammatorylung disease with retroperitoneal fibrosis in a patient with systemic IgG4-related autoimmune disease

Prostaglandin D_2 Augments Low-dose Antigen-induced Th2 Type Airway Inflammation in Mice

Prostaglandin D_2 (PGD_2), a mast cell-derived lipid mediator is detected in lage amounts in airways of asthmatics, but its role of largely unkown. To clarify the role of PGD_2 in Th2-type airway inflammation which characterizes asthma, we studied the effects of aerosolized PGD_2 on the inflammatory response to a low-dose antien challenge in airways of mice. Mice sensitized with ovalbumin (OVA) were challenged with a conventional-dose (1%) or a low dose (0.1%) aerosolized OVA. Mice received low - dose OVA challenge were pretreated with aerosolized PGD_2 (10^M) (PGD_2 plus low-dose OVA mice) or saline (low-dose OVA alone mice) 24 hrs before the OVA challenge. Some mice were pretreated with PGD_2 but challenged with saline (PGD_2 alone mice). Airway inflammation was evaluated by the numbers of eosinophils, lymphocytes and macrophages in bronchoalveolar lavage fluid. The degree of airway inflammation in the PGD_2 alone mice and the low-dose OVA alone mice were only marginal. However, the PGD_2 plus low-dose OVA mice displayed a similar degree of airway inflammation with mice received conventional-dose OVA challenge. Levels of interleukin (IL)-4 and IL-5 were significantly increased in the PGD_2 plus low-dose OVA mice than the low-dose OVA alone mice. PGD_2 (10^-10^ M) did not affect the Th2-type cytokine production by OVA specific T cells in response to OVA stimulation in vitro. Immunohistochemical analysis of lung tissue revealed that airway epithelium of the PGD_2 plus low-dose OVA alone mice were strongly stained with monoclonal antibody against macrophage-derived chemokine (MDC), a Th2 cell-specific chemokine. These results suggest that PGD_2 augments Th2 cell -type airway inflammation via epithelial experssion of MDC

キョウクウ センパ ニヨル ノウキョウ ガッペイ オ ミトメタ セイジュクガタ ジュウカク キケイシュ ノ 1レイ

症例は16 歳女性,咳嗽,発熱,左前胸部痛を主訴に来院.胸部CT にて内部不均一な径7 cm の前縦隔腫瘍及び左舌区・下葉の完全無気肺を確認,また,MRI にて前縦隔腫瘍内に脂肪組織と同一の吸収域を認め,成熟型奇形腫穿破による膿胸と診断.膿胸に対し胸腔内繊維素溶解療法,ドレナージ及び抗生剤にて加療,膿胸改善を確認した上で,前縦隔腫瘍摘出術施行,病理にて嚢胞性成熟型奇形腫と診断した.病理組織にて膵類似の腺組織を確認,穿破の原因として,腫瘍内膵酵素の存在が考えられた.成熟型縦隔奇形腫は穿破により重篤な合併症発生の危険性があり,また経過中悪性転化する可能性もあることから,早期の外科治療が重要と考えられた.A 16-year-old female visited our hospital, complaining ofcough, fever, and left precordial pain. Chest computed tomographyshowed a heterogeneous anterior mediastinal tumormeasuring 7 cm in diameter and complete atelectasis inthe lingula and lower lobe of the left lung. Magnetic resonanceimaging also showed an area of intensity identical tothat of adipose tissue in the anterior mediastinal tumor.Thus, empyema due to rupture of a mature teratoma wasdiagnosed. The empyema was treated with intra-pleural fibrinolytictherapy, drainage, and antibiotics. After confirmingresolution of the empyema, we resected the anteriormediastinal tumor and pathologically diagnosed it as cysticmature teratoma. Histopathological examination showedglandular tissue resembling the pancreas, suggesting thatthe rupture had been caused by pancreatic enzymes in thetumor. Mediastinal mature teratoma carries a risk of seriouscomplications developing due to rupture and the possibilityof malignant transformation during the diseasecourse. Thus, early surgical treatment is important