Hiroyuki Tashimo

Efficacy of Corticosteroids in the Treatment of Community-Acquired Pneumonia Requiring Hospitalization

BackgroundRecent studies suggested that administration of corticosteroids may improve clinical outcomes in patients with severe pneumonia.ObjectivesThe aim of this study was to assess the effectiveness of corticosteroids as an adjunctive therapy in community-acquired pneumonia (CAP) requiring hospitalization.Design and SettingAn open label, prospective, randomized control study was conducted from September 2003 to February 2004 in a community general hospital in Japan.PatientsThirty-one adult CAP patients who required hospitalization were enrolled.Measurements and ResultsFifteen patients received 40 mg of prednisolone intravenously for 3 days (steroid group). Sixteen patients did not receive prednisolone (control group). Both groups were also evaluated for their adrenal function. The primary endpoint was length of hospital stay. Secondary endpoints were duration of intravenous (IV) antibiotics and time required to stabilize vital signs. Both groups demonstrated similar baseline characteristics and length of hospital stay, and yet a shorter duration of IV antibiotics was observed in the steroid group (p < 0.05). In addition, vital signs were stabilized earlier in the steroid group (p < 0.05). These differences were more prominent in the moderate–severe subgroup but not as significant in the mild–moderate subgroup. The prevalence of relative adrenal insufficiency (RAI) in both groups was high (43%), yet there was no difference in baseline characteristics between patients, with or without RAI. In multiple regression models, RAI seemed to have no influence on clinical courses.ConclusionsIn moderate–severe CAP, administration of corticosteroids promotes resolution of clinical symptoms and reduces the duration of intravenous antibiotic therapy.

Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF)

Asthma is recognized as an inflammatory disease in which various cytokines are involved. Among these, granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to play a critical role in the survival of eosinophils and in the activation of antigen-presenting cells (APC). We studied the effects of neutralization of GM-CSF in a murine model of asthma, to elucidate its role in enhanced airway responsiveness and in airway inflammation. A/J mice, which are genetically predisposed to acetylcholine hyperresponsiveness, were immunized with ovalbumin (OA) and alum. Thereafter, the mice were subjected to a two-week regimen of OA inhalation, during which either goat anti-mouse polyclonal GM-CSF antibody or isotype control goat IgG was administered intranasally. Pulmonary function was then analyzed using whole body plethysmography before and after acetylcholine (Ach) inhalation. Here we show that OA inhalation following OA immunization increased airway responsiveness to acetylcholine and induced GM-CSF as well as IL-4 and IL-5 mRNA expression in the lung. The administration of GM-CSF-neutralizing antibody during OA inhalation significantly reduced this increased airway hyperresponsiveness and also inhibited airway inflammation. Thus, endogenous GM-CSF plays an important role in the process of airway inflammation and airway hyperresponsiveness after antigen-specific immunity has been established.

Leptin Enhances Survival and Induces Migration, Degranulation, and Cytokine Synthesis of Human Basophils

Basophils are the rarest leukocytes in human blood, but they are now recognized as one of the most important immunomodulatory as well as effector cells in allergic inflammation. Leptin, a member of the IL-6 cytokine family, has metabolic effects as an adipokine, and it is also known to participate in the pathogenesis of inflammatory reactions. Because there is an epidemiologic relationship between obesity and allergy, we examined whether basophil functions are modified by leptin. We found that human basophils express leptin receptor (LepR) at both the mRNA and surface protein levels, which were upregulated by IL-33. Leptin exerted strong effects on multiple basophil functions. It induced a strong migratory response in human basophils, similar in potency to that of basophil-active chemokines. Also, leptin enhanced survival of human basophils, although its potency was less than that of IL-3. Additionally, CD63, a basophil activation marker expressed on the cell surface, was upregulated by leptin, an effect that was neutralized by blocking of LepR. Assessments of basophil degranulation and cytokine synthesis found that leptin showed a strong priming effect on human basophil degranulation in response to FcεRI aggregation and induced Th2, but not Th1, cytokine production by the cells. In summary, the present findings indicate that leptin may be a key molecule mediating the effects of adipocytes on inflammatory cells such as basophils by binding to LepR and activating the cellular functions, presumably exacerbating allergic inflammation.

Effect of Procaterol, a β2 Selective Adrenergic Receptor Agonist, on Airway Inflammation and Hyperresponsiveness

BACKGROUND β-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting β2 selective drugs. Although antiinflammatory effects of β2 selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of β2 selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation β2-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma. METHODS Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation. RESULTS Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice. CONCLUSIONS Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.

Spatial and Phenotypic Characterization of Vascular Remodeling in a Mouse Model of Asthma

Asthma is a chronic inflammatory disease characterized by airway wall remodeling in which vascular remodeling is thought to be a main contributor. Vascular endothelial growth factor (VEGF) is known as a major regulator of angiogenesis and enhancer of vascular permeability. Here, we define the spatial nature of vascular remodeling and the role of VEGF and its receptors (Flt-1 and Flk-1) in the allergic response in mice (A/J) susceptible to the development of allergen-induced airway hyperresponsiveness using morphometric and quantitative approaches. Increased vascularity, vasodilatation, and endothelial cell proliferation were found in the tracheal and bronchial walls in the early and late phases of asthma. Vascular changes were observed not only in small vessels but also in larger vessels. In contrast to normal control, lung tissue from the asthma model showed dual expression for CD31 and von Willebrand factor in the endothelial cells and α-smooth muscle actin and desmin in the mural cells of the vessels, suggesting a phenotypic and functional transformation. The mRNA levels of VEGF isoforms, VEGF164 and VEGF188, were significantly increased in the tracheal and lung tissue, respectively. In addition, the mRNA level of VEGF receptor Flk-1 was significantly increased in the trachea. These results establish the existence of vascular remodeling in the airways in a mouse model of allergic asthma and support a key role for the expression of unique VEGF isoform genes as mediators of structural changes.

Pretreatment with Low Levels of FcεRI-Crosslinking Stimulation Enhances Basophil Mediator Release

Background: Basophils and mast cells are important initiator/effector cells capable of rapidly responding to IgE-mediated stimulation, but the precise mechanisms regulating their functions in vivo have not been fully identified. In this study, we assessed whether low levels of antigen can modulate activation of basophils and mast cells. Methods: Human basophils and cultured mast cells were pretreated with low concentrations of anti-FcεRI α-chain mAb (CRA-1 mAb), and their cell functions were assessed. Results: Basophils preincubated with CRA-1 mAb at as low as 1 ng/ml for 1 h showed significantly enhanced degranulation in response to various secretagogues such as MCP-1, FMLP, leukotriene B4 and Ca ionophore A23187. FMLP-induced leukotriene C4 production by basophils was also enhanced by CRA-1 mAb pretreatment. Degranulation was further enhanced when CRA-1 mAb-pretreated basophils were additionally treated with IL-3, IL-33 or leptin before stimulation with MCP-1. Priming by subthreshold CRA-1 mAb was a slow process, since 1 h of pretreatment was needed for maximal enhancement. Basophil priming also resulted from preincubation with subthreshold doses of an allergen, Der f 2. In parallel mAb experiments, CRA-1 mAb showed weak priming effects on human umbilical cord blood-derived cultured mast cells; a higher dose, 100 ng/ml, was necessary for this priming. Conclusion: These results indicate that subthreshold doses of CRA-1 mAb or allergens can prime basophils and induce exaggerated responses to various IgE-independent stimuli. This may be a potentially important mechanism that explains environmental allergen-induced exacerbation of IgE-mediated allergic diseases such as asthma.

An HIV-positive Case of Obstructive Jaundice Caused by Immune Reconstitution Inflammatory Syndrome of Tuberculous Lymphadenitis Successfully Treated with Corticosteroids

A 60-year-old man was admitted to our hospital because of a persistent fever with enlargement of multiple lymph nodes in the mediastinum and around the pancreatic head. He was diagnosed with tuberculosis and human immunodeficiency virus infection. We started antiretroviral therapy three weeks after the initiation of anti-tuberculous therapy. Two weeks later, jaundice appeared with dilatation of the biliary tract due to further enlargement of the lymph nodes, which seemed to be immune reconstitution inflammatory syndrome (IRIS). The administration of corticosteroids resolved the obstructive jaundice without surgical treatment or endoscopic drainage. Obstructive jaundice caused by IRIS should first be treated with corticosteroids before invasive treatment.

Attenuation of allergic inflammation by neutralization of IGF-I in murine asthmatic models

092 Attenuation of Allergic Inflammation by Neutralization of IGF-I in Murine Asthmatic Models N. Yamashita j, H. Tashimo 1, M. Nakajima I , H. Ishida I, M. KuramochP, E Kaneko 1, R. KawashimaJ, T. Horiuchi 2, K. Ohtal; ITeikyo University School of Medicine, Tokyo, JAPAN, 2Kanto Central Hospital, Tokyo, JAPAN. RATIONALE: It has been suggested that airway wall thickening in asthma involves the production of extracellular matrix (ECM) components, including collagen, by myofibroblasts. In this study, we tried to clarify the role of IGF-I, a progression factor of fibroblast, in asthma. METHODS: Mice were immunized with ovalubmin + alum and challenged with ovalbumin inhalation, Anti-lGF-I neutralizing antibody was continuously introduced using osmotic pump during challenge. Pulmonary function was analyzed using whole body plethysmography before and after achetylcholine inhalation. RESULTS: Anti-IGF-I neutralizing antibody significantly inhibited the elevation of airway resistance and the increase of the airway wall thickening induced with OA inhalation. Airway inflammation was also inhibited by IGF-! neutralizing antibody, confirming by BALF cell analysis and histological examination, cDNA array analysis revealed that the neutralization of IGF-1 induced the activation of caspase1 and the reduction of anti-apoptotic Bag1 mRNA. CONCLUSIONS: In conclusion, not only induction of fibroblast proliferation but also anti-apoptotic effects of IGF-I may play a role in the process of airway inflammation and remodeling of asthma. Funding: Se!f-funded