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Summary Churg–Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia; however, its mechanisms involved in the severe tissue inflammation with vasculitis are poorly understood. High mobility group box 1 (HMGB1) protein, originally identified as a DNA binding protein, also has potent pro-inflammatory and proangiogenic properties. In this study, we hypothesized that HMGB1 might be associated with CSS, and examined serum HMGB1 levels and compared those of asthma patients and healthy volunteers. We also investigated HMGB1 expression in the lesion, and eosinophil HMGB1 amount in CSS patients. We found that the serum HMGB1 levels in CSS patients were significantly higher than those of asthma patients and healthy volunteers. Eosinophils in the CSS lesion expressed HMGB1 and HMGB1 level in eosinophils from CSS patients was significantly higher than that of asthma patients, while there was no significant difference in HMGB1 levels in peripheral mononuclear cells. The serum HMGB1 level in CSS patients decreased after the steroid therapy, and showed significant positive correlations with several molecules, including soluble interleukin-2 receptor, soluble thrombomodulin, and eosinophil cationic protein in sera. We propose that HMGB1 might contribute to the pathogenesis of CSS.

Churg-Strauss syndrome (CSS) is a systemic disease that shows marked eosinophilia along with eosinophil infiltration in the tissue. Prolonged eosinophil survival plays an important role in the pathogenesis of CSS; however, its detailed molecular mechanism remains unclear. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase, and its ligand is collagen. DDR1 was expressed in human leukocytes and fibroblasts, and it plays an important role in leukocyte cytokine production and fibroblast survival in an NF-κB–dependent manner. In this study, we examined in vitro and in vivo eosinophil DDR1 expression and its function in CSS patients. The expression level of DDR1 was significantly higher in the eosinophils of CSS patients, and the predominant isoform was DDR1b. Immunohistochemical findings revealed that the tissue-infiltrating eosinophils expressed endogenous DDR1. In CSS patients, DDR1 activation inhibited Fas agonistic antibody–induced apoptosis and up-regulated Fas agonistic antibody–induced cytokine production of eosinophils in an NF-κB–dependent manner. Suppression of DDR1 expression in the eosinophils by using RNA interference and addition of the DDR1-blocking protein abolished these effects. We propose that DDR1 contributes to the eosinophil survival in the tissue microenvironment of CSS and that it might be involved in the development of CSS.

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-κB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-κB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-κB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.

Background Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia. For optimal treatment, prompt distinction of CSS from asthma is necessary; however, there are few serologic screening markers for this purpose. Vascular endothelial growth factor (VEGF), a vascular permeability factor, has been associated with other systemic vasculitis such as Wegener granulomatosis and giant-cell arteritis. Objective The aim of this study was to clarify the clinical value of the measurement of serum VEGF for the distinction of CSS from asthma. Methods We investigated serum VEGF levels in 18 CSS patients, 19 asthma patients, and 12 acute bronchitis patients. We also performed immunohistochemical analysis for VEGF. Results The serum VEGF levels of CSS patients were significantly higher than those of asthma patients and acute bronchitis patients. The sensitivity and specificity to distinguish CSS from asthma were 93.3% and 81.8%, respectively (cutoff, 600 pg/mL). Infiltrating eosinophils stained intensely positive for VEGF, and serum VEGF levels showed a significant correlation with peripheral eosinophil counts. Serum VEGF levels decreased significantly after therapy (p Conclusion VEGF is one of the useful screening markers for the distinction of CSS from asthma. We suggest that VEGF might be associated with the pathogenesis of CSS.

The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase-dependent manner from CD14-positive BALF cells of patients with deteriorated sarcoidosis. DDR1 activation also induced NF-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-kappaB inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.

Background: COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. However, no available agent can effectively cure this inflammation. A dietary supplement containing omega-3 polyunsaturated fatty acids (PUFAs) has anti-inflammatory effects. In this study, we hypothesized that nutritional support with omega-3 PUFA-rich diets may be useful for treating COPD, and we compared the clinical features and inflammatory mediator levels between the COPD patients who received an omega-3 PUFA-rich supplement and those who received a nonrich supplement. Methods: Sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) or an omega-3 PUFA-nonrich supplement (n-6 group) for 2 years. We prospectively investigated the clinical features of these patients and measured the levels of inflammatory mediators. Results: In 6-min walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation measured by pulse oximetry significantly improved in the n-3 group. Leukotriene B4 levels in serum and sputum and tumor necrosis factor- and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group. Two patients in the n-3 group and three patients in the n-6 group had mild diarrhea, and three patients in the n-3 group and three patients in the n-6 group had nausea; however, their symptoms were controllable and they improved with treatment. With multiple regression analysis, it was proved that the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study. Conclusion: We suggest nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD. (CHEST 2005; 128:3817–3827)

SummaryPulmonary tuberculosis, a granulomatous disease, has few serological markers for its activity. Recently, an increased plasma level of stromal derived factor 1 alpha (SDF-1α), which can induce strong chemotaxis of cells through its receptor CXCR4, was detected in patients with tuberculosis. In this study we investigated serum SDF-1α levels and CXCR4 expression on peripheral blood mononuclear cells (PBMCs). Fifty-five active tuberculosis patients, 30 resolved tuberculosis patients, 27 acute bronchitis patients and 8 healthy volunteers were examined. Histological expression of SDF-1α in the tuberculosis lesion and CXCR4 expression of PBMCs were also analysed. Serum SDF-1α levels in active tuberculosis patients were significantly higher than other groups. The sensitivity and specificity for the diagnosis of active tuberculosis was 88·5% and 85·3% (cutoff value = 650 pg/ml), respectively. CXCR4 expression levels on PBMCs showed a significant negative correlation with serum SDF-1α levels. Inflammatory cells including multinuclear giant cells in the lesion expressed SDF-1α. Measurement of serum SDF-1α could be a useful screening marker for the identification of active pulmonary tuberuculosis. We propose that interaction of SDF-1α and CXCR4 might be involved in the pathogenesis of pulmonary tuberculosis.

We report a new family with palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. These findings were almost identical with those in patients previously reported to have histopathologically confirmed adult-onset Alexander disease. Recently, heterozygous point mutations in the coding region of glial fibrillary acidic protein (GFAP) in patients with an infantile form of Alexander disease have been reported. We found a new heterozygous amino acid substitution, Val87Gly in exon 1 of GFAP, in the affected individuals in this family but not in 100 spinocerebellar ataxia (SCA) patients and 100 controls. Therefore, this family might have new clinical entities related to adult-onset Alexander disease and GFAP mutation.

Chronic obstructive pulmonary disease (COPD), which ranks fifth in terms of the global burden of diseases, is one of the major risk factors of post-operative pulmonary complications. Tiotropium bromide is a new inhaled bronchodilator for COPD patients with a sustained duration of action; it has superior efficacy compared to other bronchodilators. However, little is known regarding its clinical value as a preoperative treatment for COPD patients. In this study, we compared the incidence of post-operative complications between COPD patients who received with tiotropium bromide and those who did not.Retrospective study.For 1 month before surgery we examined 84 and 82 patients treated with tiotropium bromide (tiotropium group) and oxitropium bromide (oxitropium group), respectively, in combination with other medications. We performed a statistical comparison of clinical features, pulmonary functions, and postoperative complications between the 2 groups.The improvements in clinical symptoms and forced expiratory volume in 1 second were better in the tiotropium group than in the oxitropium group. The incidence of post-operative pulmonary complications (refractory bronchospasm, pulmonary infection, and acute respiratory failure) was significantly lower in the tiotropium group than in the oxitropium group. Three patients in the tiotropium group complained of dry mouth; however, the symptoms could be controlled. The incidence of post-operative non-pulmonary complications was not significantly different between the 2 groups.We propose that tiotropium bromide might be a safe and useful drug for pre-operative treatment of COPD patients.

The chemokine receptor CXCR4, which binds the chemokine stromal cell-derived factor 1, has been reported to be involved in the chemotaxis of inflammatory cells. In addition, AMD3100, an antagonist of CXCR4, has been reported to be an attractive drug candidate for therapeutic intervention in several disorders in which CXCR4 is critically involved. However, little is known about the therapeutic value of AMD3100 in the treatment of pulmonary fibrosis. In this study, we examined the effects of AMD3100 on a murine bleomycin-induced pulmonary fibrosis model. Concurrent administration of AMD3100 and bleomycin apparently attenuated bleomycin-induced pulmonary inflammation. In this process, an inhibition of neutrophil recruitment at early stage followed by the decrease of other inflammatory cell recruitment in the lung were observed. In addition, it also inhibited the expression of cytokines, including MCP-1, MIP-2, MIP-1α, and TGF-β. In contrast, when AMD3100 was administered following bleomycin treatment, the bleomycin-induced lung inflammation progressed and resulted in severe pulmonary fibrosis. In this process, an increase of inflammatory cell recruitment, an up-regulation of lung MCP-1 and TGF-β, and a remarkable activation of p44/42 MAPK in neutrophils were observed. U0126, an inhibitor of p44/42 MAPK, significantly abolished these effects. Thus, AMD3100 has dual effect on bleomycin-induced pulmonary fibrosis. Difference of inflammatory cell recruitment and activation might be associated with the dual effect of AMD3100 on bleomycin-induced pulmonary fibrosis.

金沢大学医学部附属病院血液浄化療法部, Objective. Prolonged survival of eosinophils plays au important role in the pathogenesis of Churg-Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS. Methods. TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL-induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3. Results. Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue-infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell-induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL-induced apoptosis of eosinophils from CSS patients. Conclusion. Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia. © 2007, American College of Rheumatology.

Case 1 is a 78-year-old woman in whom lung adenocarcinoma with multiple brain metastasis (cT2N3M1, stage IV) was diagnosed. She was treated with Gefitinib alone. Her lung tumor and metastatic brain lesions decreased 6 months after the start of therapy. She has no recurrence and is still alive with a good performance status after 25 months. Case 2 is an 80-year-old woman in whom lung adenocarcinoma with multiple brain (cT2N3M1, stage IV) was diagnosed. She was also treated with Gefitinib alone and her lung tumor and metastatic brain becomes improved 6 months after the start of therapy. She maintained a good performance status for more than 2 years (29 months). However, 29 months after beginning treatment, she had recurrence in bone and died 2 months later, 31 months after the start of therapy. The prognosis of non-small cell lung cancer with multiple brain metastasis is very poor and the efficacy of chemotherapy for the treatment of multiple brain metastases is limited, and longterm survival remains disappointing. We report two lung adenocarcinoma patients with multiple brain metastasis who survived more than 2 years by treatment with Gefitinib alone.

Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia. For optimal treatment, prompt distinction of CSS from asthma is necessary; however, there are few serologic screening markers for this purpose. Vascular endothelial growth factor (VEGF), a vascular permeability factor, has been associated with other systemic vasculitis such as Wegener granulomatosis and giant-cell arteritis.The aim of this study was to clarify the clinical value of the measurement of serum VEGF for the distinction of CSS from asthma.We investigated serum VEGF levels in 18 CSS patients, 19 asthma patients, and 12 acute bronchitis patients. We also performed immunohistochemical analysis for VEGF.The serum VEGF levels of CSS patients were significantly higher than those of asthma patients and acute bronchitis patients. The sensitivity and specificity to distinguish CSS from asthma were 93.3% and 81.8%, respectively (cutoff, 600 pg/mL). Infiltrating eosinophils stained intensely positive for VEGF, and serum VEGF levels showed a significant correlation with peripheral eosinophil counts. Serum VEGF levels decreased significantly after therapy (p0.001). The infiltrating eosinophils in the CSS lesion stained positive for VEGF in the immunohistochemical analysis.VEGF is one of the useful screening markers for the distinction of CSS from asthma. We suggest that VEGF might be associated with the pathogenesis of CSS.

SummaryMicroscopic polyangiitis (MPA) is a systemic necrotizing vasculitis that affects small vessels, resulting in a wide spectrum of organ involvement including the lungs. However, there are little serological markers that predict its prognosis or severity of pulmonary involvement. Vascular endothelial growth factor (VEGF) is an angiogenic mediator, which has been reported to be elevated in systemic vasculitis. In this study, we measured serum VEGF levels in 22 MPA patients with pulmonary involvement. We also investigated VEGF expression in pulmonary cells using flow cytometry analysis. We found that serum VEGF levels in MPA patients were significantly higher than those in respiratory or urinary tract infection. The serum VEGF levels decreased in parallel with the improvement of MPA symptoms. The serum VEGF levels in MPA patients who died within 5 years were significantly higher than those who survived more than 5 years. The sensitivity of VEGF levels to distinguish MPA patient with poor prognosis from those with good prognosis was 90.9%, and specificity was 81.8% (cutoff value=802.5pg/ml). The serum VEGF levels showed significant positive correlation with the composite physiological index, which indicates the severity of pulmonary lesion. In flow cytometry analysis, CD11b positive bronchoalveolar lavage fluid cells expressed VEGF. Immunohistochemically, alveolar macrophages, tissue infiltrating inflammatory cells and alveolar epithelial cells stained positive for VEGF. Measurement of serum VEGF levels in MPA might become one of the markers for prognosis and the severity of pulmonary involvement in MPA. VEGF might contribute to the development of pulmonary lesion of MPA.

COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. However, no available agent can effectively cure this inflammation. A dietary supplement containing omega-3 polyunsaturated fatty acids (PUFAs) has anti-inflammatory effects. In this study, we hypothesized that nutritional support with omega-3 PUFA-rich diets may be useful for treating COPD, and we compared the clinical features and inflammatory mediator levels between the COPD patients who received an omega-3 PUFA-rich supplement and those who received a nonrich supplement.Sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) or an omega-3 PUFA-nonrich supplement (n-6 group) for 2 years. We prospectively investigated the clinical features of these patients and measured the levels of inflammatory mediators.In 6-min walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation measured by pulse oximetry significantly improved in the n-3 group. Leukotriene B4 levels in serum and sputum and tumor necrosis factor-alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group. Two patients in the n-3 group and three patients in the n-6 group had mild diarrhea, and three patients in the n-3 group and three patients in the n-6 group had nausea; however, their symptoms were controllable and they improved with treatment. With multiple regression analysis, it was proved that the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study.We suggest nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD.

We wish to retract the article titled “Suppression of Discoidin Domain Receptor 1 by RNA Interference Attenuates Lung Inflammation” by Wataru Matsuyama, Masaki Watanabe, Yuko Shirahama, Ryuki Hirano, Hideo Mitsuyama, Ikkou Higashimoto, Mistuhiro Osame, and Kimiyoshi Arimura, [ The Journal of