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

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

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

A Case of Pulmonary Benign Metastasizing Leiomyoma Occurring after Uterine Myomectomy

Benign metastasizing leiomyoma (BML) is a very rare disease, and although it was reported as early as1939 to result from metastasis of benign uterine myoma to the lungs and lymph nodes, its pathology remainsobscure. Here, we describe a case of pulmonary BML occurring after uterine myomectomy in a42-year-old woman. She presented with a 2-week history of dry cough on exertion. Chest radiography andcomputed tomography( CT) revealed bilateral multiple nodular lesions. The patient had a history of uterinemyoma and previously underwent myomectomy. For definitive diagnosis, lung biopsy was performed byvideo associated thoracoscopic surgery. Histopathologic examination of biopsy specimens revealed pulmonaryBML occurring after uterine myomectomy. For treatment of the pulmonary BML, gonadotropin-releasinghormone was initially administered, and 1 month later the patient underwent complete hysterectomyand bilateral salpingo-oophorectomy. Chest CT 6 months after surgery showed that the size and number oflung multiple nodular lesions did not increase compared with those before surgery. In future studies, we aimto investigate a larger number of pulmonary BML cases, as well as establish specific treatments and investigatethe prognosis of the disease.Abbreviations:BML:benign metastasizing leiomyomaSS:Sjögren\u27s syndromeCT:computed tomographyH&E:hematoxylin and eosinVATS:video associated thoracoscopic surgeryCA:carbohydrate antigenIg:immunoguloblina SMA:a smooth muscle acti

Antigen Challenge-induced Expression of Amphiregulin by Mast Cells Increases Goblet-Cell Hyperplasia in a Mouse Model of Asthma

Mast cells play important roles in both acute-and late-phase allergic reactions mediated by IgE, such as those in bronchial asthma. Remodeling of the airway wall may contribute to the development of chronic refractory asthma; effective treatment for remodeling is currently lacking. Tryptase released by degranulated mast cells may participate in airway remodeling by stimulating the proliferation of airway smooth-muscle cells and fibroblasts and promoting the production of extracellular matrix. We found that continued antigen challenge produced time-dependent increases in the number of goblet cells, which are essential for sputum production, as well as the number of mast cells. Furthermore, the expression of amphiregulin released from mast cells was up-regulated by after ovalbumin challenges in mice. The number of amphiregulin-positive cells positively correlated with the degree of goblet-cell hyperplasia. Our results suggest that mast cells also play a key role in airway remodeling

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

Leukotriene C_4 in Combination with Transforming Growth Factor-β Augments Extracellular Matrix Production from Human Lung Fibroblasts

Airway remodeling has an important role in the pathogenesis of bronchial asthma and is associated with severe, intractable disease. A lot of mediators, especially cysteinyl leukotrienes (CysLTs) and transforming growth factor (TGF)-β that influence pathophysiology of bronchial asthma are involved in the formation of airway remodeling. We hypothesized that responsiveness of fibroblasts to CysLTs is not the same as that of activated myofibroblasts induced by TGF-β. We examined the effects of leukotriene C_4 (LTC_4) on collagen production from fibroblasts and myofibroblasts transformed by TGF-β. Furthermore, we investigated mRNA expression of CysLTl receptor and a-smooth muscle actin (α-SMA) as a marker of myofibroblast. TGF-β_1 stimulated collagen production from human fetal lung fibroblasts (HFL-1), but LTC_4 alone did not. Meanwhile, LTC_4 in combination with TGF-β_1 enhanced collagen production as compared with TGF-β alone. Real time PCR revealed that stimulation with TGF-β significantly upregulated CysLTIR and α-SMA mRNA expression in HFL-1. LTC_4 increased the collagen production through upregulation of CysLTIR induced by TGF-β. In the TGF-β-rich milieu such as asthma, activated myofibroblasts expressing CysLTIR can respond to CysLTs and produce abundant extracellular matrix thereby forming airway remodeling. These data suggest that leukotriene receptor antagonists may be an effective therapeutics for preventing airway remodeling in asthmatics

Airway Expression of Smad7, a TGF-β-inducible Inhibitory Molecule of TGF-β Signaling, Decreases after Repeated Airway Antigen Challenges

Transforming growth factor-β (TGF-β) is a profibrogenic cytokine that is involved in airway remodeling largely associated with chronic asthma. Accordingly, regulators of TGF-β activity could also play some role in airway remodeling in asthma. In this study, we investigated expression of Smad 7, a major intracellular inhibitor of TGF-β signaling, in the airways of mouse models of acute and chronic asthma. Sensitized, repeatedly (14 days) ovalbumin (OVA)-inhaled BALB/c mice exhibited evidence of airway remodeling including prominent subepithelial fibrosis associated with airway hyperresponsiveness (AHR) and airway inflammation (chronic asthma model) whereas sensitized, shortly OVA-inhaled BALB/c mice showed only AHR and airway inflammation (acute asthma model). Immunohistochemical analysis showed that Smad 7 immunoreactivity in the airways was increased after the development of acute and chronic asthma models and mainly detected in bronchial epithelial cells. Interestingly, Smad 7 immunoreactivity was significantly less in the airways of chronic asthma model than in those of acute asthma model, which was also confirmed by real-time PCR analysis of Smad 7. In consistent with decreased Smad 7 expression in the airways of chronic asthma model, phosphorylation of Smad 2, a marker of active TGF-β signaling, was increased in bronchial epithelial cells of chronic asthma model when compared with acute asthma model. These results suggest that decreased Smad 7 expression and Smad 2 upregulation in bronchial epithelial cells might result in increased TGF-β activity and contribute to the development of airway remodeling seen in chronic asthma

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

Effects of Cytokines and Immunosuppressants on the Production of Serum Amyloid A Protein and C-reactive Protein in HepG2 Cells

C-reactive protein (CRP) and serum amyloid A protein (SAA) are acute- phase proteins produced by the liver in response to inflammatory cytokines. The concentrations of these proteins in serum vary in parallel in most pathological conditions, but sometimes vary independently. CRP and SAA were determined in HepG2 cell culture medium supplemented with five immunosuppressants (corticosteroid, gusperimus hydrochloride, cyclosporin A, mizoribine and tacrolimus hydrate), with or without interleukin-1β(IL-1β) and interleukin-6 (IL-6). We also examined the effects of the immunosuppressants on the production of cytokines and changes in CRP and SAA production in HepG2 cells stimulated with the culture fluid from lipopolysaccharide (LPS) - treated monocytes. In HepG2 cells, production of CRP and SAA was greatly affected by IL-6 and IL-β, respectively. Prednisolone (PSL) suppressed CRP production, while it enhanced SAA production. The other four immunosuppressants did not affect CRP production, but inhibited SAA production. PSL significantly inhibited cytokine production in monocytes, while the other immunosuppressants enhanced it. In HepG2 cells incubated with the culture fluid from LPS-stimulated monocytes, CRP production was suppressed, while SAA production was enhanced. PSL suppressed CRP production in HepG2 cells by inhibiting IL-6 production in monocytes, whereas PSL increased SAA production through a direct action on the hepatoma cells. In contrast, the other immunosuppressive agents enhanced IL-β production in monocytes. The agents induced SAA production in the HepG2 cells but did not affect CRP production