The innate pulmonary granuloma: characterization and demonstration of dendritic cell recruitment and function.
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Granulomas are innate sequestration responses that can be modified by superimposed acquired immune mechanisms. The present study examined the innate stage of pulmonary granuloma responses to bead-immobilized Th1- and Th2-inducing pathogen antigens (Ags), Mycobacteria bovis purified protein derivative (PPD) and Schistosoma mansoni soluble egg Ags (SEA). Compared to a nonpathogen Ag, PPD and SEA bead elicited larger lesions with the former showing accelerated inflammation. Temporal analyses of cytokine and chemokine transcripts showed all Ag beads induced tumor necrosis factor-alpha mRNA but indicated biased interleukin (IL)-1, IL-6, and IL-12 expression with PPD challenge. All beads elicited comparable levels of CXCL9, CXL10, CCL2, CCL17, and CCL22 mRNA, but PPD beads caused biased CXCL2 CXCL5, CCL3, and CCL4 expression whereas both pathogen Ags induced CCL7. Immunohistochemical, electron microscopic, and flow cytometric analyses showed that Ag beads mobilized CD11c+ dendritic cells (DCs) of comparable maturation. Transfer of DCs from PPD Ag-challenged lungs conferred a Th1 anamnestic cytokine response in recipients. Surprisingly, transfer of DCs from the helminth SEA-challenged lungs did not confer the expected Th2 response, but instead rendered recipients incapable of Ag-elicited IL-4 production. These results provide in vivo evidence that lung DCs recruited under inflammatory conditions favor Th1 responses and alternative mechanisms are required for Th2 commitment. (+info)
A case of steroid responsive pulmonary hyalinising granuloma: complicated by deep venous thrombosis.
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A case of pulmonary hyalinising granuloma (PHG) complicated by deep venous thrombosis (DVT) is presented. The DVT was associated with the presence of a lupus anticoagulant. In the past PHG has been linked to various auto-antibodies, but to the best of the authors' knowledge, this is the first case reporting PHG in association with a lupus anticoagulant and clinically significant venous thrombosis. Historically, PHG has been regarded as poorly corticosteroid responsive. However, the patient in this case study responded dramatically to prednisone. This case study suggests that in selected patients with pulmonary hyalinising granuloma experiencing disabling symptoms and worsening pulmonary function, a trial of corticosteroids may be warranted. (+info)
Indigenous pulmonary Propionibacterium acnes primes the host in the development of sarcoid-like pulmonary granulomatosis in mice.
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Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable long-term respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4(+) T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis. (+info)
A case of pulmonary hyalinizing granuloma associated with posterior uveitis.
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A 48-year-old male was admitted to our hospital because of abnormal pulmonary shadows and a decrease in visual acuity. He had a history of tuberculosis 20 years ago. The chest roentgenogram showed multiple pulmonary nodules throughout both lung fields. No definitive diagnosis was established either by brushing cytology or biopsy through bronchoscopy or percutaneous needle biopsy. Pathological examination of open lung biopsy specimen revealed that extensive, hyalinized lamellar collagen bundles arranged in whorls, parallel arrays. Plasma cells and lymphocytes were found between the collagen bands and germinal centers were seen at the periphery of the lesion. A definitive diagnosis of pulmonary hyalinizing granuloma was made on the basis of these histopathological findings. Although there is no established treatment for pulmonary hyalinizing granuloma, during 1 month of follow-up, posterior uveitis mildly resolved with glucocorticoid treatment and there had been a slight increase in visual acuity. (+info)
Role of CCR4 ligands, CCL17 and CCL22, during Schistosoma mansoni egg-induced pulmonary granuloma formation in mice.
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Controversy persists pertaining to the role of CCR4 ligands, namely CCL17 (or thymus and activation regulated chemokine; TARC) and CCL22 (or macrophage-derived chemokine; MDC), in Th2-type cytokine-dominated responses in the lung. Accordingly, the present study addressed the relative role of each of these CC chemokines during an evolving pulmonary granulomatous response elicited by the intrapulmonary embolization of live Schistosoma mansoni eggs into S. mansoni-sensitized mice. CCL22 protein expression peaked at day 4, but CCL17 levels were not increased significantly at any time after egg challenge. CCR4 transcript and protein expression were highest at day 8 after egg embolization and CCR4 protein was prominently expressed in macrophages surrounding S. mansoni eggs. Systemic immunoneutralization of CCL22 from the time of egg injection into S. mansoni-sensitized mice for 8 days significantly decreased CCR4 protein expression, the eosinophil content, the overall size of the egg granuloma, and its hydroxyproline content. Whole lung levels of interferon-gamma were also significantly increased at day 8 in anti-CCL22-treated mice. The systemic immunoneutralization of CCL17 had a lesser effect on all of the granuloma parameters listed above, but this antibody treatment significantly decreased granuloma hydroxyproline content to a greater extent than the anti-CCL22 antibody treatment. In addition, the immunoneutralization of CCL17 significantly increased whole lung levels of interleukin (IL)-4, IL-5, IL-13, transforming growth factor-beta, IL-12, and tumor necrosis factor-alpha at day 8 after egg infusion. Thus, these studies demonstrate a major role for CCL22 and a lesser role for CCL17 during an evolving S. mansoni egg granuloma in the lung. (+info)
Prevalence of tuberculosis in small pulmonary nodules obtained by video-assisted thoracoscopic surgery.
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The prevalence of tuberculosis in small solitary lesions of the lung obtained by video-assisted thoracoscopic surgery (VATS) is still unclear. Of 103 lung lesions resected by VATS in 98 patients (47 men, 51 women), 19 were identified macroscopically as inflammatory changes, 78 were neoplastic, and 6 were undefined. Presumptive diagnosis based on microscopic analysis of fresh specimen smears treated with Papanicolaou stain was performed in 19 lesions. Of these, 11 lesions had epithelioid cells, granulomas with caseous necrosis and Langerhans-type giant cells. The 6 undefined lesions were non-inflammatory benign changes. Isolation and identification of tuberculosis were based on microscopic findings of fresh material smears and sections of fixed specimens stained with Ziehl-Neelsen's dye, cultivation using egg-based Ogawa medium, and in situ hybridization between polymerase chain reaction (PCR) products of each of the 11 lesions and specific DNA sequences for Mycobacterium tuberculosis, M. avium, and M. intracellulare. Of these 11 lesions, M. tuberculosis was confirmed in one (0.96%) by PCR and M. avium was confirmed in four by culture and PCR. Of the 78 malignant lesions, final pathologies were primary lung cancer (n=59, 70.2%) and pulmonary metastatic cancer (n=19, 22.6%). The most frequent primary malignant cancer was adenocarcinoma, which was found in 19 men and 28 women in the present study. Eight lesions in 8 men were squamous cell carcinomas. The results of the present study suggested that even though the prevalence of lung tuberculosis is low, attention should be paid to the presence of M. tuberculosis in specimens obtained by VATS. (+info)
Pulmonary Mycobacterium tuberculosis infection in leptin-deficient ob/ob mice.
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The development of active tuberculosis after infection with Mycobacterium tuberculosis is almost invariably caused by a persistent or transient state of relative immunodeficiency. Leptin, the product of the obese (ob) gene, is a pleiotropic protein produced mainly by adipocytes and is down-regulated during malnutrition and starvation, conditions closely connected with active tuberculosis. To investigate the role of leptin in tuberculosis, we intranasally infected wild-type (Wt) and leptin-deficient ob/ob mice with live virulent M. tuberculosis. Ob/ob mice displayed higher mycobacterial loads in the lungs after 5 and 10 weeks of infection, although the difference with Wt mice remained 1 log of M. tuberculosis colony forming unit. Nevertheless, ob/ob mice were less able to form well-shaped granuloma and lung lymphocyte numbers were reduced compared with Wt mice early during infection. In addition, ob/ob mice had a reduced capacity to produce the protective cytokine IFNgamma at the site of the infection early during infection and upon antigen-specific recall stimulation, and showed reduced delayed-type hypersensitivity reaction to intra-dermal tuberculin purified protein derivative. Leptin replacement restored the reduced IFNgamma response observed in ob/ob mice. Mortality did not differ between ob/ob and Wt mice. These data suggest that leptin plays a role in the early immune response to pulmonary tuberculosis. (+info)
Intragranulomatous necrosis in pulmonary granulomas is not related to resistance against Mycobacterium tuberculosis infection in experimental murine models induced by aerosol.
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Intragranulomatous necrosis is a primary feature in the natural history of human tuberculosis (TB). Unfortunately, this phenomenon is not usually seen in the experimental TB murine model. Artificial induction of this necrosis in pulmonary granulomas (INPG) may be achieved through aerosol inoculation of lipopolysaccharide (LPS) 3 weeks after Mycobacterium tuberculosis infection. At week 9 post-infection, the centre of primary granulomas became larger, showing eosinophilic necrosis. Interestingly, INPG induction was related to mice strains C57BL/6 and 129/Sv, but not to BALB/c and DBA/2. Furthermore, the same pattern was obtained with the induction of infection using a clinical M. tuberculosis strain (UTE 0335R) that naturally induces INPG. In all the mice strains tested, the study of pulmonary mRNA expression revealed a tendency to increase or to maintain the expression of RANTES, interferon-gamma, tumour necrosis factor and iNOS, in both LPS- and UTE 0335R-induced INPG, thus suggesting that this response must be necessary but not sufficient for inducing INPG. Our work supports that INPG induction is a local phenomenon unrelated to the resistant (C57BL/6 and BALB/c) or susceptible (129/Sv and DBA/2) background of mice strains against M. tuberculosis infection. (+info)