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1.
Immunity ; 51(1): 119-130.e5, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31231034

RESUMO

Tissue-resident macrophages require specific milieus for the maintenance of defining gene-expression programs. Expression of the transcription factor GATA6 is required for the homeostasis, function and localization of peritoneal cavity-resident macrophages. Gata6 expression is maintained in a non-cell autonomous manner and is elicited by the vitamin A metabolite, retinoic acid. Here, we found that the GATA6 transcriptional program is a common feature of macrophages residing in all visceral body cavities. Retinoic acid-dependent and -independent hallmark genes of GATA6+ macrophages were induced by mesothelial and fibroblastic stromal cells that express the transcription factor Wilms' Tumor 1 (WT1), which drives the expression of two rate-limiting enzymes in retinol metabolism. Depletion of Wt1+ stromal cells reduced the frequency of GATA6+ macrophages in the peritoneal, pleural and pericardial cavities. Thus, Wt1+ mesothelial and fibroblastic stromal cells constitute essential niche components supporting the tissue-specifying transcriptional landscape and homeostasis of cavity-resident macrophages.


Assuntos
Fator de Transcrição GATA6/metabolismo , Macrófagos/fisiologia , Pericárdio/imunologia , Cavidade Peritoneal/fisiologia , Cavidade Pleural/imunologia , Proteínas Repressoras/metabolismo , Células Estromais/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Fator de Transcrição GATA6/genética , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Repressoras/genética , Tretinoína/metabolismo , Proteínas WT1
2.
Eur J Immunol ; 49(7): 1038-1051, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30939218

RESUMO

Sphingosine-1-phosphate (S1P) is an important sphingolipid derived from plasma membrane and has a known role in productive phase of inflammation, but its role in neutrophil survival and resolution phase of inflammation is unknown. Here, we investigated the effects of inhibition of S1P receptors and the blockade of S1P synthesis in BALB/c mice and human neutrophils. S1P and S1PR1-3 receptors expression were increased in cells from the pleural cavity stimulated with LPS. Using different antagonists of S1PRs and inhibitors of different steps of the metabolic pathway of S1P production, we show that S1P and its receptors are involved in regulating neutrophil survival and resolution of inflammation in the pleural cavity. Given the role of the S1P-S1PR axis in resolution of inflammation, we sought to identify whether blockade at different levels of the sphingosine-1-phosphate synthesis pathway could affect neutrophil survival in vitro. Inhibitors of the S1P pathway were also able to induce human neutrophil apoptosis. In addition, blockade of S1P synthesis or its receptor facilitated the efferocytosis of apoptotic neutrophil. Taken together, our data demonstrate a fundamental role for S1P in regulating the outcome of inflammatory responses, and position S1P-S1PR axis as a potential target for treatment of neutrophilic inflammation.


Assuntos
Inflamação/imunologia , Lisofosfolipídeos/metabolismo , Neutrófilos/imunologia , Cavidade Pleural/imunologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Esfingosina/análogos & derivados , Animais , Apoptose , Sobrevivência Celular , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ativação de Neutrófilo , Transdução de Sinais , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores
3.
Cell Immunol ; 330: 126-135, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29397065

RESUMO

For decades, it has been known that the serous cavities, which include the peritoneal, pleural and pericardial cavities, harbour large numbers of macrophages. In particular, due to the ease of isolating these cells, the peritoneal cavity has been used as a convenient source of macrophages to examine many facets of macrophage biology over the last 50-60 years. Despite this, it is only recently that the true heterogeneity of serous cavity mononuclear phagocyte compartment, which includes macrophages and dendritic cells, has been revealed. Advances in technologies such as multi-parameter flow cytometry and the 'OMICs' revolution have uncovered the presence of distinct populations of mononuclear phagocytes in the serous cavities. Given that peritoneal macrophages have been implicated in many pathologies, including peritonitis, pancreatitis, endometriosis and acute liver injury, it is imperative to understand the biology of these cells. Here, we review the recent advances in understanding the identity, origin and function of discrete serous cavity mononuclear phagocyte subsets in homeostasis and how these may change when homeostasis is perturbed, focusing on peritoneal and pleural cavities and highlighting differences in the mononuclear phagocytes found in each.


Assuntos
Macrófagos/imunologia , Pericárdio/imunologia , Peritônio/imunologia , Cavidade Pleural/imunologia , Animais , Homeostase/imunologia , Humanos , Pericárdio/citologia , Peritônio/citologia , Peritonite/imunologia , Fagócitos/imunologia , Cavidade Pleural/citologia
4.
J Immunol ; 193(7): 3654-63, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25165151

RESUMO

The plasminogen (Plg)/plasmin (Pla) system is associated with a variety of biological activities beyond the classical dissolution of fibrin clots, including cell migration, tissue repair, and inflammation. Although the capacity of Plg/Pla to induce cell migration is well defined, the mechanism underlying this process in vivo is elusive. In this study, we show that Pla induces in vitro migration of murine fibroblasts and macrophages (RAW 264.7) dependent on the MEK/ERK pathway and by requiring its proteolytic activity and lysine binding sites. Plasmin injection into the pleural cavity of BALB/c mice induced a time-dependent influx of mononuclear cells that was associated with augmented ERK1/2 and IκB-α phosphorylation and increased levels of CCL2 and IL-6 in pleural exudates. The inhibition of protease activity by using a serine protease inhibitor leupeptin or two structurally different protease-activated receptor-1 antagonists (SCH79797 and RWJ56110) abolished Pla-induced mononuclear recruitment and ERK1/2 and IκB-α phosphorylation. Interestingly, inhibition of the MEK/ERK pathway abolished Pla-induced CCL2 upregulation and mononuclear cell influx. In agreement with a requirement for the CCL2/CCR2 axis to Pla-induced cell migration, the use of a CCR2 antagonist (RS504393) prevented the Plg/Pla-induced recruitment of mononuclear cells to the pleural cavity and migration of macrophages at transwell plates. Therefore, Pla-induced mononuclear cell recruitment in vivo was dependent on protease-activated receptor-1 activation of the MEK/ERK/NF-κB pathway, which led to the release of CCL2 and activation of CCR2.


Assuntos
Movimento Celular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Fibrinolisina/imunologia , MAP Quinase Quinase Quinases/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Monócitos/imunologia , Receptor PAR-1/imunologia , Receptores CCR2/imunologia , Animais , Benzoxazinas/farmacologia , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Cavidade Pleural/imunologia , Receptores CCR2/antagonistas & inibidores , Compostos de Espiro/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
5.
Exp Parasitol ; 159: 118-26, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26394284

RESUMO

Recently, a family of innate cells has been identified that respond to IL-25 and IL-33 in murine intestinal helminths. Termed Type 2 innate lymphoid cells (ILC2s) they facilitate the development of Th2 responses responsible for helminth clearance. We evaluated these cells in a tissue-invasive helminth model. Using Litomosides sigmodontis (a strong Th2 polarizing filarial infection) we observed a robust Th2 response in the pleural cavity, where adult worms reside, marked by increased levels of IL-5 and IL-13 in infected mice. In parallel, ILC2s were expanded in the pleural cavity early in the infection, peaking during the pre-patent period. L. sigmodontis also elicits a strong systemic Th2 response, which includes significantly increased levels of IgG1, IgE and IL-5 in the plasma of infected mice. Although ILC2s were expanded locally, they were not expanded in the spleen, blood, or mediastinal lymph nodes in response to L. sigmodontis infection, suggesting that ILC2s function primarily at the site of infection. The increase in ILC2s in the pleural cavity and the expansion in Th2 responses indicates a probable role for these cells in initiating and maintaining the Th2 response and highlights the importance of these cells in helminth infections and their role in Th2 immunity.


Assuntos
Filariose/imunologia , Filarioidea/imunologia , Cavidade Pleural/citologia , Células Th2/imunologia , Animais , Anticorpos Anti-Helmínticos/imunologia , Anticorpos Anti-Helmínticos/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Feminino , Gerbillinae , Linfonodos/citologia , Linfonodos/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Mediastino , Camundongos , Camundongos Endogâmicos BALB C , Cavidade Pleural/imunologia , Cavidade Pleural/parasitologia , Baço/citologia , Baço/imunologia , Células Th2/citologia , Irrigação Terapêutica
6.
Infect Immun ; 82(9): 3919-26, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25001606

RESUMO

The pneumococcus is the world's foremost respiratory pathogen, but the mechanisms allowing this pathogen to proceed from initial asymptomatic colonization to invasive disease are poorly understood. We have examined the early stages of invasive pneumococcal disease (IPD) by comparing host transcriptional responses to an invasive strain and a noninvasive strain of serotype 1 Streptococcus pneumoniae in the mouse lung. While the two strains were present in equal numbers in the lung 6 h after intranasal challenge, only the invasive strain (strain 1861) had invaded the pleural cavity at that time point; this correlated with subsequent development of bacteremia in mice challenged with strain 1861 but not the noninvasive strain (strain 1). Progression beyond the lung was associated with stronger induction of the type I interferon (IFN-I) response in the lung at 6 h. Suppression of the IFN-I response through administration of neutralizing antibody to IFNAR1 (the receptor for type I interferons) led to significantly reduced invasion of the pleural cavity by strain 1861 at 6 h postchallenge. Our data suggest that strong induction of the IFN-I response is a key factor in early progression of invasive serotype 1 strain 1861 beyond the lung during development of IPD.


Assuntos
Interferon Tipo I/imunologia , Pulmão/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Anticorpos Neutralizantes/imunologia , Bacteriemia/imunologia , Bacteriemia/microbiologia , Feminino , Pulmão/microbiologia , Camundongos , Cavidade Pleural/imunologia , Cavidade Pleural/microbiologia , Infecções Pneumocócicas/microbiologia
7.
Parasite Immunol ; 36(2): 60-77, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24112106

RESUMO

Eosinophil migration as key feature of helminth infection is increased during infection with filarial nematodes. In a mouse model of filariasis, we investigated the role of the eosinophil-attracting chemokine Eotaxin-1 on disease outcome. BALB/c and Eotaxin-1(-/-) mice were infected with the rodent filaria Litomosoides sigmodontis, and parasitic parameters, cellular migration to the site of infection, and cellular responsiveness were investigated. We found increased parasite survival but unaffected eosinophil migration to the site of infection in Eotaxin-1(-/-) mice. Expression of CD80 and CD86 was reduced on eosinophils from Eotaxin-1(-/-) mice after in vitro TLR2 stimulation and exposure to filarial antigen, respectively, suggesting a potential reduced activation state of eosinophils in Eotaxin-1 deficient mice. We further demonstrated that macrophages from Eotaxin-1(-/-) mice produce decreased amounts of IL-6 in vitro, a cytokine found to be associated with parasite containment, suggesting possible mechanisms by which Eotaxin-1 regulates activation of inflammatory cells and thus parasite survival.


Assuntos
Quimiocina CCL11/fisiologia , Eosinófilos/imunologia , Filariose/imunologia , Filarioidea/imunologia , Macrófagos/imunologia , Animais , Apresentação de Antígeno , Antígenos de Helmintos/imunologia , Movimento Celular , Células Cultivadas , Quimiocina CCL11/deficiência , Quimiocina CCL11/genética , Quimiocina CCL24/metabolismo , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Eosinófilos/fisiologia , Células Epiteliais/metabolismo , Feminino , Filariose/metabolismo , Filariose/parasitologia , Filarioidea/crescimento & desenvolvimento , Interleucina-6/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microfilárias/fisiologia , Carga Parasitária , Cavidade Pleural/imunologia , Cavidade Pleural/parasitologia , Baço/imunologia
8.
Nat Nanotechnol ; 17(2): 206-216, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34916656

RESUMO

Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.


Assuntos
Antígeno B7-H1/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Derrame Pleural Maligno/tratamento farmacológico , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/química , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia , Interferons/genética , Camundongos , Nanopartículas/uso terapêutico , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Exp Immunol ; 163(3): 333-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21303360

RESUMO

Pleural tuberculosis (TB) remains a common presentation of Mycobacterium tuberculosis (MTB) infection in HIV/TB dually infected subjects, and both cellular and acellular components of the pleural milieu promote HIV-1 replication; however, they remain uncharacterized. Using cytokine array of pleural fluid and real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunophenotype analysis, pleural fluid mononuclear cells (PFMC) were compared to systemic counterparts [i.e. plasma and peripheral blood mononuclear cells (PBMC)]. Significant increases in pleural fluid cytokines compared to plasma were limited to interleukin (IL)-6, IL-8, interferon (IFN)-γ and transforming growth factor (TGF)-ß, and did not include other T helper type 1 (Th1) (IL-2, IL-15), Th2 or Th17 cytokines. Patterns and levels of cytokines were indistinguishable between pleural fluid from HIV/TB and TB patients. Forkhead box P3 (FoxP3) mRNA in PFMC was increased significantly and correlated highly with levels of IL-6 and IL-8, less with TGF-ß, and not with IFN-γ. Among CD4 T cells, FoxP3-reactive CD25(hi) were increased in HIV/TB dually infected subjects compared to their PBMC, and up to 15% of FoxP3(+) CD25(hi) CD4 T cells were positive for IL-8 by intracellular staining. These data implicate a dominant effect of MTB infection (compared to HIV-1) at pleural sites of dual HIV/TB infection on the local infectious milieu, that include IL-6, IL-8, IFN-γ and TGF-ß and regulatory T cells (T(reg) ). A correlation in expansion of T(reg) with proinflammatory cytokines (IL-6 and IL-8) in pleural fluid was shown. T(reg) themselves may promote the inflammatory cytokine milieu through IL-8.


Assuntos
Citocinas/metabolismo , Infecções por HIV/complicações , Infecções por HIV/imunologia , Cavidade Pleural/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose Pleural/complicações , Tuberculose Pleural/imunologia , Adulto , Citocinas/sangue , Feminino , Fatores de Transcrição Forkhead/genética , Proteínas de Fusão gag-pol/genética , Expressão Gênica/genética , Infecções por HIV/sangue , Infecções por HIV/metabolismo , HIV-1/isolamento & purificação , Humanos , Interferon gama/sangue , Interferon gama/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Plasma/virologia , Cavidade Pleural/metabolismo , Cavidade Pleural/patologia , Cavidade Pleural/virologia , Derrame Pleural/imunologia , Derrame Pleural/metabolismo , Derrame Pleural/patologia , Derrame Pleural/virologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Tuberculose Pleural/sangue , Tuberculose Pleural/metabolismo , Carga Viral , Adulto Jovem
10.
J Immunol Res ; 2021: 6643808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977110

RESUMO

Tissue-resident memory T (TRM) cells are well known to play critical roles in peripheral tissues during virus infection and tumor immunology. Our previous studies indicated that CD69+CD4+ and CD69+CD8+ T cells in tuberculous pleural effusion (TPE) were antigen-specific memory T cells. However, the phenotypical and functional characteristics of CD8+ TRM cells in tuberculosis remain unknown. We found that CD103+CD8+ T cells were the predominant subset of CD103+ lymphocytes in TPE; both CD103 and CD69 expressed on memory CD8+ T cells from TPE were significantly increased compared with those from paired peripheral blood. Phenotypically, CD103+CD69+ and CD103+CD69-CD8+ T cells expressed higher levels of CD45RO than CD103-CD69+CD8+ T cells did; CD103+CD69-CD8+ T cells highly expressed CD27, CD127, and CD62L and some chemokine receptors. We further compared the functional differences among the four distinct CD45RO+CD8+ T subsets identified by CD103 and CD69 expression. In consist with our published results, CD69+CD8+ T cells, but not CD103+CD8+, produced high levels of IFN-γ after treatment with BCG in the presence of BFA. Nevertheless, CD103-CD69+ and CD103+CD69+ memory CD8+ T cells expressed higher levels of Granzyme B, while CD103+CD69- memory CD8+ T cells were characterized as a possibly immunosuppressive subset by highly expressing CTLA-4, CD25, and FoxP3. Furthermore, TGF-ß extremely increased CD103 expression but not CD69 in vitro. Together, CD103+CD8+ T cells form the predominant subset of CD103+ lymphocytes in TPE; CD103 and CD69 expression defines distinct CD8+ TRM-like subsets exhibiting phenotypical and functional heterogeneity. Our findings provide an important theoretical basis to optimize and evaluate new tuberculosis vaccines.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Derrame Pleural/imunologia , Subpopulações de Linfócitos T/imunologia , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Cavidade Pleural/citologia , Cavidade Pleural/imunologia , Cavidade Pleural/microbiologia , Derrame Pleural/sangue , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose Pleural/sangue , Tuberculose Pleural/complicações , Tuberculose Pleural/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Adulto Jovem
11.
Front Immunol ; 12: 760683, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34966384

RESUMO

Background: Malignant tumors accompanied with malignant pleural effusion (MPE) often indicate poor prognosis. The therapeutic effect and mechanism of intrapleural injection of anti-programmed cell death protein 1 (PD1) on MPE need to be explored. Methods: A preclinical MPE mouse model and a small clinical study were used to evaluate the effect of intrapleural injection of anti-PD1 antibody. The role of immune cells was observed via flow cytometry, RNA-sequencing, quantitative PCR, western blot, immunohistochemistry, and other experimental methods. Results: Intrathoracic injection of anti-PD1 monoclonal antibody (mAb) has significantly prolonged the survival time of mice (P = 0.0098) and reduced the amount of effusion (P = 0.003) and the number of cancer nodules (P = 0.0043). Local CD8+ T cells participated in intrapleural administration of anti-PD1 mAb. The proportion of CD69+, IFN-γ+, and granzyme B+ CD8+ T cells in the pleural cavity was increased, and the expression of TNF-α and IL-1ß in MPE also developed significantly after injection. Local injection promoted activation of the CCL20/CCR6 pathway in the tumor microenvironment and further elevated the expression of several molecules related to lymphocyte activation. Clinically, the control rate of intrathoracic injection of sintilimab (a human anti-PD1 mAb) for 10 weeks in NSCLC patients with MPE was 66.7%. Local injection improved the activity and function of patients' local cytotoxic T cells (CTLs). Conclusions: Intrapleural injection of anti-PD1 mAb could control malignant pleural effusion and the growth of cancer, which may be achieved by enhancing local CTL activity and cytotoxicity.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linhagem Celular Tumoral , Humanos , Injeções , Neoplasias Pulmonares/imunologia , Masculino , Camundongos Endogâmicos C57BL , Cavidade Pleural/imunologia , Derrame Pleural Maligno/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
12.
Int J Oncol ; 58(3): 359-370, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650668

RESUMO

Patients with a variety of malignancies can develop malignant pleural effusion (MPE). MPE can cause significant symptoms and result in a marked decrease in quality of life and a poor prognosis. MPE is primarily considered as an immune and vascular manifestation of pleural metastases. In the present review, the existing evidence supporting the applicability of anti­angiogenic therapy and immunotherapy for the treatment of MPE was summarized. Patients with MPE have benefited from anti­angiogenic agents, including bevacizumab and endostar; however, no relevant prospective phase III trial has, thus far, specifically analyzed the benefit of anti­angiogenic therapy in MPE. Immunotherapy for MPE may be sufficient to turn a dire clinical situation into a therapeutic advantage. Similar to anti­angiogenic therapy, more clinical data on the efficiency and safety of immunotherapy for controlling MPE are urgently required. The combined use of anti­angiogenic therapy and immunotherapy may be a promising strategy for MPE, which requires to be further understood.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Derrame Pleural Maligno/terapia , Bevacizumab/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Terapia Combinada/métodos , Células Dendríticas/imunologia , Endostatinas/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Derrame Pleural Maligno/imunologia , Derrame Pleural Maligno/mortalidade , Derrame Pleural Maligno/patologia , Prognóstico , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Evasão Tumoral
13.
Thorac Cardiovasc Surg ; 58(6): 350-3, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20824588

RESUMO

BACKGROUND: This study evaluates the tumor marker index (TMI) based on carcinoembryonic antigen (CEA) levels in serum and pleural lavage fluid as a potential prognostic determinant for patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Three hundred and eighty-three consecutive NSCLC patients were reviewed retrospectively. RESULTS: The 5-year survival of patients with normal and high serum CEA levels was 71.78% and 51.38%, respectively (P < 0.0001). The 5-year survival of patients with high CEA levels in pleural lavage fluid was 25.0%, which was significantly poorer compared with that of patients with normal lavage CEA levels (78.23%, P < 0.0001). There was a 5-year survival rate of 73.75% in patients with a TMI less than or equal to 1.0 compared to a rate of only 55.12% in patients with a TMI greater than 1.0 (P < 0.001). Both univariate and multivariate analyses indicated the independent prognostic impact of the TMI. CONCLUSIONS: The TMI based on serum and lavage CEA levels might be useful for predicting the prognosis of NSCLC patients.


Assuntos
Antígeno Carcinoembrionário/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Cavidade Pleural/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cavidade Pleural/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Irrigação Terapêutica , Fatores de Tempo , Resultado do Tratamento
14.
Pharmacology ; 86(4): 224-30, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20829647

RESUMO

OBJECTIVE AND DESIGN: Although proteinase-activated receptor (PAR)-4 has been implicated in inflammation, its role in regulating eosinophil recruitment in response to chemoattractants has not yet been demonstrated. To investigate the contribution of proteinases and PAR-4 activation to eosinophil migration in response to eotaxin-1 or leukotriene B(4) (LTB(4)), the effects of aprotinin or PAR-4 antagonist trans-cinnamoyl-YPGKF-NH(2) (tcY-NH(2)) on eosinophil migration induced by these chemoattractants were investigated. METHODS: BALB/c mice were pretreated with aprotinin or tcY-NH(2) (30 µg/mouse) prior to intrapleural injection of LTB(4) or eotaxin-1 and the number of infiltrating eosinophils was determined 48 h later. RESULTS: Aprotinin (1 mg/kg) inhibited eosinophil recruitment induced by eotaxin-1 (p < 0.01), but not that induced by LTB(4). Moreover, tcY-NH(2) treatment inhibited eosinophil recruitment in response to eotaxin-1 (p < 0.01 by ANOVA/Tukey post-test). CONCLUSION: These data suggest that aprotinin-inhibited proteinases participate in eosinophil migration induced by eotaxin-1 and that PAR-4 activation plays an important role in regulating this migration.


Assuntos
Aprotinina/farmacologia , Quimiocina CCL11/farmacologia , Eosinófilos/efeitos dos fármacos , Receptores Ativados por Proteinase/metabolismo , Animais , Movimento Celular , Cinamatos/farmacologia , Eosinófilos/metabolismo , Leucotrieno B4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/farmacologia , Ovalbumina/imunologia , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/imunologia , Cavidade Pleural/metabolismo , Pleurisia/imunologia
15.
Parasit Vectors ; 13(1): 551, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33160409

RESUMO

BACKGROUND: Pulmonary manifestations are regularly reported in both human and animal filariasis. In human filariasis, the main known lung manifestations are the tropical pulmonary eosinophilia syndrome. Its duration and severity are correlated with the presence of microfilariae. Litomosoides sigmodontis is a filarial parasite residing in the pleural cavity of rodents. This model is widely used to understand the immune mechanisms that are established during infection and for the screening of therapeutic molecules. Some pulmonary manifestations during the patent phase of infection with L. sigmodontis have been described in different rodent hosts more or less permissive to infection. METHODS: Here, the permissive Mongolian gerbil (Meriones unguiculatus) was infected with L. sigmodontis. Prevalence and density of microfilariae and adult parasites were evaluated. Lungs were analyzed for pathological signatures using immunohistochemistry and 3D imaging techniques (two-photon and light sheet microscopy). RESULTS: Microfilaremia in gerbils was correlated with parasite load, as amicrofilaremic individuals had fewer parasites in their pleural cavities. Fibrotic polypoid structures were observed on both pleurae of infected gerbils. Polyps were of variable size and developed from the visceral mesothelium over the entire pleura. The larger polyps were vascularized and strongly infiltrated by immune cells such as eosinophils, macrophages or lymphocytes. The formation of these structures was induced by the presence of adult filariae since small and rare polyps were observed before patency, but they were exacerbated by the presence of gravid females and microfilariae. CONCLUSIONS: Altogether, these data emphasize the role of host-specific factors in the pathogenesis of filarial infections.


Assuntos
Eosinófilos/imunologia , Filariose/patologia , Gerbillinae/parasitologia , Microfilárias/patogenicidade , Cavidade Pleural/parasitologia , Pólipos/imunologia , Animais , Feminino , Fibrose , Filariose/imunologia , Filariose/parasitologia , Filarioidea/patogenicidade , Pulmão/parasitologia , Pulmão/patologia , Masculino , Microfilárias/imunologia , Carga Parasitária , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Pólipos/parasitologia , Pólipos/patologia
16.
Parasitol Int ; 57(2): 201-11, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18295534

RESUMO

The filarial nematode Litomosoides sigmodontis model was used to decipher the complex in vivo relationships between filariae, granulomas and leukocytes in the host's pleural cavity. The study was performed from D5 p.i.: to D47 p.i. in resistant C57BL/6 mice, to D74 p.i. in susceptible BALB/c mice, and to D420 p.i. in permissive jirds. We showed that, during the first month, leukocytes only clustered as granulomas around shed cuticles (exuviae) and with eosinophils as the major constituents. In addition, carbohydrates residues became abundant on exuviae only, suggesting a glycan-dependent mechanism of eosinophil attachment. Neutrophils were absent from the pleural cavity of all rodents and from the murine granulomas, but they made up 25% of the granuloma cell population in jirds. After the first month of infection granulomas formed around developed adult worms and morphological evidence suggested that leukocytes preferentially clustered around altered, but still motile, worms. No carbohydrates were detected on these worms and neutrophils were abundant in those granulomas. Finally, a rare third type of granuloma was observed in the resistant mice only; they contained young newly moulted adult worms; typically these granulomas were attached to the lateral lines of the worm via eosinophils; this feature correlated with the persistence of carbohydrate residues on the worms' lateral lines. Neutrophils were always in low proportion in all granulomas from resistant mice, suggesting difference in their adhesive properties in these mice. In vitro neutrophil recruitment in resistant mice was similar to that observed in susceptible mice although they expressed less cell surface CD11b.


Assuntos
Filariose , Filarioidea/patogenicidade , Interações Hospedeiro-Parasita , Muda , Cavidade Pleural , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Eosinófilos/imunologia , Feminino , Filariose/imunologia , Filariose/parasitologia , Filariose/fisiopatologia , Filarioidea/crescimento & desenvolvimento , Gerbillinae/parasitologia , Granuloma/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Cavidade Pleural/citologia , Cavidade Pleural/imunologia , Cavidade Pleural/fisiopatologia , Especificidade da Espécie
17.
Elife ; 72018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29299998

RESUMO

Both TH2-dependent helminth killing and suppression of the TH2 effector response have been attributed to macrophages (MΦ) activated by IL-4 (M(IL-4)). To investigate how M(IL-4) contribute to diverse infection outcomes, the MΦ compartment of susceptible BALB/c mice and more resistant C57BL/6 mice was profiled during infection of the pleural cavity with the filarial nematode, Litomosoides sigmodontis. C57BL/6 mice exhibited a profoundly expanded resident MΦ (resMΦ) population, which was gradually replenished from the bone marrow in an age-dependent manner. Infection status did not alter the bone-marrow derived contribution to the resMΦ population, confirming local proliferation as the driver of resMΦ expansion. Significantly less resMΦ expansion was observed in the susceptible BALB/c strain, which instead exhibited an influx of monocytes that assumed an immunosuppressive PD-L2+ phenotype. Inhibition of monocyte recruitment enhanced nematode killing. Thus, the balance of monocytic vs. resident M(IL-4) numbers varies between inbred mouse strains and impacts infection outcome.


Assuntos
Movimento Celular , Proliferação de Células , Filariose/imunologia , Filariose/patologia , Filarioidea/crescimento & desenvolvimento , Filarioidea/imunologia , Macrófagos/fisiologia , Animais , Resistência à Doença , Suscetibilidade a Doenças , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Cavidade Pleural/imunologia , Cavidade Pleural/parasitologia
18.
Int J Parasitol ; 36(8): 903-14, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16765354

RESUMO

Sustainable control of human filariasis would benefit enormously from the development of an effective vaccine. The ability to vaccinate experimental animals, with reductions in worm burden of over 70%, suggests this aim is possible. However, in experimental vaccinations the challenge is usually administered 2 weeks after the immunisation phase and thus the protection obtained is likely to be biased by persisting inflammation. Using the murine model Litomosoides sigmodontis, we increased the time between immunisation with irradiated larvae and challenge with fully infective L3 to 5 months. Significant protection was achieved (54-58%) and the reduced worm burden was observed by 10 days p.i. The developmental stage targeted was the L3, since no nematodes died once they reached the pleural cavity of vaccinated mice, as has been previously shown in short-term protocols. However, larval developmental rate was faster in vaccinated than in primary-infected mice. Immunological assessments were made prior to challenge and then from 6 h to 34 days post-challenge. Samples were taken from the subcutaneous tissue where the larvae were inoculated, the lymph nodes through which they migrate and the pleural cavity in which they establish. Eosinophils were still present although scarce in the subcutaneous tissue of vaccinated mice before challenge. Cytokine and specific antibody production of vaccinated and challenged mice were L3-specific and Th2-biased and greatly exceeded the response of primary-infected mice. The heightened Th2 response may explain the faster development of the filarial worms in vaccinated mice. Thus, long-term vaccination protocols generated a strong memory response that led to significant but incomplete protection that was limited to the infective larval stage suggesting alternative vaccination strategies are needed.


Assuntos
Filariose/prevenção & controle , Filarioidea/imunologia , Vacinação/métodos , Vacinas/farmacologia , Animais , Anticorpos Anti-Helmínticos/sangue , Citocinas/genética , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Eosinófilos/imunologia , Eosinófilos/parasitologia , Feminino , Filariose/imunologia , Filarioidea/efeitos da radiação , Citometria de Fluxo , Humanos , Larva/imunologia , Larva/efeitos da radiação , Linfonodos/imunologia , Linfonodos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Cavidade Pleural/imunologia , Cavidade Pleural/parasitologia , RNA de Helmintos/química , RNA de Helmintos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Vacinas/imunologia
19.
Acta Cytol ; 50(5): 539-41, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17017441

RESUMO

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder occurring in patients with lymphoproliferative diseases, predominantly multiple myeloma and low grade B-cell lymphoma. This report presents the first case of CSH diagnosed on pleural fluid from a patient with multiple myeloma (MM). CASE: A 79-year-old women with IgA kappa MM underwent thoracocenthesis and thoracic drainage because of a pleural effusion. Cytologic and immunocytochemical examination of pleural fluid revealed abundant histiocytic, CD68-positive cells with prominent intracytoplasmic, needlelike, crystalloid inclusions showing strong immunopositivity for IgA heavy and kappa light chains. Identical crystals were observed on an extracellular background. No myeloma infiltration was detected. Two weeks later, examination of new pleural fluid from the patient showed a similar cytologic picture, but, in addition, isolated plasma cell features were identified. They were too few for a meaningful determination of clonality. The patient died I month after the CSH diagnosis. CONCLUSION: This case illustrates the value of cytologic examination of serous fluids from patients with plasma cell dyscrasias, not only to evaluate possible infectious or neoplastic causes but also to diagnose CSH.


Assuntos
Histiócitos/patologia , Histiocitose/diagnóstico , Histiocitose/imunologia , Imunoglobulina A/imunologia , Mieloma Múltiplo/complicações , Derrame Pleural/diagnóstico , Derrame Pleural/imunologia , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Biópsia por Agulha , Dispneia/etiologia , Dispneia/fisiopatologia , Evolução Fatal , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Histiócitos/imunologia , Histiocitose/fisiopatologia , Humanos , Subunidades de Imunoglobulinas/química , Subunidades de Imunoglobulinas/imunologia , Corpos de Inclusão/imunologia , Corpos de Inclusão/patologia , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Derrame Pleural/fisiopatologia , Costelas/patologia
20.
Sci Rep ; 6: 36829, 2016 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-27833109

RESUMO

Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer with a high mortality rate as it responds poorly to standard therapeutic interventions. Our recent studies showed that expression of endothelial cell protein C receptor (EPCR) in MPM cells suppresses tumorigenicity. The present study was aimed to investigate the mechanism by which EPCR suppresses MPM tumor growth and evaluate whether EPCR gene therapy could suppress the progression of MPM in a mouse model of MPM. Measurement of cytokines from the pleural lavage showed that mice implanted with MPM cells expressing EPCR had elevated levels of IFNγ and TNFα compared to mice implanted with MPM cells lacking EPCR. In vitro studies demonstrated that EPCR expression renders MPM cells highly susceptible to IFNγ + TNFα-induced apoptosis. Intrapleural injection of Ad.EPCR into mice with an established MPM originating from MPM cells lacking EPCR reduced the progression of tumor growth. Ad.EPCR treatment elicited recruitment of macrophages and NK cells into the tumor microenvironment and increased IFNγ and TNFα levels in the pleural space. Ad.EPCR treatment resulted in a marked increase in tumor cell apoptosis. In summary, our data show that EPCR expression in MPM cells promotes tumor cell apoptosis, and intrapleural EPCR gene therapy suppresses MPM progression.


Assuntos
Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Adenoviridae/genética , Animais , Apoptose , Linhagem Celular Tumoral , Progressão da Doença , Receptor de Proteína C Endotelial , Terapia Genética , Vetores Genéticos , Células HEK293 , Humanos , Interferon gama/fisiologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Cavidade Pleural/imunologia , Cavidade Pleural/patologia , Neoplasias Pleurais/patologia , Transdução Genética , Fator de Necrose Tumoral alfa/fisiologia
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