Angioimmunoblastic T-cell lymphoma diagnosed from pleural fluid by integration of morphologic, immunophenotypic, and molecular findings.

An 88-year-old man with end-stage renal disease on hemodialysis presented with shortness of breath and was found to have lower extremity edema and bilateral pleural effusions on a chest X-ray. A therapeutic and diagnostic thoracentesis was performed, and cytologic examination revealed atypical mononuclear cells. Based on this, flow cytometry was performed on the pleural fluid, along with immunostains on the cellblock and a next-generation sequencing (NGS) panel. A definitive diagnosis of angioimmunoblastic T-cell lymphoma (AITL) was made based on demonstrating an atypical T follicular helper cell population expressing CD10, BCL6, CXCL13, CD200, CD57, and PD1, and detection of pathogenic variants in RHOA, IDH2, and TET2. This case represents the first reported case where a primary diagnosis of AITL was made on a body fluid specimen and highlights how immunophenotyping and NGS can provide a definitive diagnosis of AITL on a cytologic specimen.

Anti-inflammatory and antinociceptive activity profile of a new lead compound - LQFM219.

LQFM219 is a molecule designed from celecoxibe (COX-2 inhibitor) and darbufelone (inhibitor of COX-2 and 5-LOX) lead compounds through a molecular hybridisation strategy. Therefore, this work aimed to investigate the antinociceptive and anti-inflammatory activities of this new hybrid compound. The acute oral systemic toxicity of LQFM219 was evaluated via the neutral red uptake assay. Acetic acid-induced abdominal writhing and CFA-induced mechanical hyperalgesia were performed to evaluate the antinociceptive activity, and the anti-oedematogenic activity was studied by CFA-induced paw oedema and croton oil-induced ear oedema. Moreover, the acute anti-inflammatory activity was determined by carrageenan-induced pleurisy. In addition, cell migration, myeloperoxidase enzyme activity, and TNF-α and IL-1ß levels were determined in pleural exudate. Moreover, a redox assay was conducted using electroanalytical and DPPH methods. The results demonstrated that LQFM219 was classified as GHS category 4, and it showed better free radical scavenger activity compared to BHT. Besides, LQFM219 decreased the number of writhings induced by acetic acid and the response to the mechanical stimulus in the CFA-induced mechanical hyperalgesia test. Furthermore, LQFM219 reduced oedema formation, cell migration, and IL-1ß and TNF-α levels in the pleural cavity and inhibited myeloperoxidase enzyme activity. Thus, our study provides that the new pyrazole derivative, LQFM219, demonstrated low toxicity, antinociceptive and anti-inflammatory potential in vitro and in vivo.

Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL.

This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation (~20 % survival). Control groups included a particle control (TiO2), chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 µm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470-715; chrysotile 495-614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 µm were observed in the lungs at the end of exposure and no fibers L > 20 µm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 fibers(L > 20 µm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 fibers(L > 20 µm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 fibers(L > 20 µm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 fibers(L > 20 µm)/lung representing 10-13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations. The exposure and lung burden results provide a sound basis for assessing the potential toxicity of the brake dust in comparison to the TiO2 particle control and the chrysotile, crocidolite and amosite asbestos control groups. The BAL results provide an initial indication of the differential response. Part 2 presents the presentation and discussion of the histopathological and confocal microscopy findings in this study through 90 days post exposure.

Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity.

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

Cytokine Response in the Pleural Fluid and Blood in Minimally Invasive and Open Esophagectomy.

BACKGROUND: Transthoracic esophagectomy for cancer triggers a massive inflammatory reaction. The data whether a minimally invasive esophagectomy (MIE) leads to less pronounced inflammatory response compared to open right-sided transthoracic esophagectomy (OE) are scarce. The aim of this study was to evaluate the extent of the inflammatory reaction, represented by levels of the pro-inflammatory interleukins IL-6 and IL-8, the anti-inflammatory IL-1 RA and the chemokines CINC-1 and MCP-1 in the right pleural fluid and the blood from patients undergoing standard OE or MIE. METHODS: Pleural drainage fluid and blood was collected at five different time points during the first 72 h following surgery, and the concentrations of IL-6, IL-8, IL-1 RA, CINC-1 and MCP-1 were analyzed using enzyme-linked immune-sorbent assays in 24 patients undergoing MIE or OE. RESULTS: The groups were matched for cancer stage and comorbidities. Pro- and anti-inflammatory mediator levels in the pleural fluid were markedly increased at the end of surgery and on postoperative days 1-3. The pleural inflammatory response of all cyto- and chemokines was lower in the MIE group, reaching significance at some time points. Cyto- and chemokine response levels measured in the blood were overall lower compared to those in the pleural fluid. The chemokines CINC-1 and MCP-1 reacted less pronounced or not at all. Preoperative pulmonary comorbidity, postoperative pulmonary morbidity and length of surgery were associated with an increased reaction in selected mediators. CONCLUSIONS: The minimally invasive technique attenuates the inflammatory response, especially locally in the thoracic compartment. Length of procedure, preoperative pulmonary comorbidity and postoperative pulmonary complications are mirrored in an increase in individual inflammatory markers in the pleural fluid. The value of the chemokines CINC-1 and MCP-1 as markers of inflammation in the setting of esophagectomy is unclear.

Cost-effectiveness of intrapleural use of tissue plasminogen activator and DNase in pleural infection: evidence from the MIST2 randomised controlled trial.

The MIST2 (Second Multicentre Intrapleural Sepsis Trial) trial showed that combined intrapleural use of tissue plasminogen activator (t-PA) and recombinant human DNase was effective when compared with single agents or placebo. However, the treatment costs are significant and overall cost-effectiveness of combined therapy remains unclear.An economic evaluation of the MIST2 trial was performed to assess the cost-effectiveness of combined therapy. Costs included were those related to study medications, initial hospital stay and subsequent hospitalisations. Outcomes were measured in terms of life-years gained. All costs were reported in euro and in 2016 prices.Mean annual costs were lowest in the t-PA-DNase group (EUR 10 605 for t-PA, EUR 17 856 for DNase, EUR 13 483 for placebo and EUR 7248 for t-PA-DNase; p=0.209). Mean 1-year life expectancy was 0.988 for t-PA, 0.923 for DNase, and 0.969 for both placebo and t-PA-DNase (p=0.296). Both DNase and placebo were less effective, in terms of life-years gained, and more costly than t-PA. When placebo was compared with t-PA-DNase, the incremental cost per life-year gained of placebo was EUR 1.6 billion, with a probability of 0.85 of t-PA-DNase being cost-effective.This study demonstrates that combined t-PA-DNase is likely to be highly cost-effective. In light of this evidence, a definitive trial designed to facilitate a thorough economic evaluation is warranted to provide further evidence on the cost-effectiveness of this promising combined intervention.

Pleural effusion related to IgG4.

PURPOSE OF REVIEW: The causes of exudative pleural effusions are diverse and frequently remain unclear despite exhaustive examinations. Recently recognized IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that can affect nearly any organ including the lungs. This review will focus on the involvement of IgG4 in exudative pleural effusion of unknown cause. RECENT FINDINGS: IgG4 is found to be involved in a proportion of patients with undiagnosed pleural effusions. Pleural involvement in IgG4-RD can be seen in isolation or association with other organ disease. Pleural thickening and/or effusion are common clinical features of IgG4-related pleural lesions, and this condition is histologically characterized by a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells in the pleura. Although the pathogenesis of IgG4-RD is poorly understood, there is a growing body of evidence that indicates an antigen-driven process requiring T-cell and B-cell interaction in which autoantibodies, plasmablasts, follicular helper T cells and CD4+ cytotoxic T lymphocytes participate. SUMMARY: The possibility of IgG4-related pleural lesion should be considered in patients with pleural effusion of unexplained cause when lymphoplasmacytic infiltration is seen in a pleural biopsy specimen. This condition is responsive to systemic steroid therapy.

Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

B-lymphocytes forming follicle-like structures in the lung tissue of tuberculosis-infected mice: Dynamics, phenotypes and functional activity.

During tuberculosis (TB) infection, B cells form follicles in close vicinity of lung granuloma. We assessed the dynamics of follicle formation, surface phenotypes and functional activity of lung B cells during TB course in genetically susceptible mice. The follicles appeared early post infection and peaked at weeks 7-8. Lung B cells resembled classical B2 cells (CD19+IgMloIgDhiCD1d-CD21/35intCD5-CD11b-CD43-), but differed from them by the absence of B2 marker CD23. Lung B-cells constitutively expressed MHC II molecules, presented mycobacterial antigens to immune CD4+ T-cells and produced high amounts of IL-6 and IL-11, but no classical type 1 (TNF-α, IFN-γ), or anti-inflammatory (IL-10, TGF-ß) cytokines. The total antibody response in tuberculous lung showed almost no specificity to mycobacteria. A panel of monoclonal antibodies obtained from lung B cells contained only few clones with reactivity to mycobacteria. Our results suggest that anti-TB B cell response in the lung has clear pathological and doubtful protective role.

Evaluation of predictive value of pleural CEA in patients with pleural effusions and histological findings: A prospective study and literature review.

OBJECTIVES: Pleural effusion recognizes heterogeneous etiology and pathogenesis and requires invasive diagnostic procedures. Usually, after pleural fluid analysis, 30-50% of patients with malignant pleural effusion exhibit negative pleural cytology, and the sensitivity of image-guided pleural needle-aspiration biopsy ranges between 60% and 70%. With the aim of differentiating between benign (BPE) and malignant (MPE) pleural effusions, several tumor markers have been assayed in the pleural fluid and the majority of studies focus on pleural carcinoembryonic antigen (p-CEA). The aims of this study were to evaluate (i) the diagnostic accuracy of p-CEA of patients with pleural effusions undergoing video-assisted thoracoscopic surgery (VATS) for diagnostic purpose, (ii) the relationship between p-CEA and serum CEA (s-CEA), and (iii) the usefulness of the p-CEA/s-CEA ratio in the diagnosis of malignant pleural effusions (MPE). DESIGN & METHODS: We prospectively enrolled in the study 134 consecutive patients with pleural effusions, scheduled for having VATS and biopsy. The final diagnosis, based on histopathology of the VATS-guided specimens, was available for all patients. p-CEA and s-CEA was assayed with a chemiluminescence immunoassay method (CLIA), applied on the Maglumi 2000 Plus automated platform (SNIBE, Shenzen, China). RESULTS: The sensitivity and accuracy of p-CEA was significantly higher than that of pleural cytology at the same specificity comparing BPE with MPE and BPE with non-small lung cancer. The sensitivity of p-CEA and PC together reached 100% (BPE vs. NSCLC) and 91.5% (BPE vs. MPE excluding mesothelioma), respectively. CONCLUSIONS: The p-CEA measurement in patients with pleural effusion of uncertain etiology is a safe and cost-effective procedure, everywhere easily available, which may help clinicians in selecting patients for further evaluations. An elevated p-CEA level in a patient with pleural effusion and negative pleural cytology suggests the need of more invasive procedure (e.g. VATS-guided biopsies), whilst low p-CEA may support a follow-up.

Serosal involvement in IgG4-related disease: report of two cases and review of the literature.

IgG4-related disease (IgG4-RD) is a recently described entity characterized by lymphoplasmacytic infiltrates, usually mimicking tumors, affecting almost every organ or system. Nevertheless, serosal involvement has been rarely reported. In this article, we report two cases of IgG4-RD with serosal involvement and review the literature. Because of the varied clinical pictures found in our review, we suggest a new terminology for the description of IgG4-RD with serosal involvement.

Productive HIV-1 infection is enriched in CD4(-)CD8(-) double negative (DN) T cells at pleural sites of dual infection with HIV and Mycobacterium tuberculosis.

A higher human immunodeficiency virus 1 (HIV-1) viral load at pleural sites infected with Mycobacterium tuberculosis (MTB) than in peripheral blood has been documented. However, the cellular source of productive HIV infection in HIV-1/MTB-coinfected pleural fluid mononuclear cells (PFMCs) remains unclear. In this study, we observed significant quantities of HIV-1 p24(+) lymphocytes in PFMCs, but not in peripheral blood mononuclear cells (PBMCs). HIV-1 p24(+) lymphocytes were mostly enriched in DN T cells. Intracellular CD4 expression was detectable in HIV-1 p24(+) DN T cells. HIV-1 p24(+) DN T cells showed lower surface expression of human leukocyte antigen (HLA)-ABC and tetherin than did HIV-1 p24(+) CD4 T cells. Upon in vitro infection of PFMC CD4 T cells from TB mono-infected subjects, Nef- and/or Vpu-deleted HIV mutants showed lower generation of HIV-1 p24(+) DN T cells than the wild-type virus. These data indicate that productively HIV-1-infected DN T cells, generated through down-modulation of surface CD4, likely by HIV-1 Nef and Vpu, are the predominant source of HIV-1 at pleural sites of HIV/MTB coinfection.

Mycobacterium tuberculosis Upregulates TNF-α Expression via TLR2/ERK Signaling and Induces MMP-1 and MMP-9 Production in Human Pleural Mesothelial Cells.

BACKGROUND: Tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) are elevated in pleural fluids of tuberculous pleuritis (TBP) where pleural mesothelial cells (PMCs) conduct the first-line defense against Mycobacterium tuberculosis (MTB). However, the clinical implication of TNF-α and MMPs in TBP and the response of PMCs to MTB infection remain unclear. METHODS: We measured pleural fluid levels of TNF-α and MMPs in patients with TBP (n = 18) or heart failure (n = 18) as controls. Radiological scores for initial effusion amount and residual pleural fibrosis at 6-month follow-up were assessed. In vitro human PMC experiments were performed to assess the effect of heat-killed M. tuberculosis H37Ra (MTBRa) on the expression of TNF-α and MMPs. RESULTS: As compared with controls, the effusion levels of TNF-α, MMP-1 and MMP-9 were significantly higher and correlated positively with initial effusion amount in patients with TBP, while TNF-α and MMP-1, but not MMP-9, were positively associated with residual pleural fibrosis of TBP. Moreover, effusion levels of TNF-α had positive correlation with those of MMP-1 and MMP-9 in TBP. In cultured PMCs, MTBRa enhanced TLR2 and TLR4 expression, activated ERK signaling, and upregulated TNF-α mRNA and protein expression. Furthermore, knockdown of TLR2, but not TLR4, significantly inhibited ERK phosphorylation and TNF-α expression. Additionally, both MTBRa and TNF-α markedly induced MMP-1 and MMP-9 synthesis in human PMCs, and TNF-α neutralization substantially reduced the production of MMP-1, but not MMP-9, in response to MTBRa stimulation. CONCLUSION: MTBRa activates TLR2/ERK signalings to induce TNF-α and elicit MMP-1 and MMP-9 in human PMCs, which are associated with effusion volume and pleural fibrosis and may contribute to pathogenesis of TBP. Further investigation of manipulation of TNF-α and MMP expression in pleural mesothelium may provide new insights into the mechanisms and rational treatment strategies for TBP.

Tuberculous pleurisy drives marked effector responses of γδ, CD4+, and CD8+ T cell subpopulations in humans.

Although tuberculous pleurisy (TP) presumably involves a hypersensitivity reaction, there is limited evidence indicating overreactive effector responses of γδ T cells and αß T cells and their interrelation with Foxp3(+) Tregs in pleural and other compartments. We found that TP induced reciprocal representations of Foxp3(+) Tregs and Mtb phosphoantigen-specific Vγ2Vδ2 T cells in different anatomic compartments. Patients with TP exhibited appreciable numbers of "proliferating" Ki-67(+) Vγ2Vδ2 T cells in the airway where Foxp3(+) Tregs were not dominant, whereas striking increases in Foxp3(+) Tregs in the blood and pleural compartments coincided with low frequencies of Vγ2Vδ2 T cells. Interestingly, anti-tuberculosis chemotherapy control of Mtb infection in patients with TP reversed reciprocal representations of Foxp3(+) Tregs and proliferating Vγ2Vδ2 T cells. Surprisingly, despite high-level Foxp3(+) Tregs, TP appeared to drive overreactive responses of IFN-γ-producing Vγ2Vδ2, CD4(+)CD25(+), and CD8(+)CD25(+) T effector subpopulations, whereas IL-22-producing Vγ2Vδ2 T cells increased subtly. Th1 effector responses were sustained despite remarkable declines in Foxp3(+) Tregs at 1 mo after the treatment. Overreactive T effector responses of Mtb-reactive γδ T cells, αß CD25(+)CD4(+), and CD25(+)CD8(+) T cell subpopulations appear to be immune features for TP. Increased Foxp3(+) Tregs might be responsive to overreactive TP but unable to influence T effector responses despite having an inverse relation with proliferating Vγ2Vδ2 T cells.

Immune targeting of the pleural space by intercostal approach.

BACKGROUND: Infectious diseases of the airways are a major health care problem world wide. New treatment strategies focus on employing the body's immune system to enhance its protective capacities during airway disease. One source for immune-competent cells is the pleural space, however, its immune-physiological function remains poorly understood. The aim of this study was to develop an experimental technique in rodents that allows for an in vivo analysis of pleural space immune cells participating in the host defense during airway disease. METHODS: I developed an easy and reliable technique that I named the "InterCostal Approach of the Pleural Space" (ICAPS) model that allows for in vivo analysis of pleural space immune cells in rodents. By injection of immune cell altering fluids into or flushing of the pleural space the immune response to airway infections can be manipulated. RESULTS: The results reveal that (i) the pleural space cellular environment can be altered partially or completely as well as temporarily or permanently, (ii) depletion of pleural space cells leads to increased airway inflammation during pulmonary infection, (iii) the pleural space contributes immune competent B cells during airway inflammation and (iv) inhibition of B cell function results in reduced bacterial clearance during pneumonia. CONCLUSION: As the importance for in-depth knowledge of participating immune cells during health and disease evolves, the presented technique opens new possibilities to experimentally elucidate immune cell function, trafficking and contribution of pleural space cells during airway diseases.

Antimicrobial peptides are highly abundant and active in postoperative pleural drainage fluids.

BACKGROUND: The human lung is considered a nonsterile organ, and surgical interventions therefore take place in a more or less contaminated operating field. Nevertheless, infectious complications of the pleural cavity are low after major lung resections. Antimicrobial peptides (AMPs) are part of the innate immunity and display a broad capacity to kill pathogens. We hypothesized that the pleural space must have a high natural antimicrobial barrier and that AMPs might effectively protect the pleural cavity. METHODS: Pleural effusions were collected after lung operations. Antimicrobial activity of the fluids against gram-positive and gram-negative pathogens was analyzed by microdilution assays. AMPs were determined by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and immunohistochemical analysis. The impact of proinflammatory triggers on AMP release from pleural mesothelial cells was evaluated. RESULTS: Antimicrobial activity assays revealed high bactericidal properties of postoperative pleural drainage fluids. They effectively killed gram-negative pathogens (Escherichia coli, Pseudomonas aeruginosa) as well as gram-positive pathogens (Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes). A variety of AMPs was detected at constantly high concentrations in the pleural fluids. They mainly derived from leukocytes and pleural epithelium. Although proinflammatory cytokine levels were elevated in the postoperative pleural fluids, AMP expression could not be augmented by Toll-like receptor (TLR) triggering or by the proinflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)α. CONCLUSIONS: We provide the first evidence of a high abundance of AMPs in postoperative pleural fluids. Our findings might explain the broad protection against infectious complications of the pleural space after major lung operations.

Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis.

Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer either protection or morbidity are not completely understood. We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM). The process requires innate response activator (IRA) B cells, a transitional B1a-derived inflammatory subset which controls IgM production via autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. The strategic location of these cells, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity.

[Pleural lymphatics and pleural diseases related to fibres]. / Lymphatiques pleuraux et pathologies liées aux fibres.

It is now well established that some pleural diseases, pleural plaques and malignant mesothelioma are related to asbestos fibre exposure although the mechanism of action of asbestos fibres is not fully understood. The development of artificial mineral fibres and carbon nanotubes, which share some morphological characteristics similar to asbestos fibres, is a present concern in the context of pleural diseases. Pleural plaques develop only in the parietal pleura, and in the 1990s, clinical observations have shown that the early development of mesothelioma also occurred on the parietal pleura. The peculiarity of the parietal pleura in contrast to the visceral pleura is the presence of "stomas" which are communication holes between the pleural cavity and the parietal pleura lymphatics. Morphological observations by thoracoscopy and experimental studies have shown that inhaled fibres translocate to the pleural space and, in human, are present in the parietal pleura at specific anthracotic areas (blackspots). Fibres accumulate on the stomas, up to block and locally induce an inflammatory reaction with cytokines release, that can be the bed of mesothelioma. However, despite the experimental data and observations in human pathology, the mechanisms of fibre translocation into the pleura is not yet clearly established.

[Pleural lymphatics and effusions]. / Lymphatiques pleuraux et épanchements.

The pleural lymphatic system has a great absorption capacity. Its most known function is fluid resorption. The pleura which cover the lungs (visceral pleura), the mediastinum, diaphragm and thoracic wall (parietal pleura) are formed by a mesothelial cell layer (mesothelium). This permeable layer is in direct contact with the vascular endothelium. The mesothelium is based over a connective tissue (interstitium) containing the blood and lymphatic vessels. The primary lymphatic vessels drain interstitium but are also in direct contact with pleural space by the stoma or openings, situated in the lower parts of parietal pleura, i.e: diaphragm, over lower ribs and mediastinum but not existing in the adjacent visceral pleura. In addition, a part of interstitial pulmonary fluid entered in the pleural cavity by passing the visceral pleura would be absorbed by these openings. The resorption process is active and directly related to the function of smooth muscles of lymphatic vessels. Besides resorption, we must emphasize that this "pumping" activity is permanent and the origin of negative pressure (the pleural void) in pleural cavity, a unique property. The other resorbed elements are molecules, bacterial and cellular debris, cells, red blood and cancer cells.