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Background and aim: Pleural effusions (PE) are a common clinical entity resulting from pathologies that affect the pleural space such as congestive heart failure, malignancy and pneumonia. The osmolality of the pleural fluid has never been studied as well as the effects of its changes on the pleural membrane. The purpose of this study was to identify the osmolality levels of PEs of different etiologies and to assess the potential effects of osmolality imbalance on the pleural permeability. Materials and methods: We measured the osmolality of the PEs of 64 consecutive patients (6 with transudative, 11 with parapneumonic and 47 with malignant pleural effusions) that were hospitalized in the University Hospital of Larissa. Subsequently, we selected clinically relevant hyper- and hypo- osmolality levels and performed assessment of the permeability of sheep parietal pleura by means of Ussing chamber experiments. Results: The mean pleural fluid osmolality was 291.7 ± 24.89 mOms/Kg (95 % CI: 285.4–297.9), and it varied among the three groups of PEs (p = 0.05). Transformed osmolality values were associated with pH and glucose levels in the PEs. After exposure of the sheep parietal pleura to 240 mOsm/kg (hyposmolar) the transmesothelial resistance (RTM) significantly increased (p < 0.05) while at 340 mOsm/kg (hyperosmolar) the RTM was not significantly altered. Conclusions: PEs osmolality differs depending on the underlying pathology and is linked to PE pH and glucose. Hypo-osmotic PEs can lead to decreased pleural permeability. These results warrant further study of the PEs osmolality levels on the function of the pleural mesothelial cells. © 2020 Elsevier B.V.

Malignant pleural effusions usually manifest in the course of metastatic cancer disease. Primary pleural tumours are rare with mesothelioma being by far the most common. Primary squamous cell carcinoma of the pleura (PSCCP) is extremely rare. It is usually asymptomatic, until it invades the pleura presenting pain as the first symptom. Our knowledge about its treatment or prognosis is limited due to its rarity. We present the case of a 48-year-old man who presented with persistent right-sided thoracic pain with chest computed tomography (CT) scan demonstrating a right-sided pleural effusion and pleural mass invading the ribs. Ultrasound-guided biopsy revealed a PSCCP. Positron emission tomography staging demonstrated metastatic lung and lymph node involvement precluding surgical therapy. We provide information about treatment, including immunotherapy as well as extended follow-up course. Immunotherapy with nivolumab resulted in prolongation of survival with good quality of life. © 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology

Versican promotes experimental tumor growth through cell- and non cell-autonomous mechanisms. Its role in mesothelioma progression has not been investigated so far. In this study we investigated the impact of tumor-derived versican in mesothelioma progression and the underlying mechanism of its action. For this purpose, versican-silenced or control ΑΕ17 and ΑΒ1 murine mesothelioma cells were intrapleuraly injected into syngeneic mice, in order to create pleural mesotheliomas and pleural effusions. Intratumoral and pleural immune subsets were assessed using flow cytometry. Mesothelioma cells were co-cultured with syngeneic macrophages to examine versican’s impact on their interaction and endothelial cells to assess the effect of versican in endothelial permeability. Versican expression was assessed in human mesotheliomas and mesothelioma-related pleural effusions and benign pleural tissue and effusions. We observed that, versican silencing reduced mesothelioma mass and pleural fluid volume by affecting tumor cell proliferation and apoptosis in vivo, while tumor cell growth remained intact in vitro, and limited pleural vascular permeability. Mice harboring versican-deficient tumors presented fewer tumor/pleural macrophages and neutrophils, and fewer pleural T-regulatory cells, compared to the control animals. Macrophages co-cultured with versican-deficient mesothelioma cells were polarized towards M1 anti-tumor phenotype and demonstrated increased tumor cell phagocytic capacity, compared to macrophages co-cultured with control tumor cells. In co-culture, endothelial monolayer permeability was less effectively stimulated by versican-deficient cells than control cells. Versican was over-expressed in human mesothelioma tissue and mesothelioma-associated effusion. In conclusion, tumor cell-derived versican stimulates mesothelioma progression by shaping a tumor friendly inflammatory milieu, mainly by blunting macrophage anti-tumor activities. © 2018, © 2018 Taylor & Francis Group, LLC.

Malignant pleural mesothelioma is resistant to currently used treatment. Angiopoieitn-1 directly promotes mesothelioma cell growth in a Tie-2-dependent fashion. Angiopoietin/Tie-2 axis may thus be valid targets for therapeutic interventions against mesothelioma. We hypothesized that a soluble angiopoietin inhibitor (Murine Tek-deltaFc) would halt mesothelioma progression in vivo by enhancing mesothelioma cell proliferation and inhibiting tumor angiogenesis. Our hypothesis was challenged on two syngeneic mesothelioma in vivo models (AB1 cells- Balb/c mice and AE17 cells-C57BL/6 mice. Even though both mesothelioma cell lines express the Angiopoietin-1/-2 and Tie-2, murine Tek-deltaFc hampered AB1 but not AE17 mesothelioma growth in vivo by enhancing tumor cell apoptosis and limiting tumor angiogenesis. Neither angiopoietins (Angs)-1 and -2 nor the inhibitor affected mesothelioma cell growth in vitro. AB1 (responding) tumors were more vascularized and displayed higher endothelial Tie-2 and lower tumor Ang-1 expression than the (non-responding) AE17 tumors. Angiopoietins-1 and -2 are expressed in tumors and pleural cavity of mesothelioma patients demonstrating the clinical relevance of our experimental observations. In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression. Tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression may predict mesothelioma response to Tek-deltaFc. © Magkouta et al.

Background and objective The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. Methods We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20-mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation. Results Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. Conclusions In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo. We used syngeneic in vivo mesothelioma models to show that temsirolimus, an mTOR inhibitor, curtailed mesothelioma growth by inducing tumour cell apoptosis, by targeting tumour angiogenesis and by modulating host immune response. This is the first report on the effects of temsirolimus impact on mesothelioma-related immune response and mesothelioma vascularization. © 2015 Asian Pacific Society of Respirology.

The impact of temsirolimus was investigated in a murine model of malignant pleural effusion (MPE) created with intrapleural injection of Lewis Lung Cancer (LLC) cells. Temsirolimus (1 or 20 mg/kg) did not affect the pleural fluid volume or the number of pleural tumour foci. In addition, temsirolimus did not affect vascular endothelial growth factor expression by LLC cells in vitro. In conclusion, temsirolimus did not curtail experimental lung-adenocarcinoma- induced MPE. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Background and objective The role of pro-inflammatory interleukin-17A (IL-17A), in pleural diseases is unknown. We sought to investigate IL-17A expression and its clinical implications in patients with pleural effusion (PE) and IL-17A involvement in the pathobiology of pleural inflammation elicited by bacterial products. Methods Pleural and blood IL-17A content was examined in 84 patients with PE of different aetiologies, and the diagnostic value of pleural IL-17A was explored in 92 patients with neutrophil-predominant PE. IL-17A contribution in pleural inflammation was evaluated in mice injected intrapleurally with either IL-17A or bacterial products with or without IL-17A-neutralizing antibodies. Results IL-17A was upregulated in the pleural space of patients with parapneumonic PE. It was detected in a minority of patients with tuberculous PE and very uncommonly in patients with malignant or other pleural exudates. Pleural fluid (PF) IL-17A levels were correlated with markers of acute pleural inflammation, as well as vascular endothelial growth factor and IL-8 levels. Among patients with neutrophil-predominant PE, PF IL-17A was detected only in those with parapneumonic PE, although the sensitivity of the test was low (

Background: Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice.Methods: Balb/c mice received single-dose urethane (1 g/kg at day 0) and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12), tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96), or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter). In addition, interleukin (IL)-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment.Results: Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis.Conclusions: Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer. © 2010 Doris et al; licensee BioMed Central Ltd.

Background: The Medical Research Council (MRC) chronic dyspnea scale (6-point) is used in different clinical conditions to grade breathlessness on daily activities. We have previously shown that in patients with histologically documented usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), the MRC dyspnea scale is useful in estimating disease severity. The aim of this study was to further investigate the usefulness of the MRC scale in IPF as a marker of survival. Methods: The records of 25 patients with histologically documented UIP/IPF were retrospectively reviewed. Clinical parameters, pulmonary function tests, and arterial blood gases at the time of diagnosis, as well as survival time were retrieved and recorded for each patient. The impact of the different variables determined at diagnosis on survival was examined using the Kaplan-Meier and uni- and multi-variate Cox-regression analyses. Results: Among the baseline clinical and physiologic parameters determined at the time of IPF diagnosis, the MRC score, the Tiffeneau index, and the total lung capacity were the only significant and independent predictors of survival. In specific, a high MRC score, a high Tiffeneau index, and a low total lung capacity at presentation were associated with shorter survival. Conclusion: In accordance with the previous work, our results indicate that the Tiffeneau index and total lung capacity (TLC) are the important determinants of survival in patients with IPF. In addition, we show that the simple MRC chronic dyspnea score estimated at the time of diagnosis is equally predictive of survival and may aid clinicians in assessing the prognosis of new cases of IPF. © 2007 Elsevier Ltd. All rights reserved.

Rationale: Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect antitumor effects and are currently being tested against human solid tumors. The antitumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (M PE), but no study has addressed the efficacy of these compounds against malignant pleural disease. Objectives; Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE. Methods: To induce MPE in mice, Lewis lung carcinoma cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol. Measurements and Main Results: ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP proteins Ras and RhoA, in tumor cells In vivo and in vitro. Conclusions: ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.

We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-kappa B activity in vitro and in vivo, which we used to drive expression of a NF-kappa B-dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-kappa B-dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-kappa B in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-kappa B inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-alpha levels. These studies indicate that tumor NF-kappa B activity regulates pleural tumor progression. This reproducible model of MPE can be used to further study the influence of specific host and tumor factors on the pathogenesis of MIRE and evaluate new therapeutic strategies.

Study objectives: To establish a murine model of pneumothorax-associated pleural eosinophilia and to examine the role of interleukin (IL)-5 and IL-13 in the pathogenesis of this reaction. Design: An animal study. Interventions: One hundred thirty-seven C57/BI-6 mice were used in this study. Wild-type animals were injected intrapleurally with 0.4 mL of air and were killed at different time points (30 min to 7 days) after the injection. IL-5 knockout and IL-13 knockout animals were killed 24 h and 48 h after the injection. Pleural inflammation was assessed by pleural lavage (PL). Measurements and results: PL cells were significantly increased following the induction of pneumothorax. The peak number of neutrophils, observed at 12 h, was 900 times higher than the control. The peak number of eosinophils, observed at 48 h, was 700 times higher than the control. Lymphocytes and mononuclear cells increased threefold and fourfold, respectively. IL-5 knockout mice had significantly less PL eosinophils than that the wild-type or the IL-13 knockout mice at 24 h (150 +/- 46/mu L, 903 +/- 244/mu L, and 912 +/- 168/mu L, respectively; p = 0.013) and 48 h (181 +/- 45/mu L, 1,587 +/- 212/mu L, and 1,379 +/- 364/mu L, respectively; p = 0.003). Conclusion: Pneumothorax induces an inflammatory reaction of the mouse pleura, mainly characterized by increased neutrophils and eosinophils. IL-5 but not IL-13 is required for pneumothorax-associated pleural eosinophilia.

Objectives: The primary aim of this study was to examine the association between pleural fluid (PF) eosinophilia, and the PF and serum levels of interleukin (IL)-5, eotaxin-2, eotaxin-3, and vascular cell adhesion molecule (VCAM)-1 in patients with post-coronary artery bypass grafting (CABG) pleural effusions. Design: A prospective observational study. Setting: A tertiary teaching hospital. Patients and methods: Thirty-eight patients with post-CABG pleural effusions were recruited into the study. An effusion that contained at least 10 % eosinophils was called “eosinophilic.” The PF and serum levels of the cytokines and VCAM-1 were measured using an enzyme-linked immunosorbent assay. Results: (1) The number of PF eosinophils significantly correlated with the number of blood eosinophils. (2) PF IL-5 levels were significantly higher than the corresponding serum levels, and there was a significant correlation between the PF and serum IL-5 levels. PF IL-5 levels significantly correlated with the PF eosinophil count, and serum IL-5 levels significantly correlated with the number of blood eosinophils. (3) PF eotaxin-3 levels were significantly higher than serum levels, and PF cotaxin-3 levels significantly correlated with the PF eosinophil count. (4) PF VCAM-1 levels were significantly lower than the corresponding serum levels, and PIT VCANI-1 levels were significantly higher in eosinophilic pleural effusions (EPEs) than in non-EPEs. Conclusion: In patients with post-CABG pleural effusions, IL-5 and eotaxin-3 are produced preferentially in the pleural cavity, and they are strongly associated with PF eosinophilia.

Purpose of review Eosinophilic pleural effusions (EPE) are defined as those that contain at least 10% eosinophils. EPEs account for 5 to 16% of exudative pleural effusions. However, their pathogenesis is poorly understood. The purpose of this review is to discuss the mechanisms that lead to eosinophilic pleural inflammation. Recent findings Eosinophilic pleural effusions are caused by the presence of air or blood or both in the pleural space, infectious or other inflammatory diseases, malignancy, pulmonary emboli, asbestos exposure, and drug reactions. Differences in the clinical features suggest that a variety of mechanisms operate to induce eosinophilic pleural inflammation and pleural fluid accumulation. Human and animal studies indicate that interleukin (IL)-5 is an important common contributor of different pathogenetic pathways. The possible role of other cytokines, chemokines, and adhesion molecules in the development of EPE is under investigation. Summary Understanding the pathogenesis of EPE will permit the development of novel therapies for the persistent, symptomatic, posttraumatic and idiopathic EPE. Anti-IL-5 treatment is an interesting option that requires further research.

Study objectives: The mechanisms responsible for the accumulation of eosinophils in pleural fluid are not fully understood. The objective of them present study was to examine the relationship between pleural fluid eosinophilia and the levels of vascular cell adhesion molecule (VCAM)-1, eotaxin, RANTES (regulated upon activation, normal T-cell expressed and secreted), and interleukin (IL)-4 in pleural effusions. Patients and methods: Thirty-one patients with eosinophilic pleural effusion (EPE) [eosinophil percentage > 10% of the pleural fluid nucleated cells] and 10 patients without EPE were evaluated. VCAM-1, eotaxin, RANTES, and, IL-4 in all pleural fluids were measured using enzyme-linked immunosorbent assay kits. IL-5 levels of the same fluids were measured in a previous study. Results: VCAM-1, eotaxin, and RANTES but not IL-4 were detectable in the pleural fluids. The mean level of VCAM-I in EPE (336 +/- 85 ng/mL) was significantly higher (p = 0.011) than that in the noneosinophilic effusions (260 +/- 34 ng/mL) [mean +/- SD]. VCAM-I levels were significantly correlated with the eosinophil count and percentage in all pleural fluids (r = 0.43, p = 0.005, and r = 0.37, p = 0.019, respectively). Multiple linear regression analysis disclosed’ that both IL-5 (beta, 0.63; p < 0.001) and VCAM-I (beta, 0.27, p = 0.025) are independent predictors of the number of eosinophils in all pleural fluids.. RANTES and eotaxin did not differ significantly between EPEs and non-EPEs, and were not correlated with the number of pleural fluid eosinophils. Conclusion: The levels of VCAM-I are increased in EPE, suggesting that VCAM-I is important in the pathogenesis of EPE. Neither eotaxin nor RANTES is associated with pleural fluid eosinophilia.