Pleural Fibrosis Research Articles

Inhibition of angiotensin II and calpain attenuates pleural fibrosis

Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT1R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT1R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis.

Inhibition of Glycogen Synthase Kinase 3β Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia–Mediated Pleural Injury in Mice

Pleural loculation affects about 30,000 patients annually in the United States and in severe cases can resolve with restrictive lung disease and pleural fibrosis. Pleural mesothelial cells contribute to pleural rind formation by undergoing mesothelial mesenchymal transition (MesoMT), whereby they acquire a profibrotic phenotype characterized by increased expression of α-smooth muscle actin and collagen 1. Components of the fibrinolytic pathway (urokinase plasminogen activator and plasmin) are elaborated in pleural injury and strongly induce MesoMT invitro. These same stimuli enhance glycogen synthase kinase (GSK)-3β activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3β mobilization from the cytoplasm to the nucleus. GSK-3β down-regulation blocked induction of MesoMT. Likewise, GSK-3β inhibitor 9ING41 blocked induction of MesoMT and reversed established MesoMT. Similar results were demonstrated in a mouse model of Streptococcus pneumoniae-induced empyema. Intraperitoneal administration of 9ING41, after the induction of pleural injury, attenuated injury progression and improved lung function (lung volume and compliance; P<0.05 compared with untreated and vehicle controls). MesoMT marker α-smooth muscle actin was reduced in 9ING41-treated mice. Pleural thickening was also notably reduced in 9ING41-treated mice (P<0.05). Collectively, these studies identify GSK-3β as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3β signaling in the control of MesoMT and pleural injury.

Calpain and Spectrin Breakdown Products (SBDP) as Potential Biomarkers in Tuberculous Pleural Effusion

SESSION TITLE: Tuberculosis SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Early diagnosis of tuberculous pleural effusion remains difficult. Calpain is a family of calcium-dependent endopeptidase that plays an important role in ECM remodeling and collagen synthesis. The aim of this study was to explore the diagnostic value of pleural fluid angiotensin-converting enzyme (ACE), Calpain-1, Spectrin breakdown products (SBDP) and matrix metalloproteinase-1 (MMP-1) measurement in tuberculous pleural effusion (TPE) and malignant pleural effusion (MP). METHODS: The study included 47 patients with TP, 28 patients with MP and 10 patients with transudate of non-tuberculous and non-malignant origin as controls. Calpain, ACE, SBDP and MMP-1 levels in pleural fluid were measured by ELISA method. RESULTS: ACE level, Calpain-1 level, SBDP level and MMP-1 level were higher in TPE than MPE and transudate (all, P value<0.05). By logistic regression analysis, ACE > 47.16 ng/mL, Calpain-1> 787 ng/mL, SBDP > 2.745 ng/mL and MMP-1 >7229 pg/mL were independent factors associated with TPE. The predicted probability based on the four predictors had an area under the ROC curve of 0.935, with 89.3% sensitivity and 89.4% specificity under the cut-off value 0.429. CONCLUSIONS: Our data suggest that ACE, Calpain-1, SBDP and MMP-1 levels could be useful biomarkers for diagnosing TPE. CLINICAL IMPLICATIONS: Early diagnpsos of tuberculous pleural effusion remains difficult. Measuring pleural effusion ACE, Calpain-1, SBDP and MMP-1 levels can improve the diagnosis and may give information about pleural fibrosis. DISCLOSURE: The following authors have nothing to disclose: Ji Young Hong, Myung Goo Lee, Chang Youl Lee No Product/Research Disclosure Information

Comparative health effects in mice of Libby amphibole asbestos and a fibrous amphibole from Arizona

This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards. The objective was to compare the health outcomes in mice exposed to either LAA or the fibrous amphiboles collected in Arizona at the Lake Mead National Recreational Area at very low doses to represent environmental exposures. In this study, the fibrous amphibole asbestos sample from Arizona (AzA) is composed of winchite (69%), actinolite (22%), and non-amphibole minerals (9%) and has a mean aspect ratio of 16.7±0.9. Fibrous amphibole asbestos from Libby (LAA) is composed of winchite (70%), richterite (9%), tremolite (5%), and non-amphibole minerals (16%) with a mean aspect ratio of 8.4±0.7. C57BL/6 mice were exposed by oropharyngeal aspiration to fiber suspensions at a very low dose of 3μg/mouse. After seven months, both LAA- and AzA-exposed mice had indices of chronic immune dysfunction related to a TH17 cytokine profile, with B cell activation, autoantibody production and proteinuria, suggesting kidney involvement. In addition, both exposures led to significant lung and pleural fibrosis. These data suggest that there is risk of pulmonary disease and autoimmune outcomes with environmental exposure to amphibole asbestos, and that this is not limited to Libby, Montana.

Asbestos-related disease in upholsterers

ABSTRACTBefore its use was banned in developed countries, asbestos was widely applied in upholstery. However, the risk of asbestos diseases among upholsterers has only rarely been reported. In this case series, we present a first series of 6 workers employed in small workshops who developed several asbestos-related diseases, including pleural plaques, pleural fibrosis, and asbestosis. Exposures were intermittent and difficult to quantify, but lung asbestos content assessed by bronchoalveolar lavage was high in the 3 patients evaluated. In conclusion, upholstery work should be considered an at-risk occupation for developing asbestos-related diseases during the 20th century.

FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice.

Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-β1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.

The physiological consequences of different distributions of diffuse pleural thickening on CT imaging.

Diffuse pleural thickening (DPT) refers to extensive visceral pleural fibrosis with adhesion formation to the parietal pleura obliterating the pleural space. The radiological definition of DPT remains controversial with most of the literature requiring the presence of an obliterated costophrenic angle (CPA) for defining DPT. We conducted a study to investigate the variable distributions of DPT and associated lung function deficit. 85 patients referred to a pleural clinic with suspected pleural thickening were screened for our study. Data were collected from 37 patients with DPT confirmed on CT by size criteria (≥3 mm thick, ≥5 cm wide and ≥8 cm in length), and 21 controls with pleural plaques but no other pleuroparenchymal pathology. 27 patients were excluded. Groups were matched to age, body mass index and smoking history. The percentage of predicted forced vital capacity showed a gradual decline from 98.9% for the control group to 83.5% in the DPT without CPA obliteration group (p < 0.05), to 79.5% in the unilateral DPT group (p < 0.001) and 66.7% in the bilateral group (p < 0.001). Similar reductions were seen in the percentage of predicted total lung capacity in the DPT with no CPA obliteration group and the bilateral DPT group. Our study shows an incremental reduction in the forced vital capacity and total lung capacity in DPT without CPA obliteration, unilateral and bilateral DPT when compared with a matched control group. Advances in knowledge: Different distributions of DPT including no CPA obliteration can cause respiratory impairment, with bilateral DPT being the worst affected.

KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis

Fibrosis involves the production of extracellular matrix proteins in tissues and is often preceded by injury or trauma. In pleural fibrosis excess collagen deposition results in pleural thickening, increased stiffness and impaired lung function. Myofibroblasts are responsible for increased collagen deposition, however the molecular mechanism of transportation of procollagen containing vesicles for secretion is unknown. Here, we studied the role of kinesin on collagen-1 (Col-1) containing vesicle transportation in human pleural mesothelial cells (HPMCs). Among a number of cargo transporting kinesins, KIF5A was notably upregulated during TGF-β induced mesothelial-mesenchymal transition (MesoMT). Using superresolution structured illumination microscopy and the DUO-Link technique, we found that KIF5A colocalized with Col-1 containing vesicles. KIF5A knock-down significantly reduced Col-1 secretion and attenuated TGF-β induced increment in Col-1 localization at cell peripheries. Live cell imaging revealed that GFP-KIF5A and mCherry-Col-1 containing vesicles moved together. Kymography showed that these molecules continuously move with a mean velocity of 0.56 μm/sec, suggesting that the movement is directional but not diffusion limited process. Moreover, KIF5A was notably upregulated along with Col-1 and α-smooth muscle actin in pleural thickening in the carbon-black bleomycin mouse model. These results support our hypothesis that KIF5A is responsible for collagen transportation and secretion from HPMCs.

Safety and efficacy of medical thoracoscopy in the management of loculated thoracic empyema

BackgroundPleural empyema can be subdivided into 3 stages: exudative, multiloculated, and organizing. In the absence of clear septation, antibiotics plus simple drainage of pleural fluid is often sufficient treatment, whereas clear septation often requires more invasive treatment. Aim of studyTo evaluate the safety and efficacy of medical thoracoscopy in the management of loculated thoracic empyema. MethodsThis study was conducted at chest department, Al-Azhar Faculty of medicine Al-Housein University Hospital in the period from October 2015 to August 2016. On 30 patients, 22 males and 8 females with age ranging between 20 and 74years (mean age 48.3±15.5years). Diagnosed as loculated thoracic empyema (27 patients) or empyema failed to respond to medical treatment or chest tube drainage (3 patients) were undergo medical thoracoscopy. ResultsA total of 30 patients with loculated empyema were managed by medical thoracoscopy. Histopathological finding of study sample were (Non-specific inflammation 23.3%, Suppurative exudative reaction 16.7%, Tuberculous caseating granuloma 23.3%, Lymphocytic Inflammation 6.7%, fibrino purulent inflammation 13.3%, adenocarcinoma 3.3, Pleural fibrosis and thickening 10% and Pleural calcification, ossification, pleurisy 3.3%). Medical thoracoscopy was considered successful without further intervention in 26 of 30 patients (86.7%), 3 patients (10%) clinically improved but lung did not expanded and referred for thoracic surgery for decortication and 1 patient (3.3%) need for surgery to fistula closure. ConclusionsOur study confirms that loculated pleural empyema could safely and successfully be treated by medical thoracoscopy.

Optical coherence tomography-based contact\xa0indentation\xa0for diaphragm mechanics in a mouse model of transforming growth factor alpha induced lung disease

This study tested the utility of optical coherence tomography (OCT)-based indentation to assess mechanical properties of respiratory tissues in disease. Using OCT-based indentation, the elastic modulus of mouse diaphragm was measured from changes in diaphragm thickness in response to an applied force provided by an indenter. We used a transgenic mouse model of chronic lung disease induced by the overexpression of transforming growth factor-alpha (TGF-α), established by the presence of pleural and peribronchial fibrosis and impaired lung mechanics determined by the forced oscillation technique and plethysmography. Diaphragm elastic modulus assessed by OCT-based indentation was reduced by TGF-α at both left and right lateral locations (p < 0.05). Diaphragm elastic modulus at left and right lateral locations were correlated within mice (r = 0.67, p < 0.01) suggesting that measurements were representative of tissue beyond the indenter field. Co-localised images of diaphragm after TGF-α overexpression revealed a layered fibrotic appearance. Maximum diaphragm force in conventional organ bath studies was also reduced by TGF-α overexpression (p < 0.01). Results show that OCT-based indentation provided clear delineation of diseased diaphragm, and together with organ bath assessment, provides new evidence suggesting that TGF-α overexpression produces impairment in diaphragm function and, therefore, an increase in the work of breathing in chronic lung disease.

Study of the reationship between expression of nuclear factor-KB in pleural and pleural fibrosis

目的 探讨胸膜核因子-κB(nuclear factor-κB，NF-κB)的表达与胸膜纤维化形成的相关性。 方法 对27例胸腔积液患儿进行胸腔镜手术治疗，术中取病理，通过HE染色分组，进行NF-κB免疫组织化学检测。 结果 无胸膜纤维化组NF-κB免疫组织化学中只有少数类上皮细胞染色，阳性细胞数低于20%，而胸膜纤维化组NF-κB免疫组织化学染色细胞数大于40%，呈强阳性表达，明显高于无胸膜纤维化组(χ2＝16.67，P<0.05)。胸膜表达NF-κB同纤维化相关检测Gamma值为0.75，呈正相关。 结论 胸膜纤维化与NF-κB存在相关性。

KIF5A is Responsible for Collagen Transport of Myofibroblasts during Pleural Fibrosis

Fibrosis is the production of extracellular matrix proteins in tissues and often proceeded by injuries. In pleural fibrosis excess collagen deposition occurs, which results in increased stiffness and thickening of pleura during tissue rearrangements. Myofibroblasts are responsible for oversecretion of collagen, however the molecular mechanism of transportation of procollagen containing vesicles for secretion is unknown. Here, we studied the role of kinesin on collagen-1 containing vesicle transportation in human pleural mesothelial cells (HPMCs). Among a number of cargo transporting kinesins, KIF5A was notably upregulated during TGF-β induced mesothelial-mesenchymal transition (MesoMT). Using superresolution structured illumination microscopy (SIM) and DUO-Link technique, we found KIF5A notably colocalizes with collagen-1 containing vesicles. KIF5A knock-down (KD) by specific siRNA significantly reduced collagen-1 secretion but not plasminogen activator inhibitor 1 (PAI-1). KIF5A KD notably attenuated TGF-β induced increase in collagen-1 localization at cell peripheries. Live cell imaging with GFP-KIF5A and mCherry-collagen-1 showed that KIF5A and collagen-1 containing vesicles moved together. Kymograph showed that these molecules continuously move with mean velocity of 0.56 μm/sec, suggesting that the movement is directional but not diffusion process. Moreover, KIF5A was notably upregulated along with collagen-1 and α-smooth muscle actin (α-SMA) (MesoMT marker) in thickening pleura of carbon-black bleomycin mouse model. All the results support that KIF5A is responsible for collagen transportation and secretion from HPMCs.

P1.04-021 Medical Thoracoscopy for the Diagnosis and Management of Pleural Effusions: Results of a Retrospective Analysis

Medical thoracoscopy is a minimally invasive procedure utilized mainly by pulmonologists for the diagnosis and management of pleural effusions. The aim of this study was to evaluate the efficacy and safety of medical thoracoscopy when performed by a combined team of pulmonologists and thoracic surgeons in a tertiary university hospital. This is a retrospective cohort analysis of all patients with pleural effusion whο underwent medical thoracoscopy at “LAIKO” Athens General Hospital from June 2013 to December 2014. Our study population included 36 patients, 18 males and 18 females, with a mean age of 61 years. All patients were submitted to medical thoracoscopy for the diagnostic evaluation of pleural effusion. Twenty-six patients (26/36, 72.2%) presented with an undiagnosed pleural effusion, six (16.7%) with known malignant, recurrent pleural effusion, three (8.3%) with parapneumonic effusion/empyema and one (2.8%) with idiopathic pleural effusion due to nephritic syndrome. Eighteen patients (18/36, 50%) underwent drainage and pleural biopsy, 9 patients (9/36, 25%) underwent drainage, pleural biopsy and talc pleurodesis, 6 patients (6/36, 16.7%) underwent drainage and talc pleurodesis due to known malignant pleural effusion and 3 patients (3/36, 8.3%) underwent drainage of their parapneumonic effusion/empyema. Among all patients (n=27) who underwent diagnostic pleural biopsy, 2 patients (7.4%) were diagnosed with primary non-small cell lung cancer, 4 (14.8%) with malignant pleural mesothelioma, 3 (11.1%) with metastatic disease of non-thoracic primary origin and 3 (11.1%) with lymphoma, while 1 patient each (3.7%) was diagnosed with tuberculosis, systemic lupus eryhtematosus, chronic inflammation, chronic pleural fibrosis and nephritic syndrome. In 3 patients (3/27, 11.1%) the biopsy was negative. Medical thoracoscopy was non-diagnostic in one patient only (1/27, 3.7%), thus producing a diagnostic yield of 97.3%. With the notable exception of one patient (1/36, 2.8%) who died due to empyema and subsequent sepsis, the remaining post procedural complications were mild, and included subcutaneous emphysema in 6 cases (6/36, 16.7%) and minor bleeding in 3 cases (3/36, 8.3%). When performed by a combined team of pulmonologists and thoracic surgeons in a tertiary level hospital, medical thoracoscopy is a relatively safe and efficacious technique for the diagnosis and management of pleural effusions in patients unable to undergo or not requiring surgical intervention.

Galectin-3 Is a Mediator of Pulmonary Fibrosis in Sickle Cell Disease: Novel Roles for Hemolysis and Acute Chest Syndrome

▪Introduction: Patients with sickle cell disease (SCD) are suspected to have more pulmonary fibrosis. High resolution computerized tomography can detect interstitial fibrosis although the etiology of this pathology is understudied. A restrictive pattern of pulmonary function is present in 74 percent of patients. We previously demonstrated profound pulmonary artery remodeling in SCD - which could undoubtedly contribute to the restrictive pulmonary findings. Interstitial fibrosis likely plays a role in impaired pulmonary function as well. However, pleural fibrosis is major cause of restrictive pulmonary function but is, as yet, poorly described in patients with SCD.Objective: To interrogate the prevalence of pleural pulmonary fibrosis in SCD and investigate a novel potential mechanism of all forms of pulmonary fibrosis in these patients.Methods: A cohort of 20 autopsies from patients with SCD was formed (10 subjects had acute chest syndrome (ACS) listed as cause of death) and clinical data abstracted from medical records. Pulmonary fibrosis and histology were scored using standard methodology. Standard techniques were used to detect pulmonary proteins and stain connective tissue. Plasma was collected from SCD patients at steady state and during ACS (n=24). Soluble analytes were quantified via ELISA.Results: The pleiotropic and pro-fibrotic cytokine, TGF-β1, clearly plays a major role in pathology of SCD. We, and others, have found that total TGF-β1 is elevated in the plasma of adult patients with SCD. Although clearly also associated with ischemic injury, we now report that elevated TGF-β1 is activated and associates with levels of plasma heme in patients. Levels of TGF-β1 dramatically increase during ACS as do levels of plasma heme. Importantly, plasma galectin-3 - a known inducer of fibrosis, is (1) increased in patients with SCD, (2) associated with TGF-β1 and levels of heme, and (3) increased during ACS. These data suggest that ACS is promoting a pro-fibrotic state.At autopsy, the most striking feature of the lung was pleural fibrosis. All adult patients exhibited significant thickening of the pleura with collagen extending into the interstitia up to 10 fold further than in control (AA) lungs. Pleural fibrosis was age-independent. Interstitial fibrosis was closely associated with advancing age. Further interrogation of lung tissue at autopsy revealed the presence of heme/hemosiderin-laden macrophages in the tissues. The number of such macrophages associated well with the degree of interstitial fibrosis. In patients who died of ACS, both the number of these macrophages and the intensity of the hemosiderin content was increased. We also observed collagen "trapped" macrophages throughout both pleural and interstitial fibrotic regions. Such macrophages co-localized with tissue galectin-3 staining. Upon scoring, the entire interstitium of the patients who died with ACS had higher galectin-3 levels than those who died without ACS. There was only modest staining in AA control lungs. In addition to heme/hemosiderin, galectin-3 was also noted in the macrophage and in numerous smooth muscle cells of pulmonary arteries with intimal hyperplasia. Monocytes embedded in the intimal layer expressed high levels of galectin-3 as did monocytes captured in the blood stream at autopsy.Higher soluble and pulmonary galectin-3 was noted in the lungs of the Townes mouse model of SCD at steady state. Similar to patients with ACS, murine pulmonary galectin-3 levels increased upon treatment of the mice with lipopolysaccharide - an inducer of inflammation and lung injury.Furthermore, both monocytes and differentiated macrophages treated in vitro with heme released galectin-3. Similar in vitro results were obtained with heme-induced TGF-β1 release.Conclusions: Our results suggest that hemolysis may contribute to the restrictive pulmonary function in SCD via heme-induced release of the pro-fibrotic protein galectin-3. Thus, the data provide evidence that a pro-fibrotic "tone" is present in the illness at "steady state". Events such as ACS invoke intermittent, but significant fibrotic injury via galectin-3. Thus, targeting galectin-3 may prove to be effective in treating fibrotic exacerbations in patients. Importantly though, pleural fibrosis is likely a significant contributor to the overall pulmonary function deficit in patients with SCD. DisclosuresNo relevant conflicts of interest to declare.

Systemic lupus erythematosus in Spanish males: a study of the Spanish Rheumatology Society Lupus Registry (RELESSER) cohort.

Objective The objective of this study was to describe the demographic, clinical, and immunological manifestations of systemic lupus erythematosus (SLE) in male patients. Methods A cross-sectional, multicenter study was carried out of 3651 patients (353 men, 9.7%, and 3298 women, 90.2%) diagnosed with SLE, included in the Spanish Rheumatology Society SLE Registry (RELESSER). Results Mean ages (18-92 years) of symptom onset were 37 (SD 17) years (men) and 32 (SD 14) years (women). Male/female ratio was 1/9. Age of onset of symptoms and age at diagnosis were higher in men than in women ( p < 0.001). Males were diagnosed earlier than females (p = 0.04) and had more cardiovascular comorbidities ( p < 0.001). Two hundred and thirty-six males (68%) with SLE required hospitalization in comparison with 1713 females (53%) ( p < 0.001). During follow-up, 208 patients died: 30 men (9.3%) and 178 women (5.9%) ( p = 0.02). As regards clinical manifestations, loss of weight ( p = 0.01), lymphadenopathies ( p = 0.02), and splenomegaly ( p = 0.02) were more common in male patients. Female patients were more likely to have inflammatory rash, alopecia, and arthritis ( p < 0.05). As for lung involvement, men with SLE had more pleural fibrosis ( p < 0.001) and pulmonary embolism ( p = 0.01). However, Raynaud's phenomenon was more common in women (35%) than in men (23.7%) ( p < 0.001); lupus nephritis was more common in men, being present in 155 (44.8%) of males versus 933 (29%) of females ( p < 0.001). Multivariate analysis showed that SLE patients with a high Charlson index (more than 3 points) and age > 50 years had a higher mortality (odds ratios 3.6 and 2.1, respectively). Furthermore, SLE patients who developed pulmonary hemorrhage, pulmonary hypertension, psychiatric involvement, complement deficiency, and hemophagocytic syndrome also had higher mortality, regardless of gender. Conclusion Patients with SLE over the age of 50 years have an increased risk of mortality. In Caucasians, age at diagnosis and symptom onset is higher in men than in women. The diagnostic delay is shorter in men. Male SLE patients present more cardiovascular comorbidities, and also more serositis, adenopathies, splenomegaly, renal involvement, convulsion, thrombosis, and lupus anticoagulant positivity than women.

Ex vivo High-resolution Optical Coherence Tomography (OCT) Imaging of Pleural Reaction after Pleurodesis Using Talc

The pleura is known as an end target organ of exposure to toxic environmental materials such as fine particulate matter and asbestos. Moreover, long-term exposure to hazardous materials can eventually lead to fatal lung disease such as diffuse pleural fibrosis or mesothelioma. Chest computed tomography (CT) and ultrasound are gold standard imaging modalities for detection of advanced pleural disease. However, a diagnostic tool for early detection of pleural reaction has not been developed yet due to difficulties in imaging ultra-fine structure of the pleura. Optical coherence tomography (OCT), which provides cross-sectional images of micro tissue structures at a resolution of 2-10 µm, can image the mesothelium with a thickness of ~100 µm and therefore enables investigation of the early pleural reaction. In this study, we induced the early pleural reaction according to a time sequence after pleurodesis using talc, which has been widely used in the clinical field. The pleural reaction in talc grouped according to the time sequence (1st, 2nd, 4th weeks) showed a significant thickening (average thickness: 45 ± 7.5 µm, 80 ± 10.7 µm, 90 ± 12.5 µm), while the pleural reaction in sham and normal groups showed pleural change from normal to minimal thickening (average thickness: 16 ± 5.5 µm, 17 ± 4.5 µm, 15 ± 6.5 µm, and 12 ± 7.5 µm, 13 ± 2.5 µm, 12 ± 3.5 µm). The measurement of pleural reaction by pathologic examinations was well-matched with the measurement by OCT images. This is the first study for measuring the thickness of pleural reactions using a biophotonic modality such as OCT. Our results showed that OCT can be useful for evaluating the early pleural reaction.

The effect of therapeutic pleural drainage on the short- and long-term sequelae of tuberculous pleural effusions

&lt;p&gt;&lt;strong&gt;Background. &lt;/strong&gt;Tuberculosis (TB) remains a common cause of pleural exudates in many parts of the globe. Pleural fibrosis with restriction is a well-known complication of tuberculous pleuritis. Current evidence suggests that pleural drainage offers little benefit over and above anti-TB treatment in improving pulmonary function.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods. &lt;/strong&gt;We enrolled 20 patients with proven tuberculous pleural effusions (mean age 32.7 years, 10 males, 12 HIV-positive), and performed therapeutic pleural drainage in 10 randomly selected cases. Pulmonary function testing (PFT), chest radiography and transthoracic ultrasound were performed on all patients before treatment and at 7 - 10 days, 3 months and 6 months.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results. &lt;/strong&gt;Complete therapeutic drainage was achieved in only 4 of the 10 patients randomised to undergo drainage. No significant immediate benefit was achieved in the 10 patients assigned to intervention. However, compared with the non-intervention group, the intervention group showed significant changes in several functional parameters at 6 months, including changes in forced vital capacity from baseline (1.40 L v. 0.65 L; &lt;em&gt;p&lt;/em&gt;&amp;lt;0.001), forced expiratory volume in 1 second (1.37 L v. 0.60 L; &lt;em&gt;p&lt;/em&gt;=0.002), total lung capacity (1.76 L v. 0.88 L; &lt;em&gt;p&lt;/em&gt;=0.034) and diffusion capacity for carbon monoxide (7.42 v. 2.19 mL/min/mmHg, &lt;em&gt;p&lt;/em&gt;=0.013). No difference was observed in the change in 6-minute walking distance (113.4 m v. 126 m; &lt;em&gt;p&lt;/em&gt;=0.798) compared with the control group at 6 months.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions. &lt;/strong&gt;Therapeutic drainage may offer additional medium- and long-term functional benefits to patients with pleural TB, in addition to anti-TB drug therapy alone, as evident in the improvement in PFT results.&lt;/p&gt;

Perspective investigations of empyema pathogenesis

Pleural empyema is one of the most serious septic diseases. Despite favorable outcome, therapeutic and prognostic strategies in empyema are needed to be improved. Further investigation of pathology and diagnostic histological criteria of acute and chronic purulent pleural inflammation and fibrosis is a perspective research direction, as morphological characteristics are important for prognosis and the optimal treatment choice. However, complete histological examination of the lung tissue and the visceral pleura is difficult in real clinical practice, because any lung damage can cause bronchial fistula. Nevertheless, histological features of the visceral pleura and the lungs are closely related to macroscopic characteristics of the pleura. Detailed study of this relationship and the search of morphological similarity of lesions in parietal pleura, visceral pleura, and the lung in patients with empyema could improve the diagnostic value of thoracoscopy, contribute to a rapid histological diagnosis and improve therapeutic approach to empyema. Current approach to the basic mechanisms and risk factors of remodeling of the extracellular matrix in pleural fibrosis was reviewed in the article. Analysis of this process could determine new mechanisms of extracellular matrix remodeling and ways to avoid fibrosis development in the adjacent lung tissue that, in turn, could underlie staging the empyema.

Safety and outcome of medical thoracoscopy as diagnostic tool for pleural and pulmonary diseases

BackgroundThe accurate diagnosis of pleural effusion is challenging because even after thoracocentesis and/or closed pleural biopsy, 25–40% of pleural effusion remains undiagnosed. Thoracoscopy is now considered the approach of choice for diagnosis of certain kinds of pleural diseases such as pleural mass, malignant pleural effusion with negative pleural fluid cytology, and in the diagnosis of pleural tuberculosis. Aim of studyTo evaluate the diagnostic utility and safety of medical thoracoscopy in patients with undiagnosed exudative pleural effusion and pulmonary parenchyma lesions. MethodsThis study was conducted on 44 patients, 21 males and 23 females with age ranging between 32 and 74years (mean age 57.59±7.1years). There were 38 patients with undiagnosed exudative pleural effusion, 3 patients with multiloculated pleural effusion, 1 patient with undiagnosed pulmonary nodules and 2 patients with undiagnosed pulmonary parenchyma ground glass appearance and reticulation. There were 21 patients with co morbidities and 23 patients without co morbidities. ResultsForty four patients with undiagnosed pleural and pulmonary lesions underwent medical thoracoscopy, multiple pleural nodules were found in 24 out of 44 patients (54.54%). Pleural mass was found in 6 patients (13.63%) and pleural thickness was found in 8 patients (18.2%). Pleura loculation and adhesion was found in 3 patients (6.8%). Pulmonary nodules were found in 1 patient (2.3%). Normal thoracoscopy was found in 2 patients (4.54%) and lung biopsy was taken. As regards histopathology there were 16 patients (36.36%) diagnosed as epithelial mesothelioma, 3 patients (6.81%) diagnosed as metastatic squamous cell carcinoma, 1 patient (2.27%) diagnosed as non Hodgkin lymphoma, and 4 patients diagnosed as tuberculosis. In patients with pleural mass 3 patients (6.81%) diagnosed as sarcomatous mesothelioma and 3 patients (6.81%) diagnosed as non Hodgkin lymphoma. In 8 patients with pleural thickness, 6 patients (13.63%) diagnosed as non specific pleurisy and 2 patients (4.54%) diagnosed as tuberculosis. In 3 patients with pleural loculation they diagnosed as pleural fibrosis. One patient with pulmonary nodules (2.27%) diagnosed as small cell carcinoma. In 2 patients with normal thoracoscopy lung biopsy showed desquamative interstitial pneumonia in 1 patient (2.27%) and usual interstitial pneumonia in 1 patient (2.27%). The diagnostic yield of medical thoracoscopy was 86.4% (38 patients with definite histopathological diagnosis and 6 patients 13.6% diagnosed as non specific pleurisy). As regards thoracoscopic complications bleeding needed blood transfusion occurred in 1 patient (2.27%) with malignant mesothelioma, surgical emphysema occurred in 3 patients (1 with metastatic squamous cell carcinoma, 1 with tuberculous pleural effusion and 1 with loculated empyema), hypotension occurred in 1 patient underwent lung biopsy (desquamative interstitial pneumonia), the total thoracoscopic complications were 11.36% which was mild and statistically non significant. ConclusionMedical thoracoscopy is safe and effective for the diagnosis of benign and malignant pleural disease and pulmonary nodules.

Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.

Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis.