Pulmonary haptoglobin and CD163 are functional immunoregulatory elements in the human lung.

BACKGROUND: The acute-phase protein haptoglobin (Hp) and its receptor CD163 serve as immunomodulators and possess anti-inflammatory besides antioxidant functions. OBJECTIVES: To further understand the role of the recently described pulmonary Hp (pHp) and its receptor CD163 in case of inflammation and infection, pHp and CD163 were investigated on mRNA and protein level to gain insight into the cellular events taking place upon stimulation with the inflammatory mediators LPS, Pam3, cytokine IL-6 and dexamethasone, and upon infection with respiratory pathogens (Haemophilus influenzae, Streptococcuspneumoniae and Chlamydia pneumoniae) by use of a human ex vivo tissue culture model and cell cultures of A549 and alveolar epithelial cells type II. In addition, pHp and CD163 expression in COPD and sarcoidosis was assessed. METHODS: We conducted experiments using 942 ex vivo cultured lung samples applying immunohistochemistry, immunocytochemistry, in situ hybridization, immunofluorescence, real-time PCR, RT-PCR, slot and Western immunoblot analyses with tissue lysates and culture supernatants as well as ELISA and cytometric bead array analyses. RESULTS: This study describes for the first time the expression, regulation and secretion of pHp and its receptor CD163 in the human lung. The release of soluble mediators from A549 cell line and human monocyte-derived macrophages was observed indicating that Hp differentially activates the release of soluble mediators and major chemoattractants. CONCLUSIONS: The findings indicate a native function of pHp and CD163 as functional pulmonary defense elements due to local expression, regulation and secretion during lung infection and as part of the inflammatory immune response of the respiratory system.

[Efficacy and safety in the treatment of pleural effusions with the PleurX catheter: a retrospective analysis]. / Nutzen und Sicherheit der Behandlung von Pleuraergüssen mit dem PleurX-Katheter: eine retrospektive Analyse.

BACKGROUND: The purpose of this retrospective study was to investigate the efficacy and safety of an indwelling pleural device (PleurX, Denver Biomedical, USA) for the treatment of recurrent pleural effusions. In cases when life expectancy tends to be very short and also surgical decortication is not recommended, pleurodesis is another treatment option but requires complete drainage of the whole pleural fluid for optimal results which is sometimes hard to achieve. The PleurX catheter is an alternative therapeutic option. METHODS AND RESULTS: We retrospectively analysed the clinical data from a total of 21 patients who were treated with a PleurX alone (11 patients) or who initially received pleurodesis and afterwards a PleurX catheter (10 patients). Mean survival was 25 weeks after initial diagnosis of the underlying disease. The mean amount of pleural effusion drained per week was 725 mL. 16 patients used the catheter until they died at least 1 - 2 times a week. The complication rate was 19 % and thus within a reasonable range when compared to other treatment options for recurrent pleural effusions. There was no statistically significant difference in clinical outcome in both groups (pleurodesis and subsequent PleurX vs. PleurX alone). The amount of evacuated pleural effusion was inversely correlated with the remaining life time. CONCLUSION: The use of an indwelling pleural device is a safe alternative treatment option for patients with chronic pleural effusions and trapped lung signs. We should be aware of this device and propagate its use at an earlier stage of malignant diseases with recurrent pleural effusions, especially when the remaining life time is short.

[Non-specific interstitial pneumonia (NSIP)]. / Nicht spezifische interstitielle Pneumonie.

Non-specific interstitial pneumonia (NSIP) belongs to the group of idiopathic interstitial pneumonias (IIP). However, NSIP can also be found in several other diseases. For example, the NSIP pattern is most commonly found in interstitial lung disease due to connective tissue disease. In this review, the definition and classification, aetiology, pathogenesis and histology, clinical symptoms, serological markers, lung function parameters, radiographic signs, treatment, and prognosis of NSIP are presented. Idiopathic NSIP as a distinct form of NSIP will be discussed separately.

[Paraneoplastic syndromes in lung cancer]. / Paraneoplastische Syndrome beim Lungenkarzinom.

Paraneoplastic syndromes occur in approximately 10% of all patients with lung cancer. They can be the first manifestation of the disease or of a recurrence. Endocrine, haematological, neuromuscular, dermatological, renal, and metabolic syndromes as well as syndromes involving the connective tissue and constitutional syndromes can be distinguished based on their clinical symptoms. In this review, the epidemiology, pathogenesis, clinical signs and treatment options for the clinically important paraneoplastic syndromes in lung cancer are discussed.

Low-frequency ultrasound permeates the human thorax and lung: a novel approach to non-invasive monitoring.

PURPOSE: Conventional sonography at 2 - 10 MHz cannot permeate the chest because ultrasound at this frequency is strongly scattered and reflected by air inclusions in the lungs. Therefore, sonography is considered impracticable for thoracic imaging. However, human thoraxes and lungs in situ were never rigorously probed with ultrasound at frequencies below 1 MHz. In addition, ultrasound is commonly applied as echo imaging rather than sound transmission. MATERIALS AND METHODS: Human subjects were studied with a transducer detector pair or an elastic thorax belt equipped with 12 sensors 5 cm apart that was wrapped around the thorax and a single pulse transmitter attached to the sternum. We focused on fast ultrasound transmission from 1 kHz to 1 MHz, coupled over thoracic sonotrodes. RESULTS: Between 1 Hz to 1 MHz, sound transmission through thorax and lungs shows three distinct bands: < 1 kHz sound is transmitted at 30 - 50 m/sec, between 1 - 10 kHz sound transmission is absent and > 10 kHz sound is transmitted with a speed of 1500 m/sec. We demonstrate that low-frequency ultrasound (10 - 750 kHz) can permeate the thorax and permits monitoring of the air and water content of human lungs. In healthy subjects at 15 kHz, the difference in sound transmission through thorax and lungs between inspiration and expiration was dynamic and spanned several decades. Sound transmission during expiration was strongly decreased in patients suffering from pulmonary emphysema or pneumothorax, but increased in patients with pleural effusions. CONCLUSION: Sound transmission in the lungs is characterized by three distinct frequency bands. Low frequency ultrasound is transmitted through the lungs and may offer a novel non-invasive approach to real time diagnostics.

[Interstitial lung disease]. / Interstitielle Lungenerkrankungen.

Vasculitis and connective tissue disease are often associated with interstitial lung disease. Involvement of lung parenchyma is found in small vessel vasculitis and mostly in ANCA-associated forms such as Wegener's granulomatosis. In addition to vasculitis and connective tissue disease, rheumatoid arthritis can lead to interstitial lung disease and lung fibrosis. Diagnostic tools include measurement of auto-antibodies, lung function test, chest X-rays and computed tomography of the thorax, as well as bronchoscopy with biopsy and bronchoalveolar lavage. The following article provides an overview of the clinical, histological and radiologic patterns of interstitial lung disease in vasculitis, rheumatoid arthritis and connective tissue disease. Treatment options will also be discussed.

[Interstitial lung diseases and pulmonary hypertension]. / Interstitielle Lungenerkrankungen und pulmonale Hypertonie.

The prevalence of pulmonary hypertension in interstitial lung disease (ILD) is high (30-40%). However, diagnosis of pulmonary hypertension in ILD is often delayed. Pulmonary hypertension can occur in the absence of advanced pulmonary dysfunction or severe hypoxia and is associated with a worse prognosis. A number of pathogenic mechanisms such as oxidative stress, cytokines, and the endothelin system have been implicated in remodeling of both the lung parenchyma and the vessels. In addition, hypoxic vasoconstriction, vascular destruction and progressive fibrosis play an important role. Since clinical signs are often non-specific echocardiography, radiology and laboratory parameters such as NT-proBNP may be helpful. However, the definitive diagnosis of pulmonary hypertension is still confirmed by right heart catheterization. Treatment options of pulmonary hypertension in ILD are limited to the treatment of the underlying diseases. Newer vasodilating drugs may improve the prognosis but have first to be evaluated in clinical trials. Lung or lung and heart transplantation is the therapeutic option in end stage disease.

[Pathophysiology and pathogens of sepsis]. / Pathophysiologie und Keimspektrum der Sepsis.

The pathophysiology of sepsis is not completely understood. Bacteria are the main cause of sepsis. Activated receptors of the innate immune system lead to an exaggerated immune response. Immune cells including activated neutrophils and macrophages express and are controlled by a variety of cytokines, chemokines, complement factors and other mediators. These proinflammatory factors induce the expression of secondary mediators such as lipids and reactive oxygen species leading to further amplification of inflammation. Due to loss of control mechanisms in sepsis the immune response causes damage of the own organism. The early phase of sepsis is characterized by a proinflammatory response. In contrast, in the late stage of sepsis an anti-inflammatory milieu is observed that can cause severe immunosuppression. An overview will be given on the recent advances in understanding the interaction of different pathophysiological mechanisms and potential therapeutic interventions in the complex and dynamic syndrome of sepsis.

[Lung and autoimmune disease--therapy]. / Lunge und Autoimmunerkrankungen--Therapie.

Pulmonary manifestations of autoimmune diseases are treated depending on the involved lung structure and the underlying disorder. In this review the therapeutic approach in the case of vascultitis, rheumatoid arthritis and connective tissue disease will be presented.

[Lung and autoimmune diseases--clinical aspects and diagnosis]. / Lunge und Autoimmunerkrankungen--Klinik und Diagnostik.

Pulmonary involvement is commonly seen in autoimmune disease. In this review the clinical presentation of pulmonary involvement in vasculitis, rheumatoid arthritis and connective tissue disease is presented. Clinical symptoms and diagnostic approach will be discussed.

Fatal outcome of a hyperinfection syndrome despite successful eradication of Strongyloides with subcutaneous ivermectin.

We report the case of a 77-year-old man who developed a Strongyloides hyperinfection syndrome following immunosuppressive therapy more than 60 years after he moved away from an area endemic for Strongyloides stercoralis. Successful eradication of the nematode was achieved with an off label subcutaneous formulation of ivermectin. However, the patient subsequently died from acute respiratory distress syndrome (ARDS). Despite a high wormload in the stool and sputum of the patient and delayed infection control measures in the hospital, testing of the medical staff revealed a very low risk of Strongyloides transmission among healthcare workers.

Expression of HCLCA1 in cystic fibrosis lungs is associated with mucus overproduction.

Mucus overproduction is typical in cystic fibrosis (CF) airway disease. The human calcium-activated chloride channel, hCLCA1, has been reported to be upregulated by interleukin (IL)-9 and to regulate the expression of mucins. Therefore, the expression of IL-9, IL-9 receptor (IL-9R) and hCLCA1 between the lungs of CF patients and healthy control subjects was compared. Endoscopic biopsy samples of bronchial mucosa from 10 CF patients and six control subjects were stained with periodic acid-Schiff. IL-9, IL-9R and hCLCA1 expression was determined by immunocytochemistry. Expression of hCLCA1 mRNA was also determined by in situ hybridisation. The present study found significant increases in IL-9, IL-9R and hCLCA1 immunoreactivity, hCLCA1 mRNA expression, and numbers of mucus-producing cells in the mucosa of CF patients compared to control subjects. Positive correlations were found between IL-9R-positive-cells with IL-9-positive cells and hCLCA1-positive cells, and between PAS-positive cells with hCLCA1-positive cells and IL-9R-positive cells. Expression of hCLCA1 mRNA was colocalised with IL-9R expression and PAS-positive staining in epithelial cells. Increased expression of interleukin-9 and interleukin-9 receptor, as well as an upregulation of the human calcium-activated chloride channel, hCLCA1, in mucus-producing epithelium of cystic fibrosis patients, support the hypothesis that interleukin-9 contributes to mucus overproduction in cystic fibrosis airway disease.

Interleukin-18 expression in BAL cells of sarcoidosis patients is decreased in vivo but protein secretion is not impaired in vitro.

Recently, increased expression of interleukin-18 (IL-18) has been shown in sarcoid airway epithelium. However, IL-18 expression has not been investigated extensively in bronchoalveolar lavage (BAL) cells in sarcoidosis yet. Expression of IL-18 and tumour necrosis factor-alpha (TNFalpha) mRNA in cells of the BAL of 23 patients with sarcoidosis and nine healthy volunteers was determined using semiquantitative RT-PCR. IL-18 protein in BAL cells was investigated by immunocytochemistry (ICC). IL-18 protein levels in BAL cell culture supernatants from patients and controls with and without LPS stimulation were measured by enzyme-linked immuno-sorbent assay. BAL cells from patients were stimulated with either IL-10 or IL-13 and IL-18 protein levels were determined. IL-18 mRNA expression was significantly decreased in BAL cells of patients compared to control subjects (1.62 +/- 0.27 vs. 4.29 +/- 0.77, P < 0.05). TNFalpha mRNA expression was significantly increased in BAL cells of patients in comparison to control subjects (0.63 +/- 0.09 vs. 0.11 +/- 0.08, P < 0.05). ICC showed less positive alveolar macrophages in sarcoidosis patients than in control subjects (26 vs. 53%). IL-18 protein levels did not differ significantly between both groups. Stimulation with IL-10 significantly reduced IL-18 protein concentration in sarcoidosis patients. Our results suggest that BAL cells may not be the main source of IL-18 production in sarcoidosis in vivo. Since IL-18 production of BAL cells was not impaired in culture antiinflammatory cytokines might contribute to decreased IL-18 expression in vivo.

Increased interleukin-13 expression in patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disorder of unknown origin. Lymphocytic inflammation is dominated by expression of Th1 type cytokines such as tumour necrosis factor alpha (TNFalpha). Interleukin 13 (IL-13) is a Th2 cytokine which is expressed by CD4+ T cells and has been shown to suppress TNFalpha in human blood monocytes. The role of IL-13 as a possible anti-inflammatory cytokine in sarcoidosis was investigated. METHODS: mRNA expression of IL-13, IL-4, IL-10, and TNFalpha in bronchoalveolar lavage (BAL) fluid cells and peripheral mononuclear blood cells (PBM) of 18 patients with sarcoidosis and nine healthy controls was assessed using RT-PCR. In addition, IL-13 protein levels in BAL cell culture supernatants from 12 patients and all controls were measured and immunocytochemistry of IL-13 protein was performed in BAL fluid cells of eight patients. TNFalpha concentrations were measured with and without stimulation with recombinant human (rh) IL-13, rhIL-10, and lipopolysaccharide (LPS). RESULTS: IL-13 mRNA expression was significantly increased in BAL cells and PBM of patients compared with controls (p<0.05). No significant difference was found in IL-4 mRNA or IL-10 mRNA expression in BAL fluid cells or PBM between the two groups. TNFalpha mRNA expression was significantly higher in BAL fluid cells of patients than controls (p<0.05). IL-13 protein levels in BAL cell culture supernatants were slightly raised in half the patients investigated but in only two controls. Immunocytochemistry detected IL-13 protein in alveolar macrophages of patients. IL-13 led to decreased TNFalpha concentrations (p<0.05). CONCLUSIONS: IL-13 expression is increased in BAL cells and PBM in sarcoidosis and IL-13 is secreted from BAL cells. Alveolar macrophages may be the cellular source. These data suggest that IL-13 might have an anti-inflammatory effect by acting on TNFalpha.

TNFalpha, interleukin-10 and interleukin-18 expression in cells of the bronchoalveolar lavage in patients with pulmonary complications following bone marrow or peripheral stem cell transplantation: a preliminary study.

Pulmonary complications pose a major clinical problem after bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). The underlying pathophysiological mechanisms are under investigation. Twenty patients with infectious or non-infectious pulmonary complications after BMT or PBSCT underwent bronchoalveolar lavage (BAL) and tumor necrosis factor-alpha (TNFalpha), interleukin-10 (IL-10) and interleukin-18 (IL-18) mRNA expression was determined in BAL cells in comparison to 11 healthy volunteers. Patients were divided into two groups (infectious pneumonia, n = 14 or idiopathic pneumonia syndrome (IPS)/bronchiolitis obliterans (BO), n = 6). TNFalpha expression was significantly increased in both patient groups compared to the control (0.40 +/- 0.07 and 0.39 +/- 0.09 vs 0.15 +/- 0.05; P < 0.05; semiquantitative PCR analysis; mean +/- s.e.m.). IL-10 expression was significantly elevated the group of patients with infectious pneumonia in comparison to normal controls (0.15 +/- 0.06 vs 0.01 +/- 0.01; P < 0.05) but not in patients with IPS/BO (0.05 +/- 0.04; P > 0.05). However, IL-10 was not expressed in BAL cells of all patients and control individuals. IL-18 expression was significantly decreased in the both patient groups (1.47 +/- 0.24 and 1.79 +/- 0.63) in comparison to the control group (4.29 +/- 0.77; P < 0.05). Survival analysis showed a significant association between elevation of TNFalpha and poor prognosis (P < 0.05). These results highlight the immunoregulatory disturbances in the lungs after BMT/PBSCT.

Positron emission tomography in the staging of small-cell lung cancer : a preliminary study.

STUDY OBJECTIVES: Small-cell lung cancer (SCLC) has an unfavorable prognosis, especially when the disease is extensive at presentation. Accurate staging procedures are therefore needed for treatment planning. Positron emission tomography (PET) is a modern noninvasive imaging technique, the value of which for the staging of SCLC was investigated in the present study. SETTING: University hospital. PATIENTS: Thirty-one patients with suspected lung cancer were investigated for staging purposes using chest radiography, CT of the thorax and abdomen, abdominal ultrasound, and bone scanning. Twenty-five patients also received PET examinations during the staging procedures. Five of these patients were found to have SCLC, while two patients had mixed lesion types. Further analysis of the latter group was carried out. RESULTS: PET detected the primary tumor in all patients, and lymph nodes in five patients. All lymph nodes were proved to be malignant by endoscopic ultrasonography-guided fine-needle aspiration. Only one patient had distant metastases, which were detected by both CT and PET. CONCLUSIONS: PET appears be a suitable imaging method in SCLC. A potential role for the technique as a standard staging procedure will need to be tested by investigating a larger number of patients in a prospective study.

Diagnosing sarcoidosis using endosonography-guided fine-needle aspiration.

STUDY OBJECTIVES: The ability to diagnose sarcoidosis cytologically has been reported previously, but the method is rarely used. Endoscopic ultrasonography (EUS) is a sensitive technique for detecting mediastinal lymph nodes, which in addition provides an opportunity to carry out guided fine-needle aspiration (FNA) cytology. We report herein on the use of EUS-FNA in the diagnosis of sarcoidosis. PATIENTS AND METHODS: Nineteen patients with suspected sarcoidosis were investigated using EUS-FNA with a linear echoendoscope and a 22-gauge Hancke-Vilman needle. MEASUREMENTS AND RESULTS: In all 19 patients, EUS revealed enlarged mediastinal lymph nodes (mean size, 2.4 cm), located subcarinally (n = 15), in the aortopulmonary window (n = 12), or in the lower posterior mediastinum (n = 5). The nodes had an isoechoic or hypoechoic appearance, with atypical vessels in five cases. The amount of aspirate obtained using EUS-FNA was adequate in all patients, and contained blood in excess of normal in some, indicating a high degree of vascularity. Cytology demonstrated epithelioid cell granuloma formation, suggesting sarcoidosis. Mycobacterial cultures were negative in all of the patients except one, in whom the final diagnosis was tuberculosis. The specificity and sensitivity of EUS-FNA in the diagnosis of sarcoidosis were 94% and 100%, respectively. CONCLUSIONS: EUS of mediastinal lymph nodes in sarcoidosis reveals certain characteristic features. However, it is not capable of differentiating the lesions from tuberculosis or malignancy. EUS-FNA is a safe and sensitive method of aspirating material for cytology and mycobacterial cultures. We believe it will provide a useful alternative in the diagnosis of sarcoidosis.

Expression of mRNA for voltage-dependent and inward-rectifying K channels in GH3/B6 cells and rat pituitary.

The expression of mRNA for voltage-dependent (Kv) and inward-rectifying K channels (Kir) was studied in clonal rat somato-mammotroph cells (GH3/B6 cells) and rat pituitary using reverse transcription-polymerase chain reaction (RT-PCR). In GH3/B6 cells transcripts for 16 different Kv channel alpha-subunits (seven Shaker-related: Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv3.2, Kv4.1, Kv5.1; six EAG: eag1, erg1, erg2, elk1-elk3; three KCNQ: KCNQ1-KCNQ3) and for five different Kir channel alpha-subunits (Kir1.1, Kir2.3, Kir3.2, Kir3.3, Kir6.2) were found. In addition, transcripts for a short isoform of Kvbeta2 and transcripts for Kvbeta3 subunits were present. In rat pituitary transcripts for 21 different Kv channel alpha-subunits (11 Shaker-related: Kv1.3, Kv1.4, Kv1.6, Kv2.1, Kv2.2, Kv3.2, Kv3.4, Kv4.1, Kv4.2, Kv4.3, Kv6.1; seven EAG: eag1, erg1-erg3, elk1-elk3; three KCNQ: KCNQ1-KCNQ3) and nine Kir channel alpha-subunits (Kir1.1, Kir2.2, Kir3.1-Kir3.4, Kir4.1, Kir6.1, Kir6. 2) were found. In addition, all tested auxiliary subunits (Kvbeta1-Kvbeta3, minK, SUR1, SUR2) are expressed in the pituitary. The results indicate that the macroscopic K currents in GH3/B6 and pituitary cells are presumably mediated by K channels constructed by a larger number of K channel alpha-subunits and auxiliary beta-subunits than previously distinguished electrophysiologically and pharmacologically.

Role of transesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer.

STUDY OBJECTIVE: Bronchoscopic methods fail to diagnose lung cancer in up to 30% of patients. We studied the role of transesophageal endosonography (EUS)-guided fine-needle aspiration (FNA; EUS-FNA) in such patients. DESIGN: Prospective study. The final diagnosis was confirmed by cytology, histology, or clinical follow-up. SETTING: University hospital. PATIENTS: Thirty-five patients (30 male and 5 female; mean age, 60.9 years; range, 34 to 88 years) with suspected lung cancer in whom bronchoscopic methods failed. Patients with a known diagnosis, recurrence of lung cancer, or mediastinal metastasis from an extrathoracic primary were excluded. INTERVENTIONS: EUS and guided FNA of mediastinal lymph nodes. RESULTS: The procedure was uneventful, and material was adequate in all. The final diagnosis by EUS-FNA was malignancy in 25 patients (11 adenocarcinoma, 10 small cell, 3 squamous cell, and 1 lymphoma) and benign disease in 9 patients (5 inflammatory, 2 sarcoidosis, and 2 anthracosis). Another patient with a benign result had signet-ring cell carcinoma diagnosed on pleural fluid cytology (probably false-negative in EUS-FNA). The sensitivity, specificity, accuracy, and positive and negative predictive values were 96, 100, 97, 100, and 90%, respectively. There were no complications. Reviewing the EUS morphology, the nodes were predominantly located in levels 7 and 8 of American Thoracic Society mediastinal lymph node mapping (subcarinal and paraesophageal region). In seven patients, the punctured nodes were < 1 cm (four malignant and three benign), which are difficult to sample by other methods. The malignant nodes had a hypoechoic, homogenous echotexture. CONCLUSIONS: EUS-FNA is a safe, reliable, and accurate method to establish the diagnosis of suspected lung cancer when bronchoscopic methods fail, especially in the presence of small nodes.