[Prevalence of Pulmonary Hypertension in Dialysis Patients with End-stage Renal Disease]. / Prävalenz der pulmonalen Hypertonie bei Dialysepatienten mit terminaler Niereninsuffizienz.

BACKGROUND: In patients with end-stage renal disease (ESRD), pulmonary hypertension (PH) is a frequent complication with different etiologies and a 17 - 56 % prevalence rate. We evaluated the impact of fluid retention measured by bioimpedance on the prevalence of PH in this patient cohort. METHODS: All patients with ESRD at the dialysis center of the Medical Clinic II of the University Hospital Gießen were invited to participate in the study and undergo non-invasive PH screening. If the screening suggested PH, patients underwent bioimpedance spectroscopy for measurement of fluid retention followed by adjustment of fluid levels to normovolemia as far as possible. Thereafter a second non-invasive screening was performed in this patient cohort after reaching normovolemia. If signs for PH persisted, patients underwent right heart catheterization for further assessment. RESULTS: 52 patients agreed to participate in the study. After the first noninvasive screening, PH was suspected in 12 patients (23 %). After adjustment of fluid levels to reach normovolemia, PH was suspected only in 4 patients (7.7 %) with confirmation in 2 patients by right heart catheterization (3.8 %). DISCUSSION: In patients with ESRD, PH is frequently associated with fluid retention as shown by bioimpedance spectroscopy. After adjustment of fluid to normal levels, PH was confirmed by invasive test in nearly 4 % of cases.

[Dynamic hyperinflation in pulmonary arterial hypertension: "hyperinflator" and "non-hyperinflator"]. / Dynamische Hyperinflation bei der pulmonal arteriellen Hypertonie: "Hyperinflator" und "Non-Hyperinflator".

BACKGROUND: The dynamic decrease in inspiratory capacity (IC) during exercise with restriction of tidal volume (VT) is known as dynamic hyperinflation (DH) and is described mostly in patients with COPD differentiating between a "hyperinflator" and a "non-hyperinflator". Recent studies have revealed DH in patients with idiopathic pulmonary arterial hypertension (iPAH), but the influence of the DH on the reduced exercise capacity with exertional dyspnoae is still being debated. METHODS: We analysed flow-volume curves during cardiopulmonary exercise testing (CPET) in idiopathic PAH (n = 19), in COPD (n = 17), in idiopathic pulmonary fibrosis (IPF) (n = 19) and a control group (n = 30). We measured IC at rest and during maximal exercise and furthermore ventilation, VT and oxygen uptake (VO2 peak). In iPAH a right heart catheter test and a 6-minute walk test (6MWT) were performed, also the B-type naturetic peptide (BNP) and the NYHA/WHO functional class were determined. RESULTS: The IC decreased significantly in 11 PAH "hyperinflators" (PAH-H) (Δ IC: - 0.34 ± 0.14 L, p < 0.001) compared to 8 PAH "non-hyperinflators" (PAH-NH) (Δ IC: 0.08 ± 0.2 L). COPD patients exhibited a characteristic hyperinflation pattern with a decrease in IC throughout exercise (Δ IC: - 0.61 ± 0.3 L, p < 0.001), while patients with IPF (Δ IC: 0.03 ± 0.15 L) and the control group responsed to exercise with a non-hyperinflator pattern (Δ IC: 0.1 ± 0.2 L). Both PAH collectives showed a reduced IC/TLC, while VT/IC was elevated with a decreased peak VO2 and max. performance compared to the control group. Correlations of the IC rest/max (L) were shown in PAH-H and PAH-NH with the VO2 peak, max. performance and VT. CONCLUSION: The analysis of flow-volume curves during CPET can indentify DH in a subgroup of patients with iPAH. The DH contributes significantly but slightly to the development of exertional limitations and dyspnoe in a subgroup of iPAH. Further studies with a larger sample size will be required to definitively measure the impact of the DH seen in these patients.

Diagnosis of CTEPH versus IPAH using capillary to end-tidal carbon dioxide gradients.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents an important differential diagnosis to idiopathic pulmonary arterial hypertension (IPAH). We hypothesised that the capillary to end-tidal carbon dioxide gradient at rest and during exercise might help differentiate CTEPH from IPAH. Patients who presented with unequivocal IPAH or CTEPH according to ventilation/perfusion scanning, pulmonary angiography, computed tomography and right heart catheterisation were included in this retrospective study and compared with healthy controls. 21 IPAH patients and 16 CTEPH patients fulfilled the inclusion criteria. Haemodynamics and peak oxygen uptake were comparable, but respiratory rates at rest and during exercise were significantly higher in CTEPH than in IPAH. End-tidal carbon dioxide was significantly lower in CTEPH versus IPAH at rest and during exercise, while capillary carbon dioxide values were similar. Correspondingly, capillary to end-tidal carbon dioxide gradients were significantly increased in CTEPH versus IPAH at rest and during exercise (median (range) 8.6 (3.0-13.7) versus 4.4 (0.9-9.0) (p<0.001) and 9.3 (3.3-13.1) versus 4.1 (0.0-8.8) mmHg (p<0.001), respectively). Although these values were closer to normal in IPAH they were still significantly elevated compared with healthy controls (2.3 (-4.8-8.1) and -1.9 (-5.7-6.2) mmHg, respectively). Capillary to end-tidal carbon dioxide gradients may help to distinguish CTEPH from IPAH based on resting and exercise values.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Pulmonary arterial hypertension]. / Pulmonalarterielle Hypertonie.

Pulmonary arterial hypertension is a chronic disorder of the pulmonary circulation characterized by an increased pulmonary artery pressure and an impaired cardiac function. It can present as idiopathic form or associated with several systemic diseases. Typical symptoms include progressive dyspnoea and exercise intolerance. When pulmonary arterial hypertension is suspected, echocardiography is the key investigation for noninvasive assessment of the disease. The diagnosis requires an invasive measurement of pulmonary hemodynamics by right heart catheterization. Treatment is based on general measures and application of pulmonary vasoactive compounds, such as prostanoids, endothelin receptor blockers and phosphodiesterase 5 inhibitors. These treatment options can be combined at progression of the disease. Lung transplantation might be an option in patients refractory to medical therapy.

[Pulmonary hypertension in hereditary haemorrhagic teleangiectasia]. / Pulmonalvaskuläre Beteiligung bei Morbus Osler.

BACKGROUND: In hereditary haemorrhagic teleangiectasia (HHT) can be accompanied by pulmonary arteriovenous vascular malformations (PAVM). Pulmonary hypertension (PH) is regarded as a rare pulmonary manifestation. METHODS AND PATIENTS: We non-invasively assessed the pulmonary circulation in 20 patients with HHT using standard resting echocardiography including contrast studies. In 14 patients a mutation in the endoglin gene was present. The other 6 patients carried a mutation in the Alk-1 gene. RESULTS: We identified 4 patients with manifest PH, among them 2 patients (both with endoglin mutations) with concurrent thromboembolism, and 2 patients (both with Alk-1 mutations) with hepatic manifestations of HHT. Two patients required specific pulmonary vasoactive therapy with sildenafil and bosentan, respectively. Another patient received embolisation therapy for hypercirculatory PH due to hepatic arteriovenous malformations. Pulmonary arteriovenous malformations were found in 8 patients (7 with endoglin, and 1 with Alk-1 mutations), among them were 2 patients with PH. CONCLUSIONS: Patients with HHT should undergo echocardiographic screening for PAVM as well as PH. When PH is detected, other conditions such as hepatic or thromboembolic diseases should be considered, regardless of the underlying genetic defect.

[Therapy of pulmonary arterial hypertension]. / Therapie der pulmonalarteriellen Hypertonie.

Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.

The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. METHODS: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. RESULTS: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). CONCLUSION: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

[Obstructive sleep apnoea and metabolic syndrome]. / Obstruktive Schlaf-Apnoe und metabolisches Syndrom.

Metabolic syndrome, i. e., the combined occurrence of obesity, arterial hypertension, insulin resistance and dyslipidaemia (increased triglycerides, reduced HDL cholesterol), is associated with a marked increase in cardiovascular risk. The prevalence of metabolic syndrome in patients with obstructive sleep apnoea (OSA) is very high. Obesity is the main risk factor for OSA and OSA itself is now considered to be the most frequent cause of secondary arterial hypertension. Due to the confounding influence of obesity, the causal connection between OSA and metabolic disturbances is less well established, however, epidemiological data are at least in favour of an independent link between OSA and insulin resistance. It is known that CPAP therapy can ameliorate OSA-associated hypertension. In contrast, the effects of CPAP treatment on insulin resistance and dyslipidaemia have to be further elucidated by large, randomised interventional trials.

Airway-centered interstitial fibrosis - an under-recognized subtype of diffuse parenchymal lung diseases.

Airway centered interstitial fibrosis (ACIF) has been recently suggesed as a rare histological pattern of interstitial lung disease of variable etiology and outcome. It is characterized by fibrosis of the respiratory bronchioles and the peribronchiolar interstitium. We describe the clinical features of 13 patients (7 female, mean age 55 years) with histologically proven ACIF in 12 cases and long-term follow up. In ten patients, exogenous agents could be detected (mould n=5, wood n=2, leather exposure n=1, occupational exposure n=2). Two patients had rheumatoid arthritis and 1 patient suffered from recurrent aspiration. In three patients no associated exposure could be detected. Eight patients were never-smokers, while five were ex- smokers. At time of diagnosis patients presented with a moderate restrictive ventilation impairment and sever reduction in diffusion capacity (VC 61%, TLC 66%, DLCOc-SB 38% pred.). All patients were started on immunosuppressive therapy with steroids which were combined with azathioprine in seven and with mycophenolate mofetil in one patient. Median time of follow up was 52 months (2-127 months). Patients with ACIF due to exogenous agents or associated with RA were stable with immunosuppressive therapy. One patient with idiopathic ACIF showed a progressive deterioration within 29 months despite immunosuppression and died while on a waiting-list for lung transplantation. In our experience ACIF is a rare finding, which is relatively frequently observed in the context of hypersensitivity pneumonitis, aspiration and rheumatoid arthritis, while idiopathic ACIF was a minority. In the majority of patients, ACIF showed a favorable long-term outcome with immunosuppressive therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 218-229).

Effects of nebulised iloprost on pulmonary function and gas exchange in severe pulmonary hypertension.

Nebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140 micro g iloprost/24h via an ultrasonic nebuliser. Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423+/-98 to 415+/-98) and percutaneous oxygen saturation increased in mean by 0.7% (90+/-6 to 91+/-5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction. Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV(1), FVC, TLC, residual volume nor in diffusions capacity, SO(2) at rest and during 6 min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6 min walking distance (6 MWD) after 3 months (246+/-113 to 294+/-115 m, P<0.05). In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients.

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

The value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions.

BACKGROUND: Transbronchial needle aspiration (TBNA) is a bronchoscopic sampling technique used for the diagnostic workup of mediastinal lymph nodes, but the value of its routine use in evaluating peripheral pulmonary lesions is not yet firmly established. DESIGN: Retrospective analysis of routine diagnostic bronchoscopies. SETTING: University teaching hospital. PATIENTS AND METHODS: One hundred seventy-two consecutive patients (126 with malignant and 46 with nonmalignant disease) who underwent bronchoscopy for a peripheral pulmonary lesion. RESULTS: In 87 patients (51%), a final diagnosis was established by bronchoscopy; diagnoses included 81 malignant lesions (69 lung cancer and 12 pulmonary metastases) and 6 benign lesions (all tuberculosis). TBNA was used in 152 of the 172 patients (89%). Other endoscopic techniques included bronchial washing (100%), bronchial brushing (45%), and transbronchial biopsy (TBB) (27%). Concerning the different bronchoscopic sampling techniques, TBNA showed a positive result in 35% of cases, in comparison to 17% for TBB, 22% for bronchial washing, and 30% for bronchial brushing. While TBNA was diagnostic in 27.5% of the malignant lesions < 3 cm in diameter, the success rate in lesions > 3 cm was 65.5% (p = 0.03). Endoscopy-related complications included pneumothorax (n = 1), self-limiting bleeding (n = 12), prolonged coughing (n = 2), and vasovagal reactions (n = 2). None of these complications required further treatment. CONCLUSION: TBNA is an effective bronchoscopic sampling technique in the diagnosis of peripheral pulmonary lesions. In our study, the use of TBNA increased the diagnostic yield of bronchoscopy from 35 to 51% without additional risk. The use of TBNA in the clinical routine should be encouraged.

Invasive pulmonary fungal infection in hematologic patients: is resection effective?

INTRODUCTION: Invasive pulmonary aspergillosis carries a high mortality in neutropenic patients. Descriptive reports have shown early surgery to be feasible with acceptably low morbidity. The possible benefit of surgery has not been investigated in comparative studies. MATERIALS AND METHODS: In a retrospective cohort study encompassing a 15-year period, 54 (8%) of 697 consecutive patients with severe hematological disease required treatment for localized invasive pulmonary aspergillosis. Patients treated by antifungal drugs (medical group, n = 24) were compared to patients treated with additional early lung resection (surgical group, n = 30). Outcomes analysed were fungal progression and survival. RESULTS: Fungal progression at six months was 17% (95% CI 3-31) in the surgical group and 52% (95% CI 34-73) in the medical group (P = 0.005). Survival at six months was 70% (95% CI 53-87) in surgically and 42% (95% CI 24-62) in medically treated patients (P = 0.009). Adjusting for differences in WHO performance score (worse in the medical group) and duration of neutropenia (longer in the surgical group) in a multivariate analysis, a difference in relative risk of death (0.26; 95% CI 0.08-0.88; P = 0.03) remained in favor of surgery. CONCLUSION: In this retrospective study surgical intervention to treat invasive pulmonary fungal disease appeared to have a beneficial effect on the impact of disease control and survival. Differences in baseline characteristics of the two patient groups calls for cautious interpretation. A prospective randomized trial seems warranted.

Progressive interstitial fibrosis of the lung in sclerodermoid chronic graft-versus-host disease.

Sclerodermoid chronic graft-versus-host disease (sGVHD) is a well-known complication in patients with a long history of chronic GVHD. Pulmonary involvement in chronic GVHD presents typically as bronchiolitis obliterans (BO). Pulmonary fibrosis after allogeneic hematopoietic stem cell transplantation (HSCT) is presumed to be caused by the long-term toxicity of the conditioning regimen or the result of lung injury elicited predominantly by viral infections or GVHD. We present two patients with late onset pulmonary fibrosis associated with moderate sGVHD of the skin after HSCT. At the initial diagnosis of chronic GVHD both patients presented with symptoms of interstitial pneumonia. Years later both patients developed moderate to severe interstitial pulmonary fibrosis in association with sGVHD. One patient showed additional clinical and histological signs of BO. While one patient responded to increased immunosuppression including total nodal irradiation (1 Gy), the other patient died due to complications related to pulmonary fibrosis.

Diagnostic yield of bronchoscopy in histologically proven invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication in neutropenic patients after high-dose chemotherapy or hematopoietic stem cell transplantation. Its diagnosis is mainly based on clinical symptoms, and radiological signs on thoracic CT scan. The value of bronchoscopy is controversial. We analyzed the diagnostic yield of bronchoscopy in 23 consecutive patients with histologically proven invasive pulmonary aspergillosis. In seven patients (30%) bronchoscopically obtained specimens were diagnostic for pulmonary fungal infection. Typical hyphae were detected by cytology in six patients and fungal cultures were positive in four cases. Patients with a positive bronchoscopic result presented more often with multiple changes on thoracic CT scan (71%; 5/7), but had received a lower median cumulative dose of amphotericine B (300 mg; 168-3010 mg) compared to patients with non-diagnostic bronchoscopy (25% multiple lesions (4/16); amphotericine dose 1100 mg, 260-2860 mg). The diagnostic yield of bronchoscopy was not associated with clinical symptoms or duration of neutropenia. Bronchoscopy allows the diagnosis of IPA in about one third of patients. Fungal cultures and cytological examination of intrabronchial specimens obtained during bronchoscopy have a high specificity, but its sensitivity is low. It is advisable to perform diagnostic bronchoscopy before starting antifungal therapy. Better diagnostic tools are urgently needed.

Surgical aspects of resection for suspected invasive pulmonary fungal infection in neutropenic patients.

BACKGROUND: Morbidity and mortality of early resection of invasive pulmonary fungal disease in neutropenic patients are still considered prohibitive for surgical treatment. METHODS: We retrospectively analyzed results of 28 (16 men, 12 women; mean age, 38.9 years) consecutive neutropenic hematologic patients who had lung resections for suspicion of invasive pulmonary fungal disease. RESULTS: We did 28 lung resections (19 lobectomies, one bilobectomy, eight single or multiple wedge resections including three video-assisted wedge resections). The disease was proved histologically in 22 (78.6%) cases. Intraoperative difficulties, such as diffuse oozing or mycotic infiltration, and solid postinflammatory adhesions were encountered in 5 (17.8%) and 6 (21.4%) patients respectively. In one case (3.6%) it lead to a major intraoperative hemorrhage. There were no intraoperative deaths, overall 30-day mortality rate was two of 28 (7.1%), overall 90-day mortality rate was seven of 28 (25%), with one death (3.6%) possibly related to surgery. Minor surgery-related complications were seen in ten (35.7%) cases, major surgery-related complications occurred in three (10.7%) cases. Twelve of 22 patients (54.5%) with proven invasive fungal infection are currently alive (mean follow-up, 32.3 months). CONCLUSIONS: Surgery-related complications and mortality are acceptable for this high risk group of patients. Resection should be carried out early for diagnostic as well as therapeutic reasons.

Compartmentalization of pro-inflammatory cytokines in tuberculous pleurisy.

Increased levels of interleukin-6 (IL-6) and IL-8 are found in various immunologically mediated inflammatory disorders. Concentrations of IL-6, IL-8 and the soluble form of the IL-6 receptor (sIL-6R) were determined in serum and effusion fluid of 25 patients with tuberculous pleurisy utilizing enzyme linked immunosorbent assays (EIA). Serum IL-6 levels were only slightly increased in patients with tuberculous pleurisy in comparison to controls (11.1 +/- 2.1 vs 7.3 +/- 1.0 pg ml-1). IL-8 could not be detected in the serum of tuberculosis patients, but it was detected in the serum of healthy controls (8.0 +/- 1.5 pg ml-1). In comparison to serum, IL-6 and IL-8 were found in high concentrations in pleural effusions (IL-6: 932 +/- 70 vs 11.1 +/- 2.1 pg ml-1, P < 0.0001; IL-8: 450 +/- 85 vs 0 +/- 0 pg ml-1). In contrast, sIL-6R concentrations were much higher in serum compared to pleural effusion levels [30,477 +/- 1905 vs 9881 +/- 1177 pg ml-1, P < 0.0001 (mean +/- SEM)]. The authors conclude that elevated levels of IL-6 and IL-8 in pleural effusions are compartmentalized at the site of active disease. The low levels of sIL-6R in the presence of high levels of IL-6 in pleural effusions, and the high levels of sIL-6R in the presence of low levels of IL-6 in serum suggest that the expression or shedding of sIL-6R may be downregulated in the presence of excessive amounts of IL-6.

Distinct endobronchial expression of matrix-metalloproteinases (MMP) and their endogenous inhibitors in lung cancer.

BACKGROUND: Degradation of extracellular matrix (ECM) and basement membranes is required for tumour cell invasion and metastasis. The ECM is degraded by matrix metalloproteinases (MMP) which are counteracted by tissue inhibitors of metalloproteinases (TIMP). In aggressive tumours the balance of proteolysis and antiproteolysis is disrupted, resulting in fast tumour progression and invasiveness. We examined MMP and TIMP expression patterns in bronchial washings of 58 consecutive lung tumour patients and 10 controls. Pathohistological investigations revealed squamous cell carcinoma (n = 23), adenocarcinoma (n = 18), small cell lung carcinoma (n = 9), and pulmonary metastases of extrapulmonary tumours (n = 8). MMP/TIMP expression was correlated to histology, location, or staging of tumours. METHODS: Expression and activity of MMP was identified by zymography and Western blotting. Expression of TIMP-1 and TIMP-2 was analysed by Western blotting and enzyme-linked immunosorbent assays. RESULTS: We identified MMP-1, MMP-2 and MMP-9, but not MMP-3 or MMP-8 in bronchial washings. All MMPs were expressed in the tumour-affected and the tumour-free parts of the lung. While MMP-1 and MMP-9 were present in all samples, the inactive precursor of MMP-2 was specifically expressed in adenocarcinoma or lung metastases of extrapulmonary tumours. No MMP-2 was found in controls. While TIMP-1 was expressed in all samples, TIMP-2 was not detectable. CONCLUSION: The tumour type-specific expression of the MMP-2 precursor in adenocarcinoma and lung metastases suggests that MMP-2 in the absence of TIMP-2 correlates with aggressive tumour progression and may serve as an indicator for poor prognosis.