Fibrinolytic and coagulation mechanisms in stages of inflammation: a study of BCG-induced pleural exudate in guinea pig.

Pleural fluid from an early, active phase of BCG-induced pleurisy was compared with fluid from late, healing phase, characterized by fibrinous adhesions. Exudates were tested for proteolytic activity on chromogenic peptide substrates designed for plasmin, tissue plasminogen activator, factor Xa, thrombin and plasma kallikrein. Considerable activity of active-phase pleural fluid was found on all of these substrates, and significantly lower values in the healing phase. Most exudates from both stages had very low fibrinogen concentration. Fibrinopeptide A, fibrinolytic products and antiplasmin were found in all exudates. Little or no fibrinolytic effect of pleural fluid was demonstrable on plasminogen free fibrin plates, despite the high activities on the low molecular weight substrates. Occurrence of alpha 2-macroglobulin-enzyme complexes is suggested as an explanation. The experimental results indicate that protease of the fibrinolytic and coagulation systems are active in the chronic inflammation of pleurisy, with higher levels of activity in active pleurisy phase.

Influence of fibrinogen fragments on human lymphocyte thymidine uptake.

Fragments of human fibrinogen were tested for ability to suppress activation of human blood lymphocytes by the lectin phytohaemagglutinin (PHA). Measurement of cellular 14C-thymidine uptake was used as an indicator of DNA synthesis and cell proliferation. The tested fragments were obtained by plasmin digestion or by CNBr fragmentation of fibrinogen. Inhibition of uptake, with good dose response relationship, was demonstrated for the plasmic fragment PL-3 and for the CNBr fragment Hol-DSK. Digests of the latter with trypsin and plasmin gave the same effects as the intact fragment. However, reproducibility was poor with PL-3. Hol-DSK gave better reproducibility, but with pronounced interbatch variations. Other fragments of fibrinogen were tested, but gave no effect in the studied concentrations. The reason for the poor reproducibility is discussed.

Tumour necrosis factor-alpha and nitric oxide, determined as nitrite, in malignant pleural effusion.

Pleurodesis treatment is often used to stop chronic pleural effusion in malignant pleurisy. During the treatment a strong intrapleural inflammation is induced leading to the cessation of exudation. In this study the concentrations of tumour necrosis factor (TNF-alpha) and nitric oxide (NO), determined as its immediate metabolite nitrite, were measured in pleural fluid, in order to investigate if they were involved in pleural inflammation and pleural fluid exudation. Determinations were made in pleural fluid from patients with malignant pleural effusion, before and during therapeutic quinacrine-induced pleural inflammation. TNF-alpha concentrations were measured by ELISA-technique and NO/nitrite by chemiluminescence. TNF-alpha increased significantly after quinacrine instillation. NO/nitrite was initially present at the same concentrations as found in normal serum, and increased significantly during treatment. Concentrations of TNF-alpha correlate with the amount of pleural fluid production after quinacrine instillation, in that a higher level of TNF-alpha is associated with more pleural fluid production. No correlation was found between TNF-alpha and NO/nitrite, whereas a weak but significant correlation was found between NO/nitrite and concentrations of another cytokine, interleukin-1 beta (IL-1 beta). The results suggest that TNF-alpha might contribute to pleural fluid exudation and that TNF-alpha and NO are of importance in induced pleural inflammation. IL-1 beta might be one of several stimuli for NO formation in this setting.

The impact of pleurodesis in malignant effusion on respiratory function.

Pleurodesis of malignant pleural effusion provides for a substantially better quality of life compared to onging exudation with the need for repeated evacuation of fluid. Successful pleurodesis leads to permanent cessation of fluid production as a result of the formation of fibrous adhesion between the lung and costal pleura which in theory, however, might restrict lung mobility. In patients with poor lung function, or with need for bilateral pleurodesis, the apprehension of further impairment of lung function often arises. The aim of this study was to evaluate the effects of pleurodesis on lung function. Therefore 10 patients with malignant pleurisy with very limited tumour were investigated. They were without radiological signs of tumour infiltration in the lung parenchyma, without visible tumour growth in the pleural space during thoracoscopy and had undergone a successful one-sided pleurodesis. Respiratory function tests were performed at different times, 1-102 months after pleurodesis. The assessment consisted of: static and dynamic spirometry, exercise testing with blood gas determination and radiospirometry. Spirometric values were slightly low, but in general within the reference limits. Blood gas determination showed no signs of alveolar hypoventilation. Radiospirometry showed a slight attenuation of activity in the treated lung but similar turnover of gas of the treated vs. the untreated side. The study showed that pleurodesis in malignant pleurisy has only minor impact on respiratory function.

Tuberculin skin test reactivity of health care students in a country with a low prevalence of tuberculosis.

SETTING: Health care students in Sweden. OBJECTIVE: To analyse the distribution of tuberculin skin test (TST) reactions and epidemiological factors related to TST reactivity. DESIGN: TST reactivity was analysed in 1190 students. A linear regression model was created for the relative contribution of background factors of TST reactivity. A subgroup of 287 non-vaccinated subjects was comparatively skin-tested with Mycobacterium avium sensitin and tuberculin. RESULTS: Among non-bacille Calmette-Guérin (BCG) vaccinated students, 91% had no TST reaction (0 mm induration) and reactions of ≥ 10 mm were found in 2.9%, whereas 34% of BCG-vaccinated students had no TST reaction and 42% had reactions of ≥ 10 mm. The expected contribution to TST reactivity was 6.0 mm for a history of BCG vaccination, 3.0 mm for a country of birth with medium/high incidence of TB and 1.6 mm per 10 years of age. The sensitin reactions exceeded the TST reactions by ≥ 3 mm in 52% of the comparatively tested subjects with TST reactions of ≥ 1 mm. CONCLUSION: BCG vaccination, cross-reactivity with non-tuberculous mycobacteria, geographic origin and age had a decisive influence on TST reactivity. Most non-vaccinated health care students were non-reactive, which highlights the need to organise preventive measures in settings where TB exposure is expected.

Activation of lymphocytes by PPD and PHA is promoted by exudate from BCG-induced pleurisy.

Cell-free pleural exudate (PE) obtained from guinea pigs with BCG-induced pleurisy was tested for influence on in vitro activation of lymphocytes by PHA and PPD. A previous study has shown poor activation of lymphocytes derived from pleural exudate and this was thought possibly to depend on inhibitory activity of the exudate. Instead of the expected suppressive effect, however, PE in the present study promoted activation of lymphocytes from most sample sites in healthy and pleuritic guinea pigs. Thus, in the presence of PE, lymphocytes derived from the pleural exudate were always activated in vitro by PHA and PPD.

Pleurography in encapsulated effusion.

Encapsulated pleural effusion was investigated radiographically in 4 patients by injection of a non-ionic water-soluble contrast medium (Amipaque) into the encapsulated site. Demonstration of the presence and extent of the cavities and their size and form was thereby achieved.

Pleurisy induced by intrapleural BCG in immunized guinea pigs.

Guinea pigs immunized with intracutaneous BCG more than 10 weeks previously responded with pleurisy to a large dose (2 mg) of BCG injected into the right pleural cavity. The pleurisy was characterized by an initial stage in which the effusion contained predominantly granulocytes. From day 3 to day 17 after induction, lymphocytes were the dominant white cells. From the day 11 onwards there was decrease of fluid volumes and cell numbers, with concomitant induration and subsequent necrosis of regional lymph nodes, swelling of the pleural wall and formation of adhesions. Fluid volumes of 4-15 ml and total lymphocyte yields of, in general, 10-100 million during days 3-11 after induction of pleurisy, make the model suitable for chemical analyses and immunologic studies.

Low in vitro response to PPD and PHA in lymphocytes from BCG-induced pleurisy in guinea pigs.

In order to study any correlation between functional properties of lymphocytes in BCG-induced pleural exudation and the development of the pleurisy a previously described experimental model was used. This model with a duration of effusion of more than 17 days has characteristic stages. From the third day and onwards there are lymphocytes in sufficient amount for in vitro cultures. Proliferation of lymphocytes from the fluid was measured as uptake of 14C-thymidine. The response of the lymphocytes to PPD tuberculin and to phytohemagglutinin (PHA) was studied, and their spontaneous activity was measured. Comparisons were made with lymphocytes from regional lymph nodes. Pleural lymphocytes sampled on the third post-induction day did not respond to PPD or PHA stimulation. In later stages, pleural lymphocytes were stimulated by PPD to approximately the same degree as the lymph node lymphocytes. The response to PHA was weak at all stages of pleurisy, though in later stages there were some cases with high values. Variations in activation ability, related to disease staging, were demonstrated. However, low activities, and variability of the responses, without concomitant variations in disease, speak against a connection between the course of disease and functional status of the lymphocytes as measured in this study.

Prospective clinical and radiologic study of zeolite-exposed Turkish immigrants in Sweden.

Ninety-four persons from the village of Karain, Turkey, now residing in Stockholm, were investigated clinically and radiologically. In this village, environmental exposure to erionite, a fibrous zeolite, occurs, and there is an extremely high risk of mesothelioma among the villagers. Since an earlier investigation of the cohort in 1980, another 4 young persons have fallen ill with malignant mesothelioma in this group, where the incidence thus approaches 1%/year and is the most common cause of death. Solitary pleural plaques were found in 6%, thickening of the interlobar pleura in 4% and other radiologic signs of affection of the pleura in 2%. Thickening of the interlobar fissures were observed in 1 patient as the first sign of mesothelioma which has remained asymptomatic until 1 year later. The comparatively low incidence of pleural lesions in the cohort is probably due to the low mean age (36 years). Further follow-up could give clues to the pathogenesis of malignant mesothelioma.

Exudative pericarditis in sarcoidosis. A case report and echocardiographic study.

Involvement of the pericardium in sarcoidosis is infrequent as earlier reported. The involvement may be accompanied by pericardial effusion. We report the case of a 43 year-old man with non-obstructive hypertrophic cardiomyopathy for almost two decades who developed an effusion in the pericardial sac. As pericardial effusion is not a part of this disease and no other common cause was found we believe that the exudation was caused by sarcoidosis which started one year earlier. This finding initiated an echocardiographic study in 18 consecutive sarcoid patients, 8 with acute and 10 with chronic disease. None had pericardial effusion and only one demonstrated a thickening of the pericardial tissue.

Pleural fibrinolytic activity is decreased in inflammation as demonstrated in quinacrine pleurodesis treatment of malignant pleural effusion.

Chronic malignant pleural exudation is generally characterized by little or no fibrin deposition. However, during induced inflammation, fibrin deposition concomitant with cessation of exudation is seen. To judge the involvement of the fibrinolytic system in this process, concentrations of fibrinolytic factors were followed in 10 patients during treatment by quinacrine instillation and tube drainage. Plasminogen and alpha-2-antiplasmin were found in low concentrations and did not show significant changes during treatment. The plasminogen activator inhibitor PAI-1, which plays an important role in the regulation of fibrinolysis, was also studied during treatment. Before treatment the concentration of PAI-1 was 21.7 +/- 12.0 (mean +/- SD) AU/ml and it increased to 86.9 +/- 25.9 AU/ml 6 h after quinacrine instillation. D-dimer, a product of the lysis of fibrin, was found in high concentrations before treatment (62.7 +/- 25.5 micrograms/ml) and in low concentrations 6 h after treatment (12.2 +/- 7.9 micrograms/ml). Thus, it was possible to demonstrate that the fibrinolytic system is activated during chronic malignant pleural exudation and, furthermore, that the activity decreases during induced inflammation.

Increased coagulation activity of the pleura after tube drainage and quinacrine instillation in malignant pleural effusion.

Chronic malignant pleural effusions are usually treated with an intrapleurally administered irritant that creates an inflammatory reaction. The induced inflammation results in fibrin deposition and termination of fluid exudation. In the present study several factors in the coagulation system in the pleural fluid were followed during treatment with tube drainage and quinacrine instillation into the pleural space. In the chronic exudative phase before treatment, both thrombin activity and fibrinopeptide A (FPA), were present at low levels. During treatment the levels increased markedly. Beta-thromboglobulin, a platelet marker, showed a similar pattern. Prothrombin, antithrombin III, prekallikrein and kallikrein inhibiting activity showed no such variations in activity. The high thrombin activity and FPA level induced by treatment reflect an active process of fibrin formation which seems to play an important role in arresting chronic pleural exudation.

Fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A in pleural effusions. High turnover of fibrinogen in pleurisy.

Fibrinogen, fibrin(ogen) degradation products (FDP) and fibrinopeptide A (FPA) were analysed in pleural fluids from 20 consecutive patients with major effusions of various aetiology. FPA is a short-lived polypeptide which is split off from fibrinogen, whereafter fibrin is formed. FDP are formed through lysis of fibrin or fibrinogen. In 18 patients no fibrinogen could be detected in pleural fluid, whereas two (both having malignant tumours) had detectable but low concentrations. High FPA concentrations, interpreted as reflecting very recent fibrin formation, were found in all pleural fluids except for one case of empyema and one transudate. Plasma concentrations were low in most cases. The same pattern was found with regard to FDP, i.e. exudates showed high concentrations, whereas plasma concentrations were low. The only patient with a transudate showed absence of fibrinogen and low concentrations of FDP and FPA. We interpret our findings as indicative of a high rate of fibrin formation and degradation in pleural exudates and have not found any differences between various types of pleural exudates. Consequently, the findings may illustrate the close association between the coagulation system and inflammatory reactions which may be common to most pleural diseases.

Quinacrine-induced pleural inflammation in malignant pleurisy: relation between drainage time of pleural fluid and local interleukin-1 beta levels.

In this study, the levels of interleukin-1 beta (IL-1 beta) were measured in pleural fluid from patients with chronic malignant pleural effusions, before and during quinacrine-induced pleurodesis. IL-1 beta levels increased significantly within 24 h after the instillation of quinacrine (p < 0.001). The levels of IL-1 beta correlated with the amount of pleural fluid production as well as with the tube drainage treatment time. Thus, the more IL-1 beta levels increased the higher pleural fluid production was seen and a longer drainage treatment time was needed. There were no correlations between IL-1 beta levels and degree of fever, recruitment of pleural leucocytes, activity of pleural coagulation or inhibition of pleural fibrinolysis.

Tenosynovitis of the hand caused by Mycobacterium terrae.

Flexor tendon synovitis caused by Mycobacterium terrae resulted in considerable permanent functional impairment of the hand in six patients. Initial symptoms were subtle and uncharacteristic. Cortisone injections aggravated the condition. Surgical treatment including synovectomy was combined with antimycobacterial chemotherapy. Early diagnosis obtained by culture of synovial biopsy material to detect mycobacteria may result in an improved outcome in chronic synovitis.

Effects of fibrinogen fragment and proteolytic enzyme on the immune system in mice.

The immunomodulating ability of fibrinogen fragment (Hol-DSK) and proteolytic enzyme with fibrinolytic activity from Aspergillus oryzae was analysed in CBA/Ca, C57Bl, C3H/HeJ and NMRI mice. Suppressive effects on the blastogenic response to mitogens were noted. No consistent suppressive effect, but sometimes an enhancing one, was recorded on the antibody responses to protein antigens. Administration of Hol-DSK or proteolytic enzyme shortly after the immunization resulted in a slight inhibition of the development of delayed hypersensitivity to picryl chloride in C57Bl but not in CBA mice. When similar administration was done simultaneously with administration of the challenging antigen of picryl chloride or sheep red blood cells in immunized mice, significant impairment of the delayed-type hypersensitivity reaction was noted. The modulating effects by Hol-DSK did not alter the in vitro bacteriocidal effects of peritoneal exudate cells from mice on Escherichia coli.