Fibrinogen metabolism in congestive circulatory insufficiency

Using 125I-labelled fibrinogen the metabolism of this protein was studied in 29 patients with II-III stage congestive circulatory insufficiency due to ischemic heart disease and rheumatic heart diseases. It was established that with the progression of circulatory insufficiency fibrinogen half-life increased. The body content of total fibrinogen increased with the gradual intensification of circulatory insufficiency due to growth of the extravascular (noncirculating) fraction. The growth is associated with the intensified egress of circulating fibrinogen into the extravascular space (thrombus, tissue, etc.). The role of disseminated intravascular clotting and consumption coagulopathy in the pathogenesis of congestive circulatory failure is discussed.     

Vasoactive hormone metabolism in the lungs of patients with congenital heart defects

The role of pulmonary metabolism of adrenaline, noradrenaline (NA), serotonin and histamine in the pathogenesis of hemodynamic disorders was examined in relation to the magnitude of intracardiac discharge (ID) in 30 patients with septal defects. Irrespective of the magnitude of arteriovenous ID, pulmonary tissue deactivation of NA is shown to be disrupted. Where ID averages 7.7 +/- 2.1 1/min, venous blood NA level is 59.8% higher (p less than 0.05) than that of patients with average ID of 3.1 +/- 0.7 1/min. A positive correlation (r = 0.51) is demonstrated between venous NA levels and ID in the latter group. The data obtained suggest that high ID values are associated with disturbed pulmonary metabolism and increased arterial levels of serotonin and NA, a significant contribution to the development of functional and morphologic vascular disorders of systemic and pulmonary circulation.     

Isolation and metabolism of granular pneumocytes from rat lungs

A population of rat lung cells enriched in granular pneumonocytes (type II cells) was prepared by modification of the method of Kikkawa (Lab. Invest.30, 76, 1974). Lungs were minced, mechanically agitated and incubated with a fluorochemical emulsion and 1% trypsin. The isolated cells were centrifuged in a discontinuous Ficoll gradient. Granular pneumonocytes were identified by the presence of cytoplasmic inclusions on Papanicolaou and acid phosphatase staining and a strongly positive alkaline phosphatase reaction. The yield at the interface between 1.058 and 1.100 density Ficoll was (4.0 ± 1.5) × 10⁶ (mean ± SD) cells per g of lung tissue consisting of 72.7 ± 9.0% granular pneumonocytes and 20.3 ± 8.4% alveolar macrophages. O₂ uptake by the cells at room temperature was 46.9 ± 5.8 nmol/h per 10⁶ cells (mean ± SE; n=5). Respiration was inhibited by oligomycin and subsequently stimulated by an uncoupler of oxidative phosphorylation. During incubation with [U-¹⁴C] glucose, the cells produced¹⁴CO₂, lactate and pyruvate at rates of 17.0 ± 2.9, 17.1 ± 1.6 and 8.7 ± 0.8 nmol/h/10⁶ cells, respectively. These results show that a cell population enriched in granular pneumonocytes can be isolated by lung trypsinization. The cells in this preparation show respiration that is coupled to oxidative phosphorylation and intact glycolytic pathways.     

Chylomicron metabolism by normal and injured isolated rat lungs

Since the lung is the first highly vascularized organ to which chylomicrons are exposed, we sought to determine whether the lung vasculature is capable of metabolizing triglyceride contained in circulating, native chylomicrons. In addition, since acute lung injury can depress other endothelial cell associated metabolic functions, we determined whether acute injury due to alpha-naphthylthiourea (ANTU) changed chylomicron triglyceride metabolism by lungs. We compared the hydrolysis of radiolabelled chylomicrons from rat mesenteric lymph by perfused lungs isolated from rats pretreated with ANTU; with the vehicle, Tween 80, alone; or untreated control rats. In all groups of lungs, we found that perfusate content and concentration of triglyceride decreased over 30 minutes of perfusion, while that of free fatty acid increased, indicating that isolated lungs are able to hydrolyze chylomicron triglyceride. Despite enhancement of hydrolysis by perfusates containing 6 gm/100 ml of bovine serum albumin, there were no differences among the groups of lungs in the extent or rate of triglyceride metabolism. The [1-14C]-oleate from chylomicron triglyceride was taken up into lung tissue during 30 minutes of perfusion and incorporated into neutral lipid, phosphatidylcholine, and phosphatidylethanolamine to a similar degree by ANTU-injured and control lungs. Lipoprotein lipase activity in homogenates of lungs from ANTU and Tween treated rats did not differ. We conclude that lungs are capable of hydrolysis of triglyceride contained in chylomicrons and that this endothelial cell associated metabolic function is not altered by acute lung injury caused by ANTU.     

Isolation and metabolism of granular pneumocytes from rat lungs

A population of rat lung cells enriched in granular pneumonocytes (type II cells) was prepared by modification of the method of Kikkawa (Lab. Invest.30, 76, 1974). Lungs were minced, mechanically agitated and incubated with a fluorochemical emulsion and 1% trypsin. The isolated cells were centrifuged in a discontinuous Ficoll gradient. Granular pneumonocytes were identified by the presence of cytoplasmic inclusions on Papanicolaou and acid phosphatase staining and a strongly positive alkaline phosphatase reaction. The yield at the interface between 1.058 and 1.100 density Ficoll was (4.0 ± 1.5) × 10⁶ (mean ± SD) cells per g of lung tissue consisting of 72.7 ± 9.0% granular pneumonocytes and 20.3 ± 8.4% alveolar macrophages. O₂ uptake by the cells at room temperature was 46.9 ± 5.8 nmol/h per 10⁶ cells (mean ± SE; n=5). Respiration was inhibited by oligomycin and subsequently stimulated by an uncoupler of oxidative phosphorylation. During incubation with [U-¹⁴C] glucose, the cells produced¹⁴CO₂, lactate and pyruvate at rates of 17.0 ± 2.9, 17.1 ± 1.6 and 8.7 ± 0.8 nmol/h/10⁶ cells, respectively. These results show that a cell population enriched in granular pneumonocytes can be isolated by lung trypsinization. The cells in this preparation show respiration that is coupled to oxidative phosphorylation and intact glycolytic pathways.     

Fibrinogen Amsterdam, Another Hereditary Abnormality of Fibrinogen

S ummary . A coagulation defect, characterized by a prolonged thrombin and pro-thrombin time, was discovered in a family without haemorrhagic diathesis. The disorder is caused by a delayed aggregation of fibrin monomers. Patient's and normal purified fibrin monomers showed the same aggregation properties, but the patient's fibrin monomers aggregated abnormally in the presence of the α₂-globulin fraction of plasma. The presence of an abnormal fibrinogen is postulated. The inheritance of this fibrinogen is compatible with an autosomal dominant trait.     

Sphingolipids in the lungs

Sphingolipids such as sphingosine-1-phosphate (S1P), ceramide, or sphingomyelin are essential constituents of plasma membranes and regulate many (patho)physiological cellular responses inducing apoptosis and cell survival, vascular permeability, mast cell activation, and airway smooth muscle functions. The complexity of sphingolipid biology is generated by a great variety of compounds, diverse receptors, and often antagonistic functions of different sphingolipids. For instance, apoptosis is promoted by ceramide and prevented by S1P, and pulmonary vascular permeability is increased by S1P2/3 receptors and by ceramide, whereas S1P1 receptors stabilize barrier integrity. Several enzymes of the sphingolipid metabolism respond to external stimuli such as sphingomyelinase isoenzymes that are activated by many stress stimuli and the sphingosine kinase isoenzymes that are activated by allergens. The past years have provided increasing evidence that these processes contribute to pulmonary disorders including asthma, chronic obstructive pulmonary disease, acute lung injury, and cystic fibrosis. Sphingolipid metabolism offers several novel therapeutic targets for the treatment of lung diseases such as emphysema, asthma, cystic fibrosis, respiratory tract infection, sepsis, and acute lung injury.     

„Fibrinogen Hannover“, ein weiteres atypisches Fibrinogen

Zusammenfassung Es wird über eine weitere Fibrinogenvariante — Fibrinogen Hannover — berichtet.Es handelt sich um eine fakultative hämorrhagische Diathese mit der von anderen Dysfibrinogenämien her bekannten Verminderung des gerinnbaren Fibrinogens bei normaler Fibrinogenkonzentration in den immunologischen Testen, bei Hitzefällung und im Staphylokokken-Klumpungstest. Auch hier waren bei Verwendung von Thrombin und thrombinähnlichen Enzymen die Gerinnungszeiten verlängert und ein Hemmeffekt auf die Fibrinbildungsgeschwindigkeit eines normalen Plasmas nachweisbar. Eine Störung der Plasminwirkung in vitro fand sich nicht.

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Summary Another abnormal fibrinogen — fibrinogen Hannover — is reported.As known from most dysfibrinogenemias the clottability is poor, while immunologic tests, heat precipitating test and the staphylococcal clumping test give normal fibrinogen concentrations. The clotting time when using thrombin or thrombin like enzymes is prolonged, it can be corrected with high thrombin concentrations or thrombin combined with calcium ions, but not with thrombin like enzymes combined with calcium ions. The mild bleeding diathesis was first noted when the patient underwent an operation.

     

Effect of diabetes on metabolism of 5-hydroxytryptamine by rat lungs perfused in situ

The effect of diabetes induced by treatment of rats with streptozotocin on metabolism of circulating 5-hydroxytryptamine (5HT) was investigated using an in situ lung perfusion preparation. Tissue uptake of 5HT and production of its metabolite, 5-hydroxyindolacetic acid, were unaffected in lungs of diabetic animals provided 2 or 20 microM exogenous 5HT. At constant perfusion pressure, pulmonary flow was not altered by substrate concentration or by streptozotocin treatment. Thus, in the experimental models of diabetes used, metabolism of circulating 5HT by the pulmonary endothelium remained unaffected.     

Platelet Alpha-granular Fibrinogen

Platelets contain approximately 3% of the total circulating pool of fibrinogen (fg). Immunofluorescence and subcellular fractionation reveal that platelet fg is stored within intracellular structures which have been confirmed as α-granules by immunoelectronmicroscopy. The nature, origin(s) and possible function(s) of α-granular fg have long been a point of controversy. Many early investigations into the properties of platelet fg were constrained by proteolysis, plasma fg contamination and lack of knowledge of γ-chain heterogeneity. Later studies on the biochemistry and origins of α-granular proteins resulted in the general consensus that platelet fg was not only identical to the major form within plasma but was almost certainly biosynthesised within the platelet precursor cell, the megakaryocyte (MK). However, the recent discovery of endocytic and pinocytic pathways within both MKs and platelets has requestioned the origin of many α-granular proteins, including fg, resulting in reappraisal of early data, and a series of experiments which culminated in the study of fg mRNA expression in purified MKs and platelets. These studies suggest that α-granular fg is derived from the plasma pool via a Gp IIb/IIIa mediated endocytic mechanism.     

Fibrinogen clearance from the pulmonary interstitium

Previous experiments demonstrated that 125I-human fibrinogen (125-RIF) instilled into the distal airway of the right lower lobe in intact dogs passed through the microairway into the interstitium. This report analyzed the subsequent interstitial clearance of this fibrinogen by analyzing plasma and lymph samples for 125I activity. This activity was separated into clottable, and trichloroacetic acid (TCA) insoluble and soluble components. Clottable and TCA-insoluble 125-RIF in the same ratio appeared in lymph from the right lymphatic duct (RD) and thoracic duct (TD). From standard mixing equations we calculate that 1.4 times as much lymph from the right lower lobe flows into the TD as into the RD. With one exception, clottable 125-RIF appeared in plasma only in the absence of an RD; this suggested the presence of accessory lymphatico-venous communications rather than back flux of 125-RIF at the capillary wall. By injecting 131I-human fibrinogen intravenously, we observed a small reduction in clottability (maximum of 10%) in lymph both from the RD and TD. Equilibration in RD lymph was only 1/5 as fast as albumin, and from the measured equilibration rate constant, and the assumption that interstitial fibrinogen clearance is entirely convective, we estimate that the pulmonary interstitial distribution volume for fibrinogen is 70% that for albumin. Non dialyzable 125-RIF products generated in the distal airway adhered to intracapillary, circulating erythrocytes. These products retained fibrinogen antigenicity, and appeared to be further degraded in the vascular compartment.     

Innate immunity in the lungs

Innate immunity is a primordial system that has a primary role in lung antimicrobial defenses. Recent advances in understanding the recognition systems by which cells of the innate immune system recognize and respond to microbial products have revolutionized the understanding of host defenses in the lungs and other tissues. The innate immune system includes lung leukocytes and also epithelial cells lining the alveolar surface and the conducting airways. The innate immune system drives adaptive immunity in the lungs and has important interactions with other systems, including apoptosis pathways and signaling pathways induced by mechanical stretch. Human diversity in innate immune responses could explain some of the variability seen in the responses of patients to bacterial, fungal, and viral infections in the lungs. New strategies to modify innate immune responses could be useful in limiting the adverse consequences of some inflammatory reactions in the lungs.