[Hot topics in obstetric anesthesia]. / "Hot topics" aus der geburtshilflichen Anästhesie.

In 2019 the annual conference of the scientific working group on obstetric anesthesiology of the German Society of Anesthesiology and Intensive Care Medicine (DGAI) took place in the usual manner. Emergency situations, such as the challenge of a preclinical birth or the recognition and treatment of an amniotic fluid embolism were discussed. In addition, topics on the correct treatment of a female patient with a known addictive disorder were of great interest as well as the discussion on the question when a transfusion should be performed in postpartum anemia and which risks accompany the increasing prevalence of obesity, especially during pregnancy. A further hot topic was the deliberation on the prevalence and differential diagnostic clarification of neurological complications after epidural anesthesia. In connection with the topic of birth, exciting and practice relevant topics for all anesthetists confronted with this field were presented and discussed. The essential aspects are summarized in this article.

A numerical simulation of neural fields on curved geometries.

Despite the highly convoluted nature of the human brain, neural field models typically treat the cortex as a planar two-dimensional sheet of ne;urons. Here, we present an approach for solving neural field equations on surfaces more akin to the cortical geometries typically obtained from neuroimaging data. Our approach involves solving the integral form of the partial integro-differential equation directly using collocation techniques alongside efficient numerical procedures for determining geodesic distances between neural units. To illustrate our methods, we study localised activity patterns in a two-dimensional neural field equation posed on a periodic square domain, the curved surface of a torus, and the cortical surface of a rat brain, the latter of which is constructed using neuroimaging data. Our results are twofold: Firstly, we find that collocation techniques are able to replicate solutions obtained using more standard Fourier based methods on a flat, periodic domain, independent of the underlying mesh. This result is particularly significant given the highly irregular nature of the type of meshes derived from modern neuroimaging data. And secondly, by deploying efficient numerical schemes to compute geodesics, our approach is not only capable of modelling macroscopic pattern formation on realistic cortical geometries, but can also be extended to include cortical architectures of more physiological relevance. Importantly, such an approach provides a means by which to investigate the influence of cortical geometry upon the nucleation and propagation of spatially localised neural activity and beyond. It thus promises to provide model-based insights into disorders like epilepsy, or spreading depression, as well as healthy cognitive processes like working memory or attention.

[Acute perioperative hemodilution without using hydroxyethyl starch : hemodynamic alterations under "controlled" hypovolemia]. / Akute perioperative Hämodilution ohne Verwendung von Hydroxyethylstärke : Hämodynamische Veränderungen unter "kontrollierter" Hypovolämie.

BACKGROUND: Up to now hydroxyethyl starch preparations have frequently been used to compensate for volume deficits accompanying blood withdrawal during acute normovolemic hemodilution. This approach was questioned with respect to the current limitations for use of hydroxyethyl starch solutions imposed by the European Medicines Agency. Because crystalloids distribute evenly across the whole extracellular compartment, 80 % of the infused solution will be "lost" to the interstitial space. Thus, a physiological adjustment of blood loss caused by hemodilution with crystalloids alone (1:5 ratio) seems hardly feasible and according to current data perhaps not even desirable. A 3:1 ratio (crystalloids versus blood loss) as applied in the current study can be regarded as a practical compromise between physiological needs and recommendations according to the literature (1.4:1) but will lead to moderate hypovolemia the hemodynamic consequences of which are not well described. AIM: The current study investigates the hemodynamic impact of a hemodilution with crystalloids under the precondition of a 3:1 substitution ratio compared to withdrawn blood. METHODS: In the context of acute perioperative hemodilution 10 otherwise healthy women graded I and II on the American Society of Anesthesiologists (ASA) classification scheduled for open gynecological cancer surgery underwent an average blood withdrawal of 1097 ± 285 ml which was substituted by an average of 3430 ± 806 ml of Ringer's lactate. The resulting deficit in blood volume was exactly quantified by a double tracer technique. Hemodynamic changes were evaluated by a combination of thermodilution and pulse contour analysis (PiCCO system®). Subsequently, the remaining volume deficit was compensated by 245 ± 64 ml of a 20 % albumin solution and hemodynamic parameters were again evaluated. RESULTS: When infusing Ringer's lactate in a 3:1 ratio compared to the actual blood loss, the blood volume decreased by 12 %. The volume effect of Ringer's lactate proved to be 17 %. While mean arterial pressure and heart rate remained constant, key hemodynamic parameters changed relevantly during the time course. A significant rise in cardiac output and myocardial contractility could be observed which was accompanied by a decrease in systemic vascular resistance. In contrast, cardiac preload and the parameters representing pulmonary vascular permeability remained unaltered. The infusion of 245 ± 64 ml of a 20 % albumin solution nearly completely restituted blood volume and led to an insignificant rise in systemic vascular resistance but did not normalize cardiac output or myocardial contractility. CONCLUSION: In the study population, the loss of intravascular fluid during perioperative haemodilution could be compensated by an increase in cardiac performance. However, whether patients with a reduced cardiac capacity (i.e. older patients) are capable to improve their cardiac output sufficiently in order to compensate hypovolemia accompanying perioperative haemodilution with crystalloids remains questionable.

Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.

BACKGROUND: Despite many clinical trials and investigative efforts to determine appropriate therapeutic intervention(s) for shock, this topic remains controversial. The use of i.v. fluid has represented the cornerstone for the treatment of hypoperfusion for two centuries. METHODS: As a part of International Acute Dialysis Quality Initiative XII Fluids Workgroup meeting, we sought to incorporate recent advances in our understanding of vascular biology into a more comprehensive yet accessible approach to the patient with hypoperfusion. In this workgroup, we attempted to develop a framework that incorporates key aspects of the vasculature into a diagnostic approach. RESULTS: The four main components of our proposal involve the assessment of the blood flow (BF), vascular content (vC), the vascular barrier (vB), and vascular tone (vT). Any significant perturbation in any of these domains can lead to hypoperfusion at both the macro- and micro-circulatory level. We have termed the BF, vC, vB, and vT diagnostic approach the vascular component (VC) approach. CONCLUSIONS: The VC approach to hypoperfusion has potential advantages to the current diagnostic system. This approach also has the distinct advantage that it can be used to assess the systemic, regional, and micro-vasculature, thereby harmonizing the approach to clinical vascular diagnostics across these levels. The VC approach will need to be tested prospectively to determine if this system can in fact improve outcomes in patients who suffer from hypoperfusion.

Dynamical energy analysis for built-up acoustic systems at high frequencies.

Standard methods for describing the intensity distribution of mechanical and acoustic wave fields in the high frequency asymptotic limit are often based on flow transport equations. Common techniques are statistical energy analysis, employed mostly in the context of vibro-acoustics, and ray tracing, a popular tool in architectural acoustics. Dynamical energy analysis makes it possible to interpolate between standard statistical energy analysis and full ray tracing, containing both of these methods as limiting cases. In this work a version of dynamical energy analysis based on a Chebyshev basis expansion of the Perron-Frobenius operator governing the ray dynamics is introduced. It is shown that the technique can efficiently deal with multi-component systems overcoming typical geometrical limitations present in statistical energy analysis. Results are compared with state-of-the-art hp-adaptive discontinuous Galerkin finite element simulations.

Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury.

BACKGROUND: Healthy vascular endothelium is coated by the glycocalyx, important in multiple endothelial functions, but destroyed by ischaemia-reperfusion. The impact of volatile anaesthetics on this fragile structure has not been investigated. We evaluated the effect of cardiac pre- and post-conditioning with sevoflurane on integrity of the endothelial glycocalyx in conjunction with coronary vascular function. METHODS: Isolated guinea pig hearts perfused with Krebs-Henseleit buffer underwent 20 min stopped-flow ischaemia (37 degrees C), either without or with 1 MAC sevoflurane. This was applied for 15 min before, for 20 min after, or both before and after ischaemia. Transudate was collected for assessing coronary net fluid extravasation and histamine release by mast cells. Coronary release of syndecan-1 and heparan sulphate was measured. In additional experiments with and without continuous sevoflurane, cathepsin B and tryptase beta-like protease activity were measured in effluent. Hearts were perfusion-fixed to visualize the endothelial glycocalyx. RESULTS: Ischaemia led to a significant (P<0.05) increase by 70% in transudate formation during reperfusion only in hearts without sevoflurane. This was accompanied by significant (P<0.05) increases in heparan sulphate (four-fold) and syndecan release (6.5-fold), with electron microscopy revealing massive degradation of glycocalyx. After ischaemia, histamine was released into transudate, and cathepsin B activity increased in effluent (P<0.05). Sevoflurane application attenuated all these changes, except for histamine release. CONCLUSIONS: Sevoflurane protects the endothelial glycocalyx from ischaemia-reperfusion-induced degradation, with both preconditioning and rapid post-conditioning being successful. The mechanism seems to involve attenuation of lysosomal cathepsin B release and to be independent from tissue mast cell degranulation.

Functional involvement of protein kinase C-betaII and its substrate, myristoylated alanine-rich C-kinase substrate (MARCKS), in insulin-stimulated glucose transport in L6 rat skeletal muscle cells.

AIMS/HYPOTHESIS: Insulin stimulates phosphorylation cascades, including phosphatidylinositol-3-kinase (PI3K), phosphatidylinositol-dependent kinase (PDK1), Akt, and protein kinase C (PKC). Myristoylated alanine-rich C-kinase substrate (MARCKS), a PKCbetaII substrate, could link the effects of insulin to insulin-stimulated glucose transport (ISGT) via phosphorylation of its effector domain since MARCKS has a role in cytoskeletal rearrangements. METHODS: We examined phosphoPKCbetaII after insulin treatment of L6 myocytes, and cytosolic and membrane phosphoMARCKS, MARCKS and phospholipase D1 in cells pretreated with LY294002 (PI3K inhibitor), CG53353 (PKCbetaII inhibitor) or W13 (calmodulin inhibitor), PI3K, PKCbetaII and calmodulin inhibitors, respectively, before insulin treatment, using western blots. ISGT was examined after cells had been treated with inhibitors, small inhibitory RNA (siRNA) for MARCKS, or transfection with MARCKS mutated at a PKC site. MARCKS, PKCbetaII, GLUT4 and insulin receptor were immunoblotted in subcellular fractions with F-actin antibody immunoprecipitates to demonstrate changes following insulin treatment. GLUT4 membrane insertion was followed after insulin with or without CG53353. RESULTS: Insulin increased phosphoPKCbetaII(Ser660 and Thr641); LY294002 blocked this, indicating its activation by PI3K. Insulin treatment increased cytosolic phosphoMARCKS, decreased membrane MARCKS and increased membrane phospholipase D1 (PLD1), a protein regulating glucose transporter vesicle fusion resulted. PhosphoMARCKS was attenuated by CG53353 or MARCKS siRNA. MARCKS siRNA blocked ISGT. Association of PKCbetaII and GLUT4 with membrane F-actin was enhanced by insulin, as was that of cytosolic and membrane MARCKS. ISGT was attenuated in myocytes transfected with mutated MARCKS (Ser152Ala), whereas overproduction of wild-type MARCKS enhanced ISGT. CG53353 blocked insertion of GLUT4 into membranes of insulin treated cells. CONCLUSIONS/INTERPRETATION: The results suggest that PKCbetaII is involved in mediating downstream steps of ISGT through MARCKS phosphorylation and cytoskeletal remodelling.

Impact of polyclonal anti-thymocyte globulins on the expression of adhesion and inflammation molecules after ischemia-reperfusion injury.

BACKGROUND: Polyclonal anti-thymocyte globulins (ATGs) are immunosuppressive agents used for the treatment and prevention of acute organ rejection after transplantation. ATGs induce apoptosis and complement-mediated cell death in peripheral T-lymphocytes and have shown a reduction of leukocyte adhesion after ischemia-reperfusion (IRI). We analyzed the impact of different ATGs upon the expression of adhesion and inflammation molecules after IRI. MATERIALS AND METHODS: The major arteries and veins of the extremities of cynomolgus monkeys were surgically isolated and flushed with Ringer's lactate at 4 degrees C. After 60 min of ischemia the limbs were reperfused with matching human blood. ATGs were added to the blood 30 min prior to the reperfusion, forming four groups: Tecelac-ATG group (n=16), Fresenius(S)-ATG group (n=16), Thymoglobulin-ATG group (n=12) and a control group (n=16). Biopsies from muscular tissue were obtained after the experiments. The expression of adhesion (ICAM-1, VCAM, PECAM, CD11b, CD62E) and inflammation (IL-1, IL-6, TNF-alpha) molecules on endothelium, leukocytes, and reperfused tissue was analyzed by means of immunohistochemistry. RESULTS: The expression of the studied adhesion molecules (ICAM-1, VCAM, PECAM, CD11b, and CD62E) was significantly increased in the control group when compared with the treated groups. The expression of IL-1, IL-6, and TNF-alpha was reduced in the ATG-groups in comparison to the control group. DISCUSSION: Our results showed that ATGs caused a reduction of the expression of adhesion and inflammation molecules both in endothelium and reperfused tissue. The inhibition of the expression of molecules required for firm cellular adhesion, may contribute to decreasing cellular graft infiltration after post-ischemic reperfusion.

A Burton-Miller inverse boundary element method for near-field acoustic holography.

An inverse boundary element method based on the Burton-Miller integral equation is proposed for reconstructing the Neumann boundary data from pressure values on a conformal surface in the near-field of an arbitrary radiating object. The accuracy of the reconstruction is compared with that of a method based on the more commonly used Helmholtz integral equation. In particular, the behavior at characteristic frequencies, which are known to be problematic in the Helmholtz integral equation for the forward problem, is examined. The effect of regularization is considered, including the L-curve parameter selection method. Numerical computations are given for noisy data generated from an internal point source.

[Methylnaltrexone. A new approach for therapy of opioid-induced obstipation]. / Methylnaltrexon. Ein neuer Ansatz zur Therapie der opioidinduzierten Obstipation.

Chronic pain patients using opioids frequently suffer from constipation which compromises well-being. Such an opioid-induced gastro-intestinal complication can occur regularly in patients in palliative care as well as in analgesic sedated intensive care patients or during prolonged perioperative pain therapy. Discomfort and distress in the affected patients can be so severely pronounced that they would rather suffer from the pain than from the side effect of constipation. Conventional therapy can be insufficient in providing satisfactory relief of constipation, mostly because this opioid-induced bowel hypomotility can be laxative-resistant. Moreover, constipation does not decrease during the course of therapy as do other side effects. It is well known that opioid-induced constipation is mediated via activation of micro-opioid receptors in the gastrointestinal tract. Selective peripheral micro-receptor antagonists (such as methylnaltrexone, Relistor) can effectively treat opioid-induced constipation. An interference with central analgesia does not occur as the molecules cannot pass the blood-brain barrier due to their charged states. A reduction of opioid therapy or the development of withdrawal symptoms can be avoided. Studies have shown that methylnaltrexone is not only safe and efficient for chronically constipated palliative care patients but offers promising therapeutic options for further patient collectives.

[Hypernatremic alkalosis. Possible counterpart of hyperchloremic acidosis in intensive care patients?]. / Hypernatriämische Alkalose. Pendant zur hyperchlorämischen Acidose in der Intensivmedizin?

BACKGROUND: With broad acceptance of Stewart's acid-base model "hyperchloremic acidosis" is regarded as an independent form of metabolic disorder. It is unknown whether hypernatremia plays a corresponding role with respect to the development of alkalosis. METHODS: A total of 201 artificially ventilated, critically ill patients were monitored for hypernatremic episodes. Inclusion criterion was a serum sodium concentration above 145 mmol/l. RESULTS: In 20 patients a total of 78 periods of elevated plasma sodium levels lasting at least 24 h were observed. In 86% of these cases sodium and chloride concentrations were simultaneously increased. The development of alkalosis correlated with the strong ion difference (r=0.80, p<0.01) but not with the serum sodium concentration (r=-0.031, p=0.78). In cases without accompanying hyperchloremia (13%) metabolic alkalosis regularly occurred and a correlation between serum sodium concentration and base excess could be verified (r=0.66, p=0.03). Alkalosis occurred in 84.8% of cases where the strong on difference exceeded 39 mmol/l. CONCLUSION: From the available data hypernatremic alkalosis could not be defined as an independent metabolic disorder. In would seem more appropriate to use the term "strong ion alkalosis" in this context.

Blood volume is normal after pre-operative overnight fasting.

BACKGROUND: Pre-operative fasting is assumed to cause a deficit in intravascular blood volume (BV), as a result of ongoing urine production and insensible perspiration. Standard regimes consist of volume loading prior or simultaneous to any anaesthetic procedure to minimise the risk of hypotension. However, fluid overload in the context of major abdominal surgery has been shown to deteriorate patient outcome. Our study aimed to quantify total intravascular BV after fasting by direct measurements and to compare it with calculated normal values in comparable non-fasted patients. METHODS: After 10 h of fasting, total plasma volume (PV) and red cell volume (RCV) were measured via the double-label technique (indocyanine green dilution and erythrocytes labelled with fluorescein, respectively) following induction of general anaesthesia in 53 gynaecological patients suffering from malignoma of the cervix. The corresponding normal values were calculated individually from age, body height and body weight. RESULTS: Measured BV, RCV and PV after fasting were 4123+/-589, 1244+/-196 and 2879+/-496 ml, respectively. The differences to the corresponding calculated normal values were not significant (3882+/-366, 1474+/-134 and 2413+/-232 ml, respectively). The measured haematocrit reflected a slight anaemic state (0.35+/-0.03). CONCLUSION: Our data suggest that even after prolonged pre-operative fasting, cardio-pulmonary healthy patients remain intravascularly normovolaemic. Therefore, hypotension associated with induction of general or neuraxial anaesthesia should perhaps be treated with moderate doses of vasopressors rather than with undifferentiated volume loading.

Impact of the time window on plasma volume measurement with indocyanine green.

Recent reports have questioned the accuracy of the indocyanine green dilution technique for measuring plasma volume. Our objective was to evaluate the impact of different time windows for monoexponential extrapolation. We retrospectively analysed 31 indocyanine green decay curves to investigate the problem in principle (group 1) and prospectively performed another 21 plasma volume measurements to estimate its practical impact (group 2). To monoexponentially extrapolate back to the specific extinction at the time of dye injection, two different time windows were applied to each decay curve, comparing the plasma volumes resulting from sampling within a short (5 min) period of time. Extrapolating back from the longer period led to a higher apparent plasma volume relative to the shorter period in both groups, the difference being 348 +/- 171 ml (group 1) and 384 +/- 131 ml (group 2; mean +/- SD; p < 0.05 each). This result was due to a reliable monoexponentiality of decay only up to the 5th min after dye injection. Thus, to estimate the initial distribution space of indocyanine green via monoexponential extrapolation, the first linear kinetic of indocyanine green decay should be taken.

[Expedition glycocalyx. A newly discovered "Great Barrier Reef"]. / Expedition Glykokalyx. Ein neu entdecktes "Great Barrier Reef."

Healthy vascular endothelium is luminally coated by an endothelial glycocalyx, which interacts with the bloodstream and assumes a filter function on the vascular wall. Although this structure was discovered nearly 70 years ago, its physiological importance has been underestimated for a long time. Recent findings indicate that the glycocalyx is, in addition to the endothelial cells themselves, a main constituent part of the vascular barrier. The existence of different colloid osmotic gradients within and beneath this structure has now led to a modification of the Starling equation. In many vascular beds the interstitial space features a protein concentration similar to that of the plasma. The inwardly directed gradient, which retains water and proteins in the vascular system, is generated beneath the glycocalyx by selective protein filtration over this structure. The endothelial glycocalyx, as an additional competent vascular permeability barrier has, therefore, not only a key role for perioperative fluid and protein shifts into the interstitial space, but it seems to be intimately involved in the pathophysiology of diabetes, arteriosclerosis, sepsis and ischemia/reperfusion, especially with respect to associated vascular dysfunctions. The fragile glycocalyx can be destroyed in the course of surgery, trauma, ischemia/reperfusion and sepsis and by inflammatory mediators such as TNF-alpha, causing leukocyte adhesion, platelet aggregation and edema formation. Recent studies have shown that protecting this structure not only maintains the vascular barrier, but constitutes an important component of a rational perioperative fluid therapy.

Pre-beta-very low density lipoproteins as precursors of beta-very low density lipoproteins. A model for the pathogenesis of familial dysbetalipoproteinemia (type III hyperlipoproteinemia).

The physical, chemical, and receptor binding properties of very low density lipoprotein (VLDL) fractions from familial dysbetalipoproteinemic (dys-beta) subjects, homozygous for apolipoprotein (apo-) E2 (E2/2 phenotype), and subjects with the E3/3 phenotype were studied to gain insights into the pathogenesis of dysbetalipoproteinemia, a disorder characterized by the presence of beta-VLDL in the plasma. Pre-beta-VLDL from dys-beta subjects were larger (27 vs. 17 x 10(6) D) and more triglyceride rich (68 vs. 43% dry weight) than beta-VLDL. Pre-beta-VLDL predominated in the Sf greater than 100 flotation fraction, whereas beta-VLDL predominated in the Sf 20-60 fraction. Because lipolysis converts large VLDL (Sf greater than 100) in vivo to smaller, more cholesteryl ester-rich VLDL (Sf 20-60), it is likely that pre-beta-VLDL are precursors of beta-VLDL. Although beta-VLDL were not found in type V hyperlipidemic E3/3 subjects, they were induced by intravenous heparinization, suggesting that lipolysis of pre-beta-VLDL in vivo can result in beta-VLDL formation. Similarly, heparinization of a dys-beta subject produced more beta-VLDL, at the expense of pre-beta-VLDL. The pre-beta-VLDL from normolipidemic and type V hyperlipidemic E3/3 subjects, respectively, had 90 and 280 times the affinity for the apo-B,E(LDL) receptor than did the pre-beta-VLDL from dys-beta subjects. Heparin-induced beta-VLDL from type V hyperlipidemic subjects had a sixfold higher binding affinity than did heparin-induced beta-VLDL from dys-beta subjects. These data suggest that pre-beta-VLDL from E2/2 subjects interact poorly with lipoprotein receptors in vivo, decreasing their receptor-mediated clearance and increasing their conversion to beta-VLDL during lipolytic processing.

High receptor binding affinity of lipoproteins in atypical dysbetalipoproteinemia (type III hyperlipoproteinemia).

Familial dysbetalipoproteinemia (or type III hyperlipoproteinemia) is characterized by the presence of abnormal, cholesteryl ester-rich beta-very low density lipoproteins (beta-VLDL) in the plasma. Subjects with typical dysbetalipoproteinemia are homozygous for an amino acid substitution in apolipoprotein (apo-) E at residue 158 and have defective apo-E-mediated binding of both pre-beta-VLDL and beta-VLDL to apo-B,E(LDL) (or LDL) receptors (1988. Chappell, D.A., J. Clin. Invest. 82:628-639). To understand the effect of substitutions in apo-E at sites other than residue 158, nine dysbetalipoproteinemic (dys-beta) subjects who were either homozygous or heterozygous for substitutions in apo-E at atypical sites were studied. These substitutions occurred at residue 142 (n = 6), 145 (n = 2), or 146 (n = 1) and are known to cause less defective binding than does the 158 substitution. The chemical composition and electrophoretic mobility of pre-beta-VLDL and beta-VLDL from atypical and typical dys-beta subjects were indistinguishable. However, lipoproteins from atypical and typical dys-beta subjects differed in their affinity for the apo-B,E(LDL) receptor on cultured human fibroblasts. The pre-beta-VLDL and beta-VLDL from atypical dys-beta subjects had 640- or 17-fold higher affinity, respectively, than did corresponding lipoproteins from typical dys-beta subjects. The higher binding affinity of lipoproteins from atypical dys-beta subjects was associated with a higher ratio of apo-E to total apo-C. Since higher binding affinity should cause more rapid receptor-mediated clearance of beta-VLDL in atypical than in typical dys-beta subjects in vivo, the mechanism of beta-VLDL accumulation may differ in these two groups.

Very low density lipoproteins stimulate surfactant lipid synthesis in vitro.

Surfactant synthesis is critically dependent on the availability of fatty acids. One fatty acid source may be circulating triglycerides that are transported in VLDL, and hydrolyzed to free fatty acids by lipoprotein lipase (LPL). To evaluate this hypothesis, we incubated immortalized or primary rat alveolar pre-type II epithelial cells with VLDL. The cells were observed to surface bind, internalize, and degrade VLDL, a process that was induced by exogenous LPL. LPL induction of lipoprotein uptake significantly increased the rates of choline incorporation into phosphatidylcholine (PC) and disaturated PC, and these effects were associated with a three-fold increase in the activity of the rate-regulatory enzyme for PC synthesis, cytidylyltransferase. Compared with native LPL, a fusion protein of glutathione S-transferase with the catalytically inactive carboxy-terminal domain of LPL did not activate CT despite inducing VLDL uptake. A variant of the fusion protein of glutathione S-transferase with the catalytically inactive carboxy-terminal domain of LPL that partially blocked LPL-induced catabolism of VLDL via LDL receptors also partially blocked the induction of surfactant synthesis by VLDL. Taken together, these observations suggest that both the lipolytic actions of LPL and LPL-induced VLDL catabolism via lipoprotein receptors might play an integral role in providing the fatty acid substrates used in surfactant phospholipid synthesis.

Receptor-mediated mechanisms of lipoprotein remnant catabolism.

Chylomicron and VLDL are triglyceride-rich lipoprotein particles assembled by the intestine and liver respectively. These particles are not metabolized by the liver in their native form. However, upon entry into the plasma, their triglyceride component is rapidly hydrolyzed by lipoprotein lipase and they are converted to cholesterol-rich remnant particles. The remnant particles are recognized by the liver and rapidly cleared from the plasma. This process is believed to occur in two steps. (i) An initial sequestration of remnant particles on hepatic cell surface proteoglycans, and (ii) receptor-mediated endocytosis of remnants by hepatic parenchymal cells. The initial binding to proteoglycans may be facilitated by lipoprotein lipase and hepatic lipase which possess both lipid- and heparin-binding domains. The subsequent endocytic process may be mediated by LDL receptors and/or LRP. Both receptors have a high affinity for apoE, a major apolipoprotein component of remnant particles. The lipases may also serve as ligands for these receptors. An impairment of any component of this complex process may result in an accumulation of remnant particles in the plasma leading to atherosclerosis and coronary heart disease.