Dextran Anaphylaxis Research Articles

Micropuncture measurements of interstitial fluid pressure in rat nasal mucosa during early inflammatory reactions.

Interstitial fluid pressure (Pif) has been studied in rat nasal mucosa during early inflammatory reactions induced by dextran anaphylaxis and local application of histamine. Pif was measured by using sharpened micropipettes connected to a servo-controlled counterpressure system. Access to the nasal mucosa was obtained from the facial side of the head through a small cavity drilled in the nasal bone. During dextran anaphylaxis, Pif increased significantly from control values of 2.2 +/- 0.4 to 3.8 +/- 0.21 mmHg (P < 0.05) within 1 h. Corresponding Pif values for histamine were 1.6 +/- 0.9 and 2.9 +/- 0.9 mmHg (P < 0.05), respectively. These measurements support the hypothesis that a major driving force for the rapid exudation across inflamed respiratory mucosa is a hydrostatic pressure gradient created by increased mucosa Pif. When the transvascular fluid shifts accompanying the inflammatory reactions are prevented by circulatory arrest, Pif decreased significantly to subatmospheric values, -0.8 +/- 0.8 and -3.3 +/- 1.2 mmHg in the dextran and histamine group, respectively (P < 0.05). The decrease in Pif in the nasal mucosa after inflammatory stimuli, during circulatory arrest, provides further evidence for "active" modulation of Pif through changes in mechanical properties of the interstitial matrix. The decrease in Pif seen under these circumstances reveals a possible mechanism participating in the rapid and initial edema formation after inflammatory provocations.

Hydroxyethyl starch antibodies in humans: incidence and clinical relevance.

Hydroxyethyl starch (HES) is a plasma expander used for perioperative i.v. fluid management, as well as for resuscitation from trauma and shock. HES is very well tolerated, and the incidence of anaphylactic reactions is lower than with dextran or gelatin. Dextran anaphylaxis is caused by circulating dextran-reactive antibodies (ABs) of the immunoglobin G (IgG) class found in most adults. Histamine release from mast cells induces adverse reactions after gelatin infusion. The cause of adverse reactions due to HES is not yet clear. To investigate AB formation due to HES, we collected sera of 1004 patients at least 14 days after starch administration. Using a highly sensitive enzyme-linked immunoabsorbent assay technique, we found one patient with a low 1:10 titer of HES-reactive ABs (immunoglobin M [IgM] class). Despite repeated HES infusions, no clinical reaction could be detected in this patient. On the basis of a binomial distribution, a one-tailed confidence interval (99%) was used to calculate the percentage of the occurrence of ABs in general with maximum of 33 in 10,000 persons (IgM) and 23 in 10,000 persons (IgG). We suggest that HES-reactive ABs are extremely rare and that they do not necessarily induce anaphylaxis. Other mechanisms may be responsible for adverse reactions due to HES. The frequency of antibody formation due to hydroxyethyl starch, a commonly used plasma expander, was prospectively investigated in 1004 patients. Only one patient showed transient antibody formation, which was not harmful to the patient. This low antigenicity could explain the excellent tolerance of hydroxyethyl starch compared with other plasma expanders.

α-Trinositol prevents increased negativity of interstitial fluid pressure in rat skin and trachea induced by dextran anaphylaxis

The new anti-inflammatory agent α-trinositol ( d-myo-inositol-1,2,6-trisphosphate), is suggested to act on the cellular adhesion receptor towards extracellular matrix components, the β 1-integrins, and may therefore represent a novel principle for therapy of the phenomena associated with acute inflammation. Increased negativity of interstitial fluid pressure ( p if) is a major driving force for the rapid edema formation in trachea and skin associated with dextran anaphylaxis in the rat. We therefore used this experimental model to study the effect of α-trinositol in skin and trachea of pentobarbital anesthetized rats. p if was measured with sharpened glass capillaries (3–7 μm) connected to a servocontrolled counterpressure system. α-Trinositol (10 mg) was given before or after dextran. Circulatory arrest was induced 2 min after i.v. dextran to limit the increased capillary fluid filtration associated with the anaphylactic reaction. This increased filtration will otherwise raise interstitial volume and thereby p if and cause an underestimation of a potential increased negativity of p if. In the trachea, p if was 0.0±1.0 mmHg (S.D.) and −1.4±0.5 mmHg in controls given saline vehicle and α-trinositol ( P>0.05), respectively, and fell to −8.5±2.7 mmHg after dextran ( P<0.01). α-Trinositol given 2 min prior to or after dextran resulted in p if of −1.7±1.2 mmHg ( P>0.05 versus control, P<0.01 versus dextran) and −4.7±3.0 mmHg ( P<0.01 versus control and dextran), respectively. In skin, i.v. dextran caused p if to fall from −0.6±0.5 to −4.6±1.9 mmHg ( P<0.001). When α-trinositol was given prior to dextran the corresponding figures were −0.4±0.8 and −0.9±1.1 mmHg, respectively ( P>0.05). Subdermal administration of α-trinositol after i.v. dextran and circulatory arrest normalized p if in concentration of 100, 10 and partly at 1 mg/ml. Thus, α-trinositol prevented the increased negativity of p if induced by dextran anaphylaxis when administered prior to as well as after dextran showing that the α-trinositol also could influence an already started inflammatory reaction.

Prevention of dextran anaphylaxis. Ten years experience with hapten dextran.

Prevention of dextran anaphylaxis. Ten years experience with hapten dextran.

A novel physiological function for platelet-derived growth factor-BB in rat dermis.

1. The present experiments describe a role for platelet-derived growth factor-BB and cellular adhesion receptors towards extracellular matrix molecules (beta 1-integrins) in control of interstitial fluid pressure (Pif). 2. Pif was measured in rat skin with sharpened glass capillaries (3-7 microns) connected to a servocontrolled counter-pressure system. 3. The collagen and laminin-binding alpha 2 beta 1-integrin is involved in the control of Pif since subdermal injection (5 microliters) of monoclonal hamster anti-rat alpha 2 beta 1-integrin IgG (anti-alpha 2 beta 1) resulted in increased negativity of Pif. Control Pif averaged -0.88 +/- 0.23 mmHg (+/- S.D.) and decreased to -2.50 +/- 0.35 mmHg (P < 0.05) and -3.88 +/- 1.45 mmHg (P < 0.05) at anti-alpha 2 beta 1 concentrations of 0.56 and 1.12 mg ml-1, respectively. 4. The effect of anti-alpha 2 beta 1 was abolished when platelet-derived growth factor-BB (PDGF-BB) (200 ng ml-1) was injected together with anti-alpha 2 beta 1. 5. The time- and dose-responses of PDGF-BB to counteract increased negativity of Pif were studied further using dextran anaphylaxis as an experimental model inducing increased negativity of Pif in skin. Control Pif averaged -0.33 +/- 0.43 mmHg and fell to -4.10 +/- 1.47 mmHg within 10 min after dextran (P < 0.01). Subsequent subdermal injection of PDGF-BB at 200 ng ml-1 normalized Pif in 10-20 min which became -1.37 +/- 1.23 mmHg (P < 0.01 versus dextran, P > 0.05 versus control). PDGF-BB had little or no effect at 50 ng ml-1. PDGF-AA and basic fibroblast growth factor had no effect on Pif. 6. The in vivo function reported for PDGF-BB has not been described previously and provides further evidence for active participation of connective tissue cells in control of Pif by altering tension on extracellular matrix structures.

The relationship between interstitial fluid pressure and volume in rat trachea.

A change of interstitial fluid volume (IFV) will normally change the interstitial fluid pressure (Pif) so as to counteract further fluid movement across the capillaries and changes in IFV. Contrary to this, several acute inflammatory reactions in the trachea are associated with increased negativity of Pif, which will 'actively' generate oedema. To outline further the role of Pif in interstitial fluid balance in the trachea, interstitial compliance (delta IFV/delta Pif) was measured in pentobarbital anaesthetized rats. IFV was measured as the plasma equivalent extravascular distribution space of [51Cr]EDTA. Pif was measured in the same animal with sharpened glass pipettes (diameter 3-6 microns) connected to a servocontrolled counterpressure system. In dehydration (30 mL saline i.v., n = 10) interstitial compliance was 0.083 mL g dry wt-1 mmHg-1. Since control IFV was 1.046 mL g dry wt-1 (n = 10) the interstitial compliance is 8% of IFV per mmHg. In overhydration (30 mL NaCl, n = 10) and dextran anaphylaxis (1 mL dextran 70, n = 10) compliance remained the same for the first 15% increase in IFV and then increased several-fold since Pif did not increase more than 2 mmHg above control level. The increased negativity of Pif by -10 mmHg associated with acute inflammation will require a reduction of IFV by 80% when interstitial compliance is 8% per mmHg. A more likely explanation is therefore that structural rearrangements are responsible for the events leading to increased negativity of Pif in acute inflammation.

Neurogenic inflammation in rat trachea is accompanied by increased negativity of interstitial fluid pressure.

The present experiments were performed to investigate whether neurogenic inflammation in rat trachea (with edema formation and protein extravasation when the circulation is intact) induced by electrical field stimulation of neuropeptide-containing C fibers in the vagal nerve is accompanied by increased negativity of interstitial fluid pressure (P(if)). Increased negativity of P(if) in the trachea occurs in dextran anaphylaxis and mast cell degranulation and facilitates edema formation under these circumstances. Experiments were performed after circulatory arrest had been induced in pentobarbital anesthesia to prevent edema formation, which will raise P(if) and potentially cause underestimation of an increased negativity of P(if). After induction of circulatory arrest, the vagal nerve was isolated and placed in a stimulating electrode. The trachea was then exposed and covered with mineral oil, and measurement of P(if) was started as soon as possible thereafter. P(if) was measured with sharpened glass capillaries (tip diameter, 3 to 7 microns) connected to a servocontrolled counterpressure system. P(if) in the control group (n = 12) did not change throughout the observation period. Electrical stimulation of the left vagal nerve caused P(if) to fall in all experiments, from -1.1 +/- 1.1 mm Hg in the control condition to an average of -10.6 +/- 3.4 mm Hg (n = 9, P < .01). In some experiments, a continuous recording of P(if) was obtained, showing that the reduction of P(if) started within 30 seconds after onset of stimulation to reach and later remain at a stable level within a few minutes. The experimental protocol was repeated after the C fibers had been nearly depleted of neuropeptides with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)

Hapten inhibition of dextran anaphylaxis. Nine years of post-marketing surveillance of dextran 1

All spontaneous reports to the manufacturer and to WHO's database INTDIS regarding adverse reactions to clinical dextran after preinjection of dextran 1 and to dextran 1 alone 1983–1991 were collected. During 1983–1991 a total of 4.8 million doses of Promit ® were sold in fourteen countries. The incidence of severe DIAR (grades III–V) to clinical dextran after the prophylactic use of hapten inhibition was approximately one case per 200,000 doses of dextran 1. In Sweden, where reporting of severe adverse drug reactions is mandatory, the incidence was one case per 70,000. This indicates a 35-fold reduction in the incidence of severe DIAR compared with the use of clinical dextran without dextran 1. Only two fatal reactions were reported ; the incidence was therefore one case per 2.4 million doses, indicating a 77-fold reduction. Both these occurred in patients with extremely high titers of DRA. Side effects to dextran 1, mostly mild, were reported in one case per 100,000 doses. These side effects were not antibody mediated. It is concluded that the introduction of hapten inhibition with dextran 1 has greatly reduced the risk for serious side effects to dextran, making dextran one of the safest colloids in use.

Increased negativity of interstitial fluid pressure in rat trachea in dextran anaphylaxis.

This study shows that, in rat trachea, dextran anaphylaxis is associated with increased negativity of interstitial fluid pressure (Pif) as measured with sharpened glass capillaries (tip diameter 3-7 microns) connected to a servo-controlled counterpressure system. Experiments were carried out in pentobarbital-anesthetized Wistar-Møller rats. Pif in the control situation was -2.5 +/- 0.38 (SD) mmHg. The mean pressure in animals killed 2 min after initiation of the anaphylactic reaction by injection of 1 ml of 10% Dextran 70 in 0.9% NaCl was -10.3 +/- 2.6 mmHg. In another experimental series, interstitial fluid volume was measured after dextran administration but without inducing circulatory arrest. Interstitial fluid volume increased from 0.94 +/- 0.16 to 1.56 +/- 0.42 ml/g dry wt after 10 min to 1.57 +/- 0.30 and 1.10 +/- 0.27 ml/g dry wt after 30 and 60 min, respectively. The increased negativity in Pif in tracheal mucosa in the early phase of dextran anaphylaxis will markedly increase the transcapillary net filtration pressure in the initial phase of edema development.

Hapten inhibition and dextran anaphylaxis

Hapten inhibition with dextran 1 has been used in Sweden since 1982 to prevent severe anaphylactic reactions to dextran. This has led to a reduction in the reports of severe reactions to dextran from 22 per 100,000 units of dextran used between 1975 and 1979, to 1.2 per 100,000 units between 1983 and 1985. The number of fatal reactions decreased from 23 to one. More than 600,000 units of dextran were used during each period.

Hapten Inhibition in the Dextran Antidextran System and Its Application to Prevent Dextran Anaphylaxis in Man

Hapten Inhibition in the Dextran Antidextran System and Its Application to Prevent Dextran Anaphylaxis in Man

Built-in hapten inhibition of anaphylaxis by the low molecular weight subfractions of a B 512 dextran fraction of MW 3,400.

(1) Passive antidextran dextran anaphylaxis was produced in guinea pigs challenged with B 512 dextran fractions or subfractions. By Sephadex separation of a weakly anaphylactogenic parent dextran fraction of weight average molecular weight (M&lt;sub&gt;w&lt;/sub&gt;) 3,400 subfractions of widely varying M&lt;sub&gt;w&lt;/sub&gt; and anaphylactogenicity were obtained. (2) The weakly anaphylactogenic parent fraction produced no mortality, whereas its most anaphylactogenic subfraction produced 80% mortality. Calculations showed, that the parent dextran fraction was composed of non- or weakly anaphylactogenic and strongly anaphylactogenic subfractions, occurring in a molar ratio of 3:1. (3) Built-in hapten inhibition was thus exerted within the parent dextran fraction by its low molecular weight subfractions, reducing the anaphylactogenicity of the higher molecular subfractions. Generally, the lower the average molecular weight of a homopolymer fraction, the more pronounced should be the effect of built-in inhibition. (4) It is proposed to designate this built-in hapten inhibition of fractions of dextran or other homopolymers as ‘inherent’ hapten inhibition, in contrast to that produced by adding low molecular, non-anaphylactogenic fractions to higher molecular, anaphylactogenic fractions upon challenge of sensitized animals.

Hapten inhibition of passive antidextran dextran anaphylaxis in guinea pigs. Role of molecular size in anaphylactogenicity and precipitability of dextran fractions.

High titred antidextran antisera have been raised in rabbits by prolonged immunization with soluble conjugates between isomaltose oligosaccharides or dextran m&lt;sub&gt;w&lt;/sub&gt; 4,400 and bovine serum albumin in complete Freund’s adjuvant. Guinea pigs sensitized with such antisera exhibited anaphylactic shock on i.v. challenge with fractions of hydrolyzed B512 dextran. The severity of anaphylaxis depended on the amount of sensitizing antibody and the dose and molecular size of the challenging dextran fraction. In maximally sensitized animals, fractions of m&lt;sub&gt;w&lt;/sub&gt; 3,600 or larger were anaphylactogenic and smaller molecular size fractions were nonanaphylactogenic. In submaximally sensitized animals, dextran fractions of m&lt;sub&gt;w&lt;/sub&gt; 10,500 or less were foundnonanaphylactogenic. In addition, nonanaphylactogenic dextran fractions produced desensitization, i.e. protection from anaphylaxis due to subsequent or simultaneous injection of more high molecular and anaphylactogenic dextran fractions. When the molar ratio in a mixture of nonanaphylactogenic/anaphylactogenic fractions was about 7.6, protection was complete with reduction of mortality from 100 to 0%. A molar ratio of 1.9, corresponding to a 13-percent by weight admixture of nonanaphylactogenic dextran, still significantly reduced mortality from 100 to 50%. From the ability to form precipitates with antidextrans and to elicit anaphylaxis in sensitized guinea pigs, and from the absence of these properties, the approximate molecular size range of bivalent and monovalent dextran B512 fractions was found to correspond to m&lt;sub&gt;w&lt;/sub&gt; 3,600 and m&lt;sub&gt;w&lt;/sub&gt; 1,430, respectively. The practical applicability of hapten inhibition is discussed.