Intravenous Injection Of Endotoxin Research Articles

Evidence for an Essential Role of Tissue Factor Dependent Blood Coagulation in the Pathogenesis of the Local Shwartzman Reaction

ABSTRACT Adherence and aggregation of leukocytes within the vessels of a prepared skin site has been shown to be essential for the pathogenesis of the local Shwartzmanreaction (LSR)(Argenbright and Barton: J Clin Invest 89: 259, 1992). We have now performed experiments in rabbits to evaluate whether coagulation within the vessels of a prepared site is a second requirement for the reaction. Skin sites were prepared by an intradermal injection of endotoxin 24 hours before a provoking intravenous injection of endotoxin. Thirteen control rabbits all developed the LSR. Seven of 12 rabbits given warfarin to achieve anticoagulation approximating that used therapeutically in humans before the provoking injection were protected against the LSR (p=0.003). Five of ninerabbits given anti-rabbit factor X IgG before the provoking injection to yield mean values in individual rabbits of between 7% and 18% plasma factor X activity wereprotected against the LSR (p=0.009). Six of 11 rabbits given anti-rabbit factor VII IgG before the provoking injection to yield mean values in individual rabbits of between <0.5% and 2.2% were protected against the LSR (p=0.007). Four rabbits failed to develop the LSR at an endotoxin-prepared skin site when an infusion of tissue factor (TF) causing substantial intravascular coagulation was substituted for a provokinginjection of endotoxin. It would appear that two events are required for the pathogenesis of the LSR provoked by endotoxin: formation of aggregated masses of WBC in the prepared skin vessels and deposition of fibrin due to TF-initiated coagulation.

Effect of TCV-309, a novel platelet activating factor antagonist, on hemodynamics in dogs with endotoxin-induced shock.

The therapeutic effects of TCV-309, a novel platelet activating factor antagonist, on hemodynamics in endotoxin-induced shock were evaluated. Ten Beagle dogs were used under general anesthesia and artificial ventilation. After intravenous injection of endotoxin (3 mg/kg), TCV-309 (1 mg/kg) was administered intravenously to the dogs. The results showed that the depression of mean aortic pressure, cardiac output, left ventricular stroke work index and urine volume which occurred in endotoxin shock was significantly improved by administration of TCV-309. These results suggested that TCV-309 was a useful therapeutic for the circulatory disturbance in endotoxin shock.

Increased prostaglandin I 2 and thromboxane A 2 production by rat dental pulp after intravenous administration of endotoxin

The effect of systemic endotoxin (lipopolysaccharide from Escherichia coli 0111:B4) on prostaglandin I 2 (PGI 2) and thromboxane A 2 (TXA 2) production by rat dental pulp was investigated. Intravenous injection of endotoxin increased ex vivo production of both PGI 2 and TXA 2 by the pulp tissue, when determined by radioimmunossay. A significant effect on PGI 2 and TXA 2 production was observed with endotoxin doses of greater than 2 and 0.4 mg/kg, respectively. A significant increase was also observed at 30 min after injection of 10 mg/kg endotoxin, reaching a maximum after 60 min for both PG and TX production. Endotoxin (10 mg/kg for 60 min) also increased TXA 2 but not PGI 2 production in lung tissue, but had no effect in jejunal tissue. Indomethacin (10 μM) completely inhibited PGI 2 and TXA 2 production by the pulp of physiological saline- and endotoxin-treated rats. Further, arachidonic acids (10 μM) significantly increased PG and TX production by the pulp of saline- but not of endotoxin-treated rats. Endotoxin (100 μg/ml) had no in vitro effect on PG or TX production when incubated with isolated pulp, lung and jejunal tissues, suggesting that the endotoxin-induced increases in PG and TX production are an indirect effect. The endotoxin-induced increase in TXA 2 production, but not in PGI 2 production, by the pulp tissue was significantly suppressed by WEB 2170, a platelet-activating factor (PAF) antagonist. These results indicate that arachidonate metabolism in pulp tissue is susceptible to endotoxaemia in comparison with the lung and jejunum, and further suggest that the endotoxin-induced increase in, at least, TXA 2 production by the pulp is mediated by PAF.

Model for whole body production of tumour necrosis factor-alpha in experimental endotoxaemia in healthy subjects.

1. Tumour necrosis factor-alpha is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-alpha in disease in vivo. 2. In the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-alpha synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor-alpha (50 micrograms/m2) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-alpha produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-alpha (9.5 +/- 5.0 ml min-1 kg-1) and the area under the tumour necrosis factor-alpha concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor-alpha showed evident two-compartment kinetics with an initial rapid disappearance (t1/2 5.1 +/- 2.2 min) and a terminal slower elimination (t1/2 49 +/- 5 min). Tumour necrosis factor-alpha synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 micrograms (52.7 +/- 34.7 micrograms). The changes in time of the serum concentrations of tumour necrosis factor-alpha after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor-alpha production (74% of the total amount) and slow tumour necrosis factor-alpha production (26%).(ABSTRACT TRUNCATED AT 250 WORDS)

Endotoxin-induced defenestration of the hepatic sinusoidal endothelium: a factor in the pathogenesis of cirrhosis?

Defenestration and capillarisation of the hepatic sinusoidal endothelium occurs early in the pathogenesis of cirrhosis, both in patients suffering from alcohol abuse and in animal models. It is possible also that alcohol abuse promotes the absorption of bacterial endotoxins from the gastrointestinal tract. In this study we have investigated the effects of a single intravenous injection of endotoxin on the hepatic sinusoidal endothelium of rats. Seven days after the dose of endotoxin, the porosity of the sinusoidal endothelium was reduced to 40% of that of controls, due to a decrease in both diameter and number of fenestrae. The livers examined 14 days after dosing exhibited normal porosity. We postulate that bacterial endotoxins play a role in the pathogenesis of cirrhosis by modulating the fenestrated sinusoidal endothelium (liver sieve).

The fate of intravenously injected endotoxin in normal rats and in rats with liver failure

The elimination of endotoxin from the blood was studied in rats with D-galactosamine–induced liver failure and in normal controls after intravenous injection of various doses of endotoxin. Endotoxin was found to localize in liver tissue by immunohistochemical staining with factor C, which is derived from amebocyte lysate of the horseshoe crab and which reacts specifically with endotoxin. Before injection, the blood endotoxin concentrations were normal both in control rats and in rats with liver failure. The blood concentrations of endotoxin were significantly higher after intravenous injection of endotoxin in the D-galactosamine–induced liver failure group (p<0.05) and decreased much more slowly (p<0.05). Endotoxin concentrations were also significantly higher after in vitro incubation with plasma from rats with liver failure (p<0.05). After intravenous injection of endotoxin (1 mg/kg), endothelial and Kupffer cells in the liver sinusoids were positively stained for endotoxin in the control group, but not stained or faintly stained in the liver failure group. Endotoxemia in liver failure thus results from reduced inactivation of endotoxin in plasma and from impaired hepatic clearance. (HEPATOLOGY 1994;19:1251–1256.)

The fate of intravenously injected endotoxin in normal rats and in rats with liver failure

The elimination of endotoxin from the blood was studied in rats with D-galactosamine-induced liver failure and in normal controls after intravenous injection of various doses of endotoxin. Endotoxin was found to localize in liver tissue by immunohistochemical staining with factor C, which is derived from amebocyte lysate of the horseshoe crab and which reacts specifically with endotoxin. Before injection, the blood endotoxin concentrations were normal both in control rats and in rats with liver failure. The blood concentrations of endotoxin were significantly higher after intravenous injection of endotoxin in the D-galactosamine-induced liver failure group (p < 0.05) and decreased much more slowly (p < 0.05). Endotoxin concentrations were also significantly higher after in vitro incubation with plasma from rats with liver failure (p < 0.05). After intravenous injection of endotoxin (1 mg/kg), endothelial and Kupffer cells in the liver sinusoids were positively stained for endotoxin in the control group, but not stained or faintly stained in the liver failure group. Endotoxemia in liver failure thus results from reduced inactivation of endotoxin in plasma and from impaired hepatic clearance.

The distribution of 3H-labeled endotoxin in the kidney of liver cirrhotic rats.

Although the etiology and pathogenesis of progressive renal failure is largely unknown, endotoxin is supposed to be one of the contributory factors. However, the distribution of endotoxin in liver cirrhosis has not been clarified. Therefore we studied the distribution of 3H-labeled endotoxin in the kidney in rats with CCl4-induced liver injury. Daily inhalations of CCl4 on rats for 6 and 10 weeks produced liver fibrosis (LF group, N = 5) and cirrhosis (LC group, N = 5), respectively. At 6 or 10 weeks, animals were sacrificed 24 hours after an intravenous injection of endotoxin labeled with 3H at the galactose moiety (12,000 cpm/1 g body weight). In the liver, 3H-labeled endotoxin was taken up mainly by Kupffer cells as determined by autoradiography. Compared to control rats, in rats of the LC or LF group the measured amount of 3H-labeled endotoxin per gram kidney or ml blood increased, while that of the liver was significantly decreased. A positive correlation of the amount of 3H-labeled endotoxin per weight or volume respectively was shown between kidney and blood, but not between lung or spleen and blood. These results suggest that overflow of endotoxin due to decreased inactivation in the liver causes endotoxemia in liver injury and that the resulting endotoxemia may directly affect the kidney. The resulting endotoxin-induced vasoconstriction may be a contributory factor for the progressive renal failure frequently observed in liver cirrhosis.

Interleukin-6 and tumor necrosis factor in cerebrospinal fluid: changes during pyrogen fever

Several peptides (cytokines), viz., interleukin-1 (IL-1), interferon-α (IFN-α), interleukin-6 (IL-6), tumor necrosis factor (TNF), are formed in response to conditions causing tissue inflammation or damage and are implicated in reactive changes of the host, including fever, while IL-1 has been considered an important mediator of fever, the other cytokines, specifically IL-6 and TNF, have recently acquired prominence. The present study extends earlier research on IL-6 and addresses the question of the role of IL-6 and TNF in the genesis of fever. Experiments were conducted in the conscious cat, and IL-6 and TNF were assayed concomitantly in cerebrospinal fluid (CSF) from the third ventricle using specific bioassays. In the absence of fever, IL-6 was usually below the threshold of the assay (4–32 pg/ml), while TNF appeared measurable (424±57 pg/ml) in most experiments. A single intravenous injection of endotoxin (bolus) or continuous infusion of IL-1 at doses eliciting a sustained fever increased CSF levels of IL-6, but had no effect on concentrations of TNF. Intracerebroventricular injection of a pyrogenic dose of endotoxin led to an elevation of TNF and IL-6 and, in either case, the effect was manifest during the latent period before the fever. In addition, by the same route, IL-1 caused a rise in IL-6. We conclude that brain is intrinsically capable of producing both IL-6 and TNF depending on the site of challenge. However, since IL-6 CSF levels are elevated regardless of the site of pyrogen injection, IL-6 lends itself better to a role in the pathogenesis of fever.

Nuclear magnetic resonance Hahn spin-echo decay (T2) in live rats with endotoxin lung injury.

To determine the possibility of using nuclear magnetic resonance imaging to study experimentally induced lung injury, we measured in the lungs of spontaneously breathing living rats the time course of both the Hahn spin-echo decay (T2) and the proton density after endotoxin injury. In order to minimize artifacts arising from motions of the nearby chest wall and heart, we used a motion-insensitive technique (the interleaved line scan). A typical Hahn T2 measurement was obtained over a region of interest from a series of images each with a different echo time, which ranged from 16 to 110 ms. Lung water content was determined by integrating the proton density over the region of interest. The Hahn T2 and proton density were measured before and at 1, 3, 6, and 9 h after intravenous injection of endotoxin. The effects of the treatment administered before and after endotoxin injection were also evaluated. Endotoxin treatment caused lengthening of both fast (T2f) and slow (T2s) Hahn T2 components but had no significant effect on the proton density, consistent with the notion that endotoxin causes lung injury without significant lung water accumulation in rats. However, the methylprednisolone treatment prevented the lengthening of T2s but did not seem to have a significant effect on T2f. Our results suggest that NMR imaging can be used to detect and monitor experimental lung injury in intact living animals, even in the absence of variations of lung water content.

The role of induction of nitric oxide synthesis in the altered responses of jugular veins from endotoxaemic rabbits.

1. Endotoxaemia is characterized by hypotension, peripheral vasodilatation and a reduced response to vasoconstrictors. Clinical studies have indicated that venodilatation contributes to the haemodynamic changes, although there is no direct evidence for abnormal venous reactivity. In the present study, the role of nitric oxide (NO) in modifying the responses of rabbit isolated jugular veins was examined in vitro, 4 h after intravenous injection of endotoxin. 2. Treatment with endotoxin reduced the contractile response to the thromboxane-mimetic, 9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha (U-46619). This affect was endothelium-independent. The response was partially restored by the NO synthase inhibitor. NG-monomethyl-L-arginine (L-NMMA 300 microM). 3. Jugular veins from control animals did not contract to L-NMMA whereas those from endotoxin-treated animals showed concentration-dependent contractions to L-NMMA. The contractions produced by L-NMMA were reversed by L-arginine but not by D-arginine. Treatment of the animals with dexamethasone (4 mg kg-1) 1 h prior to administration of endotoxin significantly attenuated the response to L-NMMA. 4. The response to sodium nitroprusside did not differ significantly between veins from control and endotoxin-treated animals. Endothelial denudation did not alter the sensitivity of the veins to sodium nitroprusside. Acetylcholine produced endothelium-dependent relaxations which were similar in veins from control and endotoxin-treated animals. 5. The results of this study demonstrate that intravenous administration of endotoxin induces hyporesponsiveness to U-46619 in jugular veins. This effect is mediated, at least in part, by the induction of NO synthesis in smooth muscle. The induction is prevented by prior treatment with dexamethasone.

Arterial baroreflexes are not essential in mediating sympathoadrenal activation in conscious endotoxic rats

We examined the contributions of arterial baroreceptor reflexes in mediating sympathoadrenal activation during endotoxicosis. Conscious rats with chronic sinoaortic denervation (SAD) or sham-operation (SHAM) were subject to endotoxin treatment (5 mg/kg, i.v.). Hemodynamic responses, renal sympathetic nerve activity (RSNA) and plasma catecholamines were assessed at different times post endotoxin infusion. In both SAD and sham groups, intravenous endotoxin injection induced a rapid and significant sympathoadrenal activation, as indicated by a parallel elevation of RSNA and plasma catecholamines. Such activation peaked 15–30 min following endotoxin and was sustained throughout the 2–3 h protocol. The early response of the sympathoad-renal system to endotoxin is more profound in SAD rats compared to sham rats. We propose that the afferent neural input from arterial baroreceptors is not essential in mediating sympathoadrenal activation during sepsis. The elimination of feedback buffering mechanisms with SAD may account for the augmented sympathetic response seen in SAD animals.

Fever response of sheep in the peripartum period to gram-negative and gram-positive pyrogens.

We have measured body temperatures and serum iron concentrations of sheep in the peripartum period following administration of endotoxin and Staphylococcus aureus cell walls. Both the rise in rectal temperature and the fall in serum iron concentration following intravenous injection of S. aureus were the same immediately pre- and postpartum as they were 5 weeks after parturition. The rise in rectal temperature following intravenous endotoxin injection immediately pre- and postpartum was significantly less than that of the same ewes 5 weeks later. However, the fall in serum iron concentration following endotoxin injection was significantly suppressed only prepartum. We conclude that fever is not suppressed in sheep in the peripartum period, but the response to endotoxin is suppressed, through complex processes incidental to the mechanism responsible for the maintenance of gestation and induction of labour.

Effect of activated protein C on impaired fibrinolysis in rats with obstructive jaundice.

We studied the effect of activated protein C (APC) on impaired fibrinolysis using a rat model in which disseminated intravascular coagulation (DIC) is induced by the intravenous injection of endotoxin in rats with obstructive jaundice. An intravenous injection of endotoxin in rats with obstructive jaundice resulted in pulmonary hemorrhages and a marked increase in the plasma levels of tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor activity. Prophylaxis with APC before the injection of endotoxin resulted in a decrease of the number of lung hemorrhages and an accelerated release of t-PA antigen. Thus, DIC in obstructive jaundice may be due to impairment of fibrinolysis and an increased susceptibility of endothelial cells to endotoxin. APC may be effective as a treatment for patients with obstructive jaundice associated with DIC.

Prevention of endotoxin‐induced increase of cerebral oxygen consumption in dogs by propranolol pretreatment

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were studied in experimental endotoxic shock in dogs. Eight animals were pretreated with a beta-adrenoceptor blocking agent, propranolol (PPL), per os 12 mg/kg once a day for 7 days. Ten animals served as controls. After an intravenous injection of endotoxin, 1 mg/kg, CBF decreased in both groups, with no significant differences between the groups. CMRO2 increased in the control animals by about 18% from the baseline value both 1 and 2 h after the injection of endotoxin. CMRO2 in the PPL-pretreated animals was unchanged after endotoxin. The CMRO2-reactions to endotoxin in control and PPL animals were significantly different after both 1 and 2 h (P less than 0.05). The present results indicate that the increase in CMRO2 following intravenous endotoxin is mediated via beta-adrenoceptors.

Shwartzman Reaction

The local and generalized Shwartzman reactions are models of thrombohemorrhagic skin necrosis and DIC, respectively. An intravenous preparatory injection of endotoxin followed by an intradermal injection of endotoxin 24 hours later elicits a thrombohemorrhagic lesion only at the site of intradermal injection of endotoxin in the local Shwartzman reaction. Two intravenous injections of endotoxin spaced 24 hours apart induced a systemic generalized Shwartzman reaction characterized by coagulopathy, petechial hemorrhages, microthrombi, and decreased circulating platelets similar to DIC. Of particular interest is the observation that thrombohemorrhagic lesions of the Shwartzman reaction only develop at sites of intradermal injections of endotoxin. Microthrombi composed of platelets and leukocytes only adhere or accumulate in dermal vessels after an intradermal injection of endotoxin. Prior to the endotoxin injection, biopsies of skin show normal vessels without microthrombi or significant inflammation. Since endothelial cells line the small vessels in the dermis, where a Shwartzman reaction appears to be initiated, it is likely that endothelial cells are important for initiating a local Shwartzman reaction. IL-1 and TNF can substitute for the intradermal injection of endotoxin in the local Shwartzman reaction, induce endothelial cells to become thrombogenic, and can induce the expression of cell adhesion molecules on endothelial cells making endothelial cells more sticky for leukocytes. These observations suggest that endothelial cells play a central role in the local Shwartzman reaction and may be important in understanding diseases associated with thrombohemorrhagic skin necrosis.

Reduced Amino Acid Transport in Skeletal Muscle Caused by a Circulating Factor During Endotoxemia

The present study was designed to determine whether reduced amino acid uptake in skeletal muscle during endotoxemia is due to associated hypotension or is caused by a factor present in plasma. Three series of experiments were performed. In the first series of experiments, mean arterial pressure (MAP), heart rate, and amino acid uptake in incubated soleus muscles were measured after intravenous injection of endotoxin (1 mg/kg) in male Sprague-Dawley rats (40 to 60 g). Amino acid transport was measured by determining intracellular uptake of [3H]-alpha-amino-isobutyric acid (AIB) during 2 hours of incubation. In the second series of experiments, hypotension was induced by bleeding and muscle amino acid uptake was measured. In the third series of experiments, whole plasma or a low molecular weight fraction (less than 10,000 d) of plasma from endotoxin-injected rats was added in vitro to incubated muscles and amino acid uptake was determined. One hour after injection of endotoxin, MAP was reduced from 80 +/- 2 mmHg to 54 +/- 4 mmHg (p less than 0.05). AIB uptake was reduced by 20% (p less than 0.05) 2 hours after endotoxin injection. When MAP was maintained at 50 mmHg for 1 hour by bleeding, no changes in muscle AIB uptake were noted. When plasma obtained from rats 2 hours after endotoxin injection was added to incubated soleus muscles, AIB uptake was reduced by 22%. This effect was duplicated by a fraction of endotoxic plasma containing substances with a molecular weight less than 10,000 d. The present results suggest that reduced muscle amino acid uptake during endotoxemia is not due to associated hypotension, but may be caused by a circulating factor(s) with a molecular weight less than 10,000 d.

Evidence for the involvement of a plasma kallikrein-kinin system in the immediate hypotension produced by endotoxin in anaesthetized rats.

1. In vitro incubation of normal rat plasma with endotoxin from E. coli (3-10 mg ml-1) in the incubation mixture) caused a dose-dependent increase in levels of free kinin and plasma kallikrein in the presence of o-phenanthroline, together with a mirror-image, dose-dependent decrease in the residual levels of the precursors, plasma prekallikrein and high-molecular-weight kininogen. Low-molecular-weight kininogen levels were not modified. 2. Intravenous injection of endotoxin (3-30 mg kg-1) into the femoral vein of anaesthetized rats resulted in dose-dependent hypotension. In blood collected up to 15 min after injection, the levels of prekallikrein and high-molecular-weight kininogen in plasma were decreased while levels of the active forms, plasma kallikrein and free kinin, showed a transient increase in the blood 1 min after administration of endotoxin. 3. A degradation product of bradykinin, des-Phe8-Arg9-bradykinin, as measured by a newly developed enzyme immunoassay, was detectable up to 5 min after administration of endotoxin. 4. Intravenous infusion of soybean trypsin inhibitor inhibited both the formation of bradykinin and des-Phe8-Arg9-bradykinin and the initial hypotension. 5. It can be concluded from our results that plasma prekallikrein is activated in the blood immediately after administration of endotoxin to rats and that bradykinin is a major cause of the immediate hypotension.

Endotoxin-induced hypercoagulability: A possible aggravating factor of alcoholic liver disease†

The present experiments were designed to study the effect of chronic ethanol consumption on endotoxin toxicity. The intravenous injection of endotoxin produced a more pronounced increase of serum AST and ALT activities in chronic ethanol-fed rats, when compared to controls. The activities of hepatic mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase, were also distinctly decreased by endotoxin treatment in chronic ethanol-fed rats. Consistent with these biochemical alterations, light and electron microscopic examinations revealed severe liver injury after endotoxin injection in chronic ethanol-fed rats. Furthermore, the increase of blood BUN and creatinine levels accompanied by the degeneration of the renal tubulus and slight infiltration of neutrophils into the glomerule were produced by endotoxin treatment and were more conspicuous in chronic ethanol-fed rats than controls. Therefore, the biochemical and histological evidence indicates that endotoxin markedly potentiates organ injury after chronic ethanol consumption. In addition, a more pronounced decrease in blood antithrombin III activity accompanied by an increase in fibrin degradation product level in blood was recognized in chronic ethanol-fed rats receiving endotoxin, when compared to controls receiving endotoxin. This increase of blood fibrin degradation product level correlated well with the decrease of antithrombin III activity (r = -0.6116; p less than 0.005). These findings of blood antithrombin III activity and fibrin degradation product level indicate that the coagulation-fibrinolysis system is more activated by endotoxin treatment after chronic ethanol consumption. Furthermore, the activation of the coagulation-fibrinolysis system was well correlated with biochemical and histological alterations representing hepatorenal involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of low molecular weight dextran on platelet pulmonary trapping during endotoxin-induced shock

In vivo behaviour of Indium-111-labelled platelets were followed simultaneously in the lungs, liver, spleen and kidneys in 16 adult sheep which were exposed to intravenous injection of endotoxin (10 micrograms/kg body wt.). The effects on the respiratory function and the central hemodynamics were also followed. Eight sheep received, 30 min after the endotoxin challenge, continuous intravenous infusion of low molecular weight dextran during 4 h while the other eight animals served as controls. A marked pulmonary and hepatic platelet sequestration was observed during and just after the endotoxin infusion and was followed by a marked platelet disaggregation within 30 min in both the groups. Three hours after the endotoxin a second wave of platelet sequestration occurred in the control animals, both in the lungs and in the liver, but no such increase was seen in the low molecular weight dextran-treated group. Within the kidneys only minor changes occurred during the experiment period. In the spleen, however, there was a decrease in platelet sequestration after endotoxin in both groups. Less marked hemodynamic and respiratory alterations occurred in the dextran-treated group compared to the controls. It was concluded that low molecular weight dextran decreases sequestration of platelets in the lungs and in the liver of sheep during endotoxic shock.