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PubMed2006

[Correlation of changes in circulating bone marrow stem cells in pregnant rabbits after acute myocardial infarction with serum estradiol].

OBJECTIVE: To investigate the changes in circulating bone marrow stem cells in pregnant rabbits after AMI (AMI) and their relationship with estradiol. METHODS: Three groups of rabbits were used, namely pregnancy and AMI group, AMI group without pregnancy, and sham operation group with pregnancy. The ratio of CD90(+) cells in the peripheral blood was determined with flow cytometry in all the rabbits, and serum estradiol level measured. Four weeks after AMI, hemodynamic measurements were carried out. The morphological changes of the myocardial tissues were examined with ImageJ 1.31. RESULTS AND CONCLUSION: Four weeks after AMI, the two pregnancy groups showed a higher Left ventricular end systolic pressure(LVESP) and+dp/dtmax, lower left ventricular end-diastolic pressure (LVEDP) and -dp/dtmax and high levels of CD90(+) cells in peripheral blood than AMI group without pregnancy (P<0.01). The ratio of circulating CD90(+) cells increased gradually with gestational age and peaked at the end stage of pregnancy. After delivery the circulating CD90+ cell ratio decreased sharply, showing a significant correlation with serum estradiol level (r=0.725, P<0.01). Four weeks after AMI, the pregnancy group had smaller myocardial infarction (MI) volume than the non-pregnant group (22.17+/-6.34% vs 38.86+/-5.97%, P<0.05). Circulating bone marrow stem cells increased during pregnancy with gestational age and peaked at the end stage of pregnancy. Ten days after delivery, the stem cells resumed basically the normal level. The proportion of circulating bone marrow stem cells was significantly correlated with the level of serum estradiol during pregnancy, and mobilization of the bone marrow stem cells induced by acute ischemic event in pregnant rabbits was advanced. 4 weeks after AMI, the pregnant rabbits showed better heart contraction and diastolic function than the non-pregnant ones.

Animals↗
PubMed2006

Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state.

The risk for thrombosis is significantly increased in systemic lupus erythematosus (SLE), affecting both venous and arterial vessels. Activated platelets are known to participate in thrombus formation and growth. A general feature of activated cells is the shedding of microparticles (MP) which support coagulation by exposure of negatively charged phospholipids and possibly tissue factor (TF). In this work we characterized circulating MP in patients with SLE and their relationship with a procoagulant state. Thirty patients with SLE (aged 15-72 years, mean age 38 years) and 20 healthy controls (aged 22-54 years, mean age 34 years) were studied; patients fulfilled 4 revised criteria for SLE. The number and cellular source of circulating MP were determined by flow cytometry using double labeling with specific monoclonal antibodies and annexin V. Thrombin generation was measured as the endogenous thrombin potential (ETP) without the addition of exogenous phospholipids and TF; under these conditions the generation of thrombin depended directly on the number of MP present in plasma. Thrombin anti-thrombin (TAT) and plasmin-antiplasmin (PAP) complexes were measured by ELISA. Compared to the controls, circulating MP were significantly elevated in the patient group (1218 +/- 136 vs 653 +/- 74 x 10(3)/ml plasma, p: 0.0007). In both groups, most of these MP were of platelet origin (927 +/- 131 vs 517 +/- 72 x 10(3)/ml plasma, p:0.009 ). ETP was higher among patients as compared to the controls (804 +/- 64 vs 631 +/- 37 nM thrombin, p: 0.025). Plasma levels ofTAT in patients and controls were 3.4 +/- 0.8 and 1.4 +/- 0.5 microg/L, respectively (p:0.04), and of PAP complexes were 62.5 +/- 14 and 24.05 +/- 2.5 microg/ml, respectively (p: 0.014). The number of platelet-derived MP correlated significantly with thrombin generation (r: 0.42; p: 0.038) and TAT levels (r: 0.40; p: 0.035). We did not find an association of circulating MP with disease activity nor with the presence of antiphospholipid antibodies. The increased number of circulating platelet-derived microparticles and their association with high ETP and activation of the coagulation system suggest that these microparticles play an important role in the pathogenesis of the prothrombotic state in SLE patients.

Adolescent↗
PubMedDate not supplied

Suppression of circulating interleukin-6 concentrations is associated with decreased endothelial activation in rheumatoid arthritis.

BACKGROUND: Circulating interleukin (IL)-6 concentrations are associated with endothelial activation in rheumatoid arthritis (RA). OBJECTIVE: To assess endothelial activation before and after suppression of cytokine production in RA. METHODS: Twenty-one patients (mean (SD) age 59 (9) years; disease duration 6 (4) years) were treated with intraarticular methylprednisolone acetate (417 (152) mg) together with disease modifying agent (DMARD) initiation (n = 10) or intensification (n = 11) employing methotrexate (n = 11), leflunomide (n = 8), minocyclin (n = 6) and sulphasalazine (n = 1). Disease activity, circulating cytokines (IL-1, tumor necrosis factor alpha (TNF-alpha) and IL-6) and biomarkers of endothelial activation (circulating vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1)) were evaluated before and 2 weeks after treatment. RESULTS: The intervention resulted in reductions in 8 disease activity markers (p < or = 0.002). Serum IL-6 concentrations decreased from 17 (2.9) to 4.9 (4.6) pg/ml (p = 0.0008). Serum IL-1 and TNF-alpha levels did not change (p > or = 0.4). Serum VCAM-1 concentrations decreased from 912 (402) to 752 (252) (p = 0.003), ICAM-1 from 398 (205) to 323 (179) (p = 0.04) and ELAM-1 from 68 (28) to 53 (25) (p = 0.02) pg/ml, respectively. Baseline rheumatoid factor titers were associated with reductions in VCAM-1 (r(s) = 0.481, p = 0.03). In multivariable regression models, decreases in circulating interleukin-6 concentrations were associated with reductions in VCAM-1 (p < 0.0001), ICAM-1 (p = 0.005) and ELAM-1 (p = 0.02) independent of changes in disease activity, weight and blood pressure. CONCLUSION: Our results suggest that suppression of circulating IL-6 concentrations attenuates atherogenesis in active RA.

Antirheumatic Agents↗
PubMed2006

[Changes in lymph circulation in rats with experimental disseminated intravascular coagulation].

OBJECTIVE: To explore changes in lymph circulation in rats with experimental disseminated intravascular coagulation (DIC). METHODS: Thirty-two male Wistar rats were randomly divided into two groups: DIC group and sham-operation group, with 16 rats in each group.In each group, 8 rats were used to observe the lymphatic circulation of intestinal mesentery, and the others were used to observe lymphatic dynamics. Experimental DIC model was replicated by injecting dextran 500 via jugular vein in Wistar rats. The changes in lymph circulation were observed in these rats with lymphology methods. RESULTS: During the phase of DIC, the contractility of mesenteric micro-lymphatic (ML), the intestinal lymph flux, lymphocytes output were obviously decreased, and there was a few monocytes in the lymph fluid, but the lymph fluid viscosity was increased. After treatment with normal saline (NS), the contractility of ML, the intestinal lymph flux, lymphocytes output were obviously increased, and there was a large amount of monocytes in the lymph fluid, with significant difference compared with sham-operation group (all P<0.05). Moreover, the lymph fluid viscosity was decreased compared with sham-operation group (P<0.05). CONCLUSION: The disturbance in lymph circulation mainly includes depression of contractility of lymphatics, the transport function of lymph circulation, and increased lymph fluid viscosity.

Animals↗
PubMed1991

The effect of ERCP on circulating pancreatic enzymes and pancreatic protease inhibitors.

The pathogenesis of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis is poorly understood. To elucidate a role for pancreatic enzymes in ERCP-induced pancreatitis, we measured serum amylase, lipase, trypsin, and elastase in 25 patients undergoing ERCP. Serum alpha 1-antitrypsin and alpha 2-macroglobulin, two major pancreatic protease inhibitors, also were measured. All pancreatic enzymes measured rose significantly after ERCP. Pancreatic duct cannulation was associated with a greater elevation in serum amylase and lipase. Circulating alpha 2-macroglobulin was reduced by 7% (p = 0.04) 6 h after ERCP, whereas circulating alpha 1-antitrypsin increased over the same time period. Papillotomy, stent placement, or underlying disease did not influence changes any further. Three patients developed ERCP-induced pancreatitis. All three patients had circulating alpha 2-macroglobulin levels below 243 mg/dl (p = 0.03). The ERCP-induced alterations in circulating pancreatic enzymes and their inhibitors are similar to changes seen in clinical pancreatitis. Low circulating alpha 2-macroglobulin levels may predispose to ERCP-induced pancreatitis.

Acute Disease↗
PubMed1991

Proliferation and degeneration of circulating CFU-GM in 15 adult normal subjects. Can any ontogenetic relationship be deduced from these data?

We studied, in 15 normal adults, the "in vitro" proliferation and differentiation of circulating CFU-GM, in order to assess their implication in the processes that regulate the dynamic equilibrium of granulopoiesis, analogous to bone marrow CFU-GM, and to deduce by their growth behaviour the ontogenetic relationship between CFU-GM subpopulations in the circulating and bone marrow compartments respectively. We found that "in vitro" proliferation of circulating CFU-GM predominates over their degeneration. We believe circulating CFU-GM and bone marrow CFU-GM are not implicated in granulopoiesis regulation in the same manner, and that circulating CFU-GM are more immature than bone marrow CFU-GM when taking proliferation and GM-CSF response into account. One cannot ignore the hypothesis that cells that "in vivo" are quiescent, are recruited "in vitro" with GM-CSF. Finally we would like to draw attention to the parallelism between CFU-GM classification in types 1 and 2 using monoclonal antibodies to track surface antigens, and our classification obtained by using a new mathematical model that takes the "birth" and "dead" of cellular aggregates into account.

Adult↗
PubMedDate not supplied

[Examination of circulating stem cells from the granulocyte-monocyte line in patients with Hodgkin's disease].

The formation of granulocyte-monocyte colonies by bone marrow cells cultured in a semiliquid environment is a widely applied technique of granulocytopoiesis examination. Applying this method the number of circulating in blood stem cells of the granulocyte-monocyte line (CFC-GM) has been assessed in 35 patients with Hodgkin's disease. In 12 patients the number of circulating in blood CFC-GM prior to the irradiation has been greater as compared with the norm accepted for our investigation. It has been the greatest in patients with nodular sclerosis type of Hodgkin's disease. In 25 patients smaller than accepted as normal number of circulating in the blood CFC-GM has been present particularly in patients with mixed cellularity type of Hodgkin's disease. Following the application of chemotherapy according to MOPP scheme during the first two weeks no circulating CFC-GM have been present in blood. The lowest number of stem cells in blood has been observed prior to IV and VI course of chemotherapy. The interruption of treatment for 8 weeks resulted in major increase of the number of circulating CFC-GM in the blood.

Adult↗
PubMed1990

Human platelet factor 4 and its C-terminal peptides: heparin binding and clearance from the circulation.

Human platelet factor 4 (PF4), a high affinity heparin binding protein, is released from stimulated platelets and stored at vascular sites, predominantly in liver, from where it can be brought back into circulation by heparin. We attempted to define structural requirements for PF4 binding to heparin and for the pattern of its clearance from the circulation. Intact PF4 bound strongly to heparin agarose and was eluted at 1.4 M NaCl, while reduced PF4 and PF4 C-terminal peptides PF4 (47-70) and PF4 (58-70) bound weakly and were eluted at 0.2-0.5 M NaCl. 125I-radiolabeled intact PF4, reduced PF4 and C-terminal PF4 peptides injected into rabbits were cleared from the circulation in a biphasic pattern with components having half-life time of 1-2 min and 20-140 min. Heparin eliminated the fast component of PF4 clearance, but it did not affect clearance of reduced PF4 or C-terminal PF4 peptides. In contrast to reduced PF4 and PF4 (47-70), intact PF4 that accumulated in the liver and spleen, was displaced by heparin into circulating blood. In conclusion, specific binding sites and native conformation of the molecule are critical for high affinity PF4 binding to insolubilized heparin and for a pattern of PF4 clearance from the circulation in the presence of heparin.

Animals↗
PubMed1985

Circulating acid-labile interferon in chronic versus acute, HBV-related liver disease. A marker of immune-mediated hepatocellular damage?

An acid-labile Interferon was detected in the circulation of 76.1% of patients with chronic active type B hepatitis, in 30% of patients with acute type B hepatitis, studied within 15 days from starting of symptoms, and in 25% of patients with acute type B hepatitis studied 4 to 6 weeks after the admission. Patients in the third group showing evidence of circulating Interferon had also a delayed recovery and tardive HBsAg clearance. Circulating immune complexes were detected in 85.7% of patients of the first group, in 63.3% of patients of the second group, and in 25% of patients of the third group. We suggest that an acid-labile circulating Interferon could be related to immune-mediated hepatocellular damage (evidenced by circulating immune complexes) in hepatitis B virus infection, gradually disappearing during recovery from acute hepatitis or persisting indefinitely in chronic active hepatitis.

Acute Disease↗
PubMed1987

Circulating parasite antigen(s) in lymphatic filariasis: use of monoclonal antibodies to phosphocholine for immunodiagnosis.

Hybridoma cell lines producing monoclonal antibodies (MAb) against a 200 kD antigen found circulating in the sera of microfilaremic patients infected with Wuchereria bancrofti were obtained by immunizing mice with a partially purified antigen preparation. A sensitive MAb (CA101)-based ELISA for measuring circulating parasite antigen was capable of detecting antigen in the sera of 93% of patients with microfilaremia, 46% of those with lymphatic obstruction, and 56% of patients with tropical pulmonary eosinophilia syndrome. Circulating antigen was absent from sera of normal controls, and "false positives" were recorded in only two of 17 patients with nonfilarial helminth infections. By ELISA and immunoblot analysis, it was shown that three of the monoclonals raised to this 200 kD antigen were directed to epitopes of phosphocholine (PC). Two MAb (CA86, CA101) were identified as having the T15 idiotype previously associated with antibodies to the PC of pneumococcal teichoic acid; one was untypeable. All three of these anti-PC MAb reacted with adult, microfilaria, and larval antigen preparations, and by immunoblotting showed multiple banding patterns that indicated the presence of PC determinants on many different antigenic molecules. On the other hand, target antigens of CA101 which were found in the circulation of infected patients were limited to three species with apparent m.w. of 200, 160, and 78 kD. The 200 kD antigen was seen more frequently than the other two antigens. Other T15 anti-PC MAb derived from mice not immunized with filarial antigen showed similar patterns of reactivity with circulating filarial antigen.

Animals↗
PubMed1988

IgE-dependent humoral immune response in Echinococcus multilocularis infection: circulating and basophil-bound specific IgE against Echinococcus antigens in patients with alveolar echinococcosis.

Clinical symptoms of immediate-type hypersensitivity (ITH) and specific IgE against Echinococcus granulosus antigens are frequently present in patients with hydatid cysts. In alveolar echinococcosis (AE) due to E. multilocularis, clinical manifestations related to ITH have never been reported. The IgE-dependent humoral immune response was evaluated in 30 patients with AE. Circulating specific IgE (sIgE) were determined with two different methods of radio-allergo-sorbent test. Serum sIgE were determined sequentially in 18 patients over 15 months. Specific IgE bound to circulating basophils were assessed with two tests in vitro, measuring specific degranulation and histamine release. The respective abilities of E. granulosus and E. multilocularis antigens to reveal bound and circulating IgE antibodies were also assayed. Despite the absence of clinical symptoms of ITH and the frequent lack of circulating sIgE, an immunological response involving IgE was always present in human AE: basophil-bound sIgE were revealed in every patient by histamine release and degranulation tests; these tests were constantly negative in control subjects. Echinococcus granulosus extracts were more effective for detecting circulating sIgE; however E. multilocularis antigenic preparation induced a histamine release significantly higher than E. granulosus extracts. These results suggest that IgE-dependent humoral immune response could play a role in the host-parasite relationship in AE. Moreover, the sensitivity of the tests used to detect basophil-bound sIgE was higher than that of the usual serological tests, and the basophil degranulation test could be used to confirm diagnosis of AE in endemic countries.

Adult↗
PubMedDate not supplied

Dietary salt, blood pressure and circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine in patients with essential hypertension.

The effects of dietary salt on circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16 PAF) in patients with essential hypertension were studied by gas chromatography/mass spectrometry with negative ion chemical ionization. Circulating levels of C16 PAF in patients with essential hypertension (18.1 +/- 5.3 pg/ml, n = 16) were not changed compared with those in normotensive subjects (17.2 +/- 7.2 pg/ml, n = 14). Although changes in circulating levels of C16 PAF were small with changes in dietary salt, net changes in circulating C16 PAF levels significantly and positively correlated with net changes in mean arterial blood pressure (r = 0.47, P less than 0.05). Changes in C16 PAF levels also correlated with changes in creatinine clearance (r = 0.55, P less than 0.05). However, changes in C16 PAF levels did not correlate with changes in plasma sodium concentration, plasma chloride concentration and plasma volume. These results indicate that C16 PAF plays an antihypertensive role and this may be reflected as small changes in circulating levels of C16 PAF.

Adult↗
PubMed1989

Elevated circulating tumor necrosis factor-alpha in patients with Kawasaki disease.

The mechanism of vascular injury in Kawasaki disease (KD) is unclear. Recent studies suggest a role for circulating antibodies that are cytotoxic for endothelial cell antigens inducible by cytokines. Tumor necrosis factor-alpha (TNF, cachectin) is a monocyte- or macrophage-derived cytokine that has an important role as an effector molecule in various inflammatory processes. To study the possible involvement of TNF in KD, we measured the levels of circulating TNF in 39 patients with KD at various stages of the disease by using a newly developed sensitive radioimmunoassay. The TNF levels in sera from the acute and subacute phases of the disease were significantly (p less than 0.001) higher than in sera taken in the convalescence phase or in sera from children without inflammatory disease. In all patients from whom serial samples were available, the TNF level was higher during the acute and subacute phases than during convalescence. Coronary aneurysms developed in four of the patients, and these patients were among those who had the highest levels of circulating TNF during the acute and subacute phase (51.1 +/- 13.6 pg/ml (mean +/- SD) vs 30.4 +/- 15.8 pg/ml in patients without coronary aneurysms; p less than 0.001). No differences in circulating TNF levels were observed between patients who received as treatment aspirin plus intravenous immunoglobulin and those who received aspirin alone. The results show that the levels of circulating TNF are increased in acute KD and support the hypothesis that this cytokine may be involved in the pathogenesis of the vascular injury in KD.

Adolescent↗
PubMed1989

[Study of excitation circulation around an unexcitable myocardial obstacle].

An experimental model of tachy-arrhythmias due to myocardial excitation wave circulation round an unexcitable obstruction was explored. Artificial openings of various sizes and shapes in an isolated rabbit left atrium posed as obstacles. Acetylcholine, having a potent effect on the refractory period of atrial cells, was used to alter refractory characteristics. It has been demonstrated that differences in the sensitivity to the action of pharmacologic agents on both re-entry types can actually be absent. Acetylcholine is shown to shorten the period of circulation round the hole, i.e. act on such circulation in the same fashion as it does on the leading cycle, in a wide range of hole diameters, approaching the ones comparable with the size of the atrium. Sensitivity to acetylcholine only disappears when a labyrinth is set up with artificially prolonged circulation pathway. The action of acetylcholine can be attributed to the absence of tissue with fully recovered excitability between the anterior and posterior fronts of the wave circulating round the obstacle.

Acetylcholine↗
PubMed1988

Appearance and phenotypic characterization of circulating Leu 19+ cells in cancer patients receiving recombinant interleukin 2.

The effects of recombinant interleukin 2 (rIL-2) therapy on peripheral blood mononuclear cells expressing the Leu 19 surface marker were evaluated in 20 cancer patients. Leu 19 is a protein with a molecular weight of 220,000 expressed on 15% of normal peripheral blood mononuclear cells and is found on a majority of cells that mediate non-major histocompatibility complex-restricted cytotoxicity. Increased relative and absolute numbers of circulating Leu 19+ cells were observed in all patients receiving rIL-2. Increases in Leu 19+ cells were due in part to the development of a subpopulation of "bright" Leu 19+ cells (Leu 19b+) that possessed a higher density of membrane Leu 19 antigen than Leu 19+ cells assayed prior to therapy. Further characterization of rIL-2 induced Leu 19+ cells by dual immunofluorescence revealed considerable phenotypic heterogeneity within this population based on the coexpression of "dim" CD8 (CD8d+), CD16, and CD2 markers. The percentage of Leu 19+ CD8d+ cells was increased during rIL-2 therapy and comprised up to 60% of all circulating Leu 19+ cells. CD16+ and CD16- subsets of Leu 19+ cells were also increased by rIL-2. The density of CD16 antigen coexpression varied inversely with the density of Leu 19. Conversely, whereas the percentage of Leu 19 cells coexpressing CD2 was also increased by rIL-2 administration, the density of CD2 antigen expression was higher on the Leu 19b+ subset of cells. The development of circulating lymphokine-activated killer activity in three patients was temporally associated with the development of increased levels of circulating Leu 19+ cells. These studies demonstrate that rIL-2 administration induces preferential increases in cells expressing the natural killer and lymphokine-activated killer cell-associated marker Leu 19 and that these increases are associated with the development of circulating lymphokine-activated killer activity. Furthermore, Leu 19+ cells are comprised of phenotypically heterogeneous subsets which undergo characteristic changes during rIL-2 administration.

Antigens, Differentiation↗
PubMed1989

Incorporation of a circulating protein into alpha granules of megakaryocytes.

In order to determine whether or not proteins circulating in plasma can be incorporated into megakaryocytes and platelets, horseradish peroxidase (HRP) was injected intravenously into guinea pigs and these cells were examined for uptake by cytochemistry and electron microscopy. Enriched samples of megakaryocytes enabled ultrastructural analysis of large numbers of these rare bone marrow cells. In megakaryocytes, more than 50% of alpha granules contained HRP between 75 minutes and 7 hours after injection. At 24 hours, 25% of the megakaryocyte granules were peroxidase positive; less were so by 48 hours and none at 4 days. Thus, the findings demonstrate that a circulating protein can be endocytosed by megakaryocytes and rapidly packaged into alpha granules. A precipitous drop in circulating platelet numbers was observed 45 minutes after injection. At this time, circulating platelets showed the tracer only on the platelet plasma membrane, and none in platelet granules. Platelet numbers increased to 35% by 7 hours and only the platelet granules contained HRP. These platelets secreted the HRP stored in granules in response to thrombin. Unfortunately, our present studies do not allow us to distinguish between direct endocytosis by the platelet and/or shedding of new platelets from recently labeled megakaryocytes. Our studies are the first to demonstrate an endocytic pathway by which megakaryocytes can incorporate a circulating protein into alpha granules. An important physiologic implication of this endocytic pathway is the possible origin of certain alpha granule proteins from plasma.

Animals↗
PubMed1985

Binding and receptors for human albumin polymers and IgM/HBs circulating complex in HBsAg chronic carriers.

Binding activity for polymerized human serum albumin (pHSA-binding), studied in passive haemoagglutination, receptors for polymerized human serum albumin (pHSA-receptors), studied in ELISA, as well as the circulating IgM/HBs complex were tested in 71 chronic carriers of HBsAg with and without liver pathology. We found that 73.2% of the sera were reactive for pHSA-binding while 45% were reactive for pHSA-receptors and 42.2% for the circulating IgM/HBs complex. The distribution and mode of association of these 3 markers showed a close correlation with the e-antigen in circulation (HBeAg) and with liver disease (p less than 0.05). We further observed that pHSA-binding can be present in the absence of pHSA-receptors, suggesting the possible existence of further reactants in the serum-pHSA reaction. We did not observe any correlations between the circulating IgM/HBs complexes, pHSA-binding and pHSA-receptors. Blocking experiments, in fact, confirmed the non-involvement of polymerized human serum albumin in the formation of the circulating IgM/HBs complex. Elution experiments showed that, in addition to HBsAg, class-G immunoglobulins are also directly involved in the serum-pHSA reaction.

Adult↗
PubMed1988

Pulmonary removal of circulating endotoxin results in acute lung injury in sheep.

Endotoxemia has often been associated with the development of the adult respiratory distress syndrome. Our previous studies have shown that sheep, a popular animal model for adult respiratory distress syndrome, have abundant resident pulmonary intravascular macrophages that rapidly remove inorganic particles and live bacteria from the circulating blood. In this study, we examine the fate of circulating endotoxin in sheep and correlated the site of uptake with early morphologic evidence of tissue injury. Mature sheep and rats received intravenous 125I-labeled lipopolysaccharide (LPS). The dose was 0.8 microgram/kg in sheep and 17.0 micrograms/kg in rats. 125I-LPS clearance from the blood was assayed by gamma-counting of blood samples drawn over 1 hour and was correlated with circulating leukocyte numbers. The distribution of 125I-LPS was determined by gamma-counting of samples of major organs and tissues at time of necropsy. Lungs and liver were examined morphologically in both species. The half-life of circulating 125I-LPS was 2.38 minutes in sheep, and 12.39 minutes in rats. The endotoxin content of the lungs after injection was 77.58% of the total recovered dose in sheep, but only 2.02% in rats. Neutrophil margination occurred in the lungs of both species. In sheep, almost 25 minutes elapsed before peripheral neutrophil numbers decreased by 50%, much longer than the time required for LPS sequestration in the lungs. Rapid LPS uptake by the sheep lungs was associated with early (10-minute) ultrastructural changes including signs of pulmonary intravascular macrophage activation and microvascular congestion. By 60 minutes, many capillaries were occluded with neutrophils, platelets, and fibrin. There was interstitial edema, and endothelial cells showed evidence of severe injury. We conclude that in contrast to the rat, the sheep clears circulating endotoxin more rapidly and preferentially sequesters it in the lungs. Subsequent release of mediators by activated pulmonary intravascular macrophages may then lead to influx of other inflammatory cells and cascading injury.

Animals↗