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PubMed2005

Effect of intraperitoneal application of an endotoxin inhibitor on survival time in a laparoscopic model of peritonitis in rats.

Gram-negative sepsis due to fecal peritonitis is a hazardous disease with a high percentage having a lethal course. The inflammatory effects are induced by endotoxin release. We performed this study to evaluate the potential of direct intraperitoneal application of an endotoxin inhibitor in a laparoscopic peritonitis model in rats. The human feces specimen was prepared, and a standard fecal specimen (0.5 ml/kg b.w.) was applied via minilaparotomy. The rats were randomized to two studies. First, rats were randomized to three groups to define the survival time: (1) rats without further manipulation; (2) rats with laparoscopic lavage using NaCl; (3) rats with laparoscopic lavage using endotoxin inhibitor. Second, rats underwent the same procedure used in the first part of the study and an additional group with only NaCl lavage without peritonitis was randomized. To evaluate the immunologic or biochemical effects, animals were killed at a standard time of 20 hours until the postmortem examination was established. Interleukins 6 and 10 (IL-6, IL-10), malondialdehyde, and protein carbonyl group levels in plasma and particularly in peritoneal fluid were assayed. The first part of the experiment showed significantly increased survival after endotoxin inhibitor lavage. In the second part, administration of endotoxin inhibitor intraperitoneally caused a significant reduction of IL-6 in the peritoneal fluid, in contrast to that in the other groups. Laparoscopic application of endotoxin inhibitor intraperitoneally thus produced a beneficial effect on survival and reduction of IL-6 in peritoneal fluid. Hence, it is possible to influence the inflammation cascade by causing intraperitoneal endotoxin inhibition.

Animals↗
PubMed2001

Correlation between plasma endotoxin, plasma cytokines, and plasminogen activator inhibitor-1 activities in septic patients.

The objective of this study was to evaluate the relation between the clinical and plasma parameters and the changes in plasma endotoxin activity with 2 hours of endotoxin-adsorbing therapy using polymyxin B (PMX). A total of 88 consecutive patients were admitted for PMX treatment of severe sepsis or septic organ failure. Standard supportive care was continued without alteration during PMX treatment. Endotoxin, tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-10, and plasminogen activator inhibitor-1 (PAI-1) activities and clinical parameters were measured before, immediately after, and the day after PMX treatment. The mean APACHE II and III scores were 24.2 +/- 1.0 and 85.8 +/- 3.0, respectively. The 2-week survival rate was 51.1%. In survivors, TNFalpha, IL-6, IL-10, and PAI-1 activities were significantly decreased during the 2-hour PMX treatment, the following day, or both times. There was no significant change in the parameters, except for TNFalpha, after PMX in nonsurvivors. In the subgroup whose plasma endotoxin decreased more than 30%, IL-6, TNFalpha, and PAI-1 significantly decreased after 2 hours of PMX or the following day (or both), but all four parameters in nonsurvivors showed no significant change. Hence PMX adsorbed plasma endotoxins and contributed to reductions in plasma proinflammatory cytokine levels and to improved clinical parameters during the 2-hour treatment. Changes in these parameters correlated with changes in plasma endotoxin activity in survivors whose plasma endotoxin levels were adequately reduced.

APACHE↗
PubMed1998

[Effect of E. coli endotoxin on auto-/paracrine function and endothelial cell loss of donor corneas in organ culture].

Corneal cells are known to participate in the regulation of local inflammatory processes by secretion of cytokines. As the corneal endothelium may be exposed to endotoxin in organ culture and endotoxin is known to trigger inflammatory reactions, we investigated the effect of endotoxin from E. coli on organ cultured donor corneae with respect to autocrine and paracrine functions and the endothelial viability and density. 6 pairs of donor corneae were transferred to organ culture. Medium samples were taken prospectively from day 0 to day 20. On day 10 the medium was changed and one of each pair was incubated with 50 micrograms/ml of endotoxin while the other was immersed in standard organ culture medium. The samples were screened for IL-1, -2, -4, -5, -6, -8, -10, TNF alpha and GM-CSF by ELISA. In addition endothelial cell counts were performed at day 0, after 10 and after 20 days of organ culture, using the fixed frame technique. All endotoxin-incubated organ culture media showed significantly increased IL-6 and -8 levels compared to the fellow cornea and to pre-exposure levels (P < or = 0.004). In the endotoxin-treated corneae a significantly higher endothelial cell loss occurred (P = 0.007) and signs of degeneration were observed. None of the other cytokines (IL-1 alpha, IL-2, IL-4, IL-5, IL-10, GM-CSF and TNF alpha) were detected during either the first (1 to 10-day) or the second (11 to 20-day) phase of incubation. A correlation seems to exist between an increase in IL-6 and -8 induced by endotoxin, and endothelial cell loss in organ culture.

Adult↗
PubMed2004

Development of a hybrid delta-endotoxin and its expression in tobacco and cotton for control of a polyphagous pest Spodoptera litura.

A hybrid delta-endotoxin protein was designed against a polyphagous lepidopteran insect pest Spodoptera litura, which is tolerant to most of the known delta-endotoxins. The hybrid delta-endotoxin was created by replacing amino acid residues 530-587 in a poorly active natural Cry1Ea protein, with a highly homologous 70 amino acid region of Cry1Ca in domain III. The truncated delta-endotoxins Cry1Ea, Cry1Ca and the hybrid protein Cry1EC accumulated in Escherichia coli to form inclusion bodies. The solubilised Cry1EC made from E. coli was 4- fold more toxic to the larvae of S. litura than Cry1Ca, the best known delta-endotoxin against Spodoptera sp. None of the two truncated toxins, solubilised from E. coli caused larval mortality. However, trypsinised Cry1Ca protoxin obtained from E. coli and solubilised from inclusion bodies caused mortality of S. litura with LC50 513 ng/ml semi synthetic diet. A synthetic gene coding for the hybrid delta-endotoxin Cry1EC was designed for high level expression in plants, taking into consideration several features found in the highly expressed plant genes. Transgenic, single copy plants of tobacco as well as cotton were developed. The selected lines expressed Cry1EC at 0.1-0.7% of soluble leaf protein. Such plants were completely resistant to S. litura and caused 100% mortality in all stages of larval development. Hence, unlike in E. coli, the hybrid delta-endotoxin folded into a functionally active conformation in both tobacco and cotton leaves. The truncated Cry1EC expressed in tobacco leaves was about 8-fold more toxic (LC50 58 ng/ml diet) compared to expression in E. coli.

Amino Acid Sequence↗
PubMed1979

Changes in surface charge density on liposomes induced by Escherichia coli endotoxin.

Changes in surface charge density of liposomes induced by E. coli endotoxin were studied by microelectrophoresis. Endotoxin altered the surface charge of phosphatidylcholine liposomes from neutral to negative. The negative charge of the endotoxin-phosphatidylcholine complex was neutralized electrostatically by binding with Ca2+ (2 mM). Phosphatidylcholine liposomes were made positive by addition of the positively charged detergent, hexadecyltrimethylammonium chloride. Endotoxin made the positively charged liposomes less charged. On the other hand, phosphatidylserine liposomes which were negatively charged became less charged in the presence of high concentration of endotoxin (8 mg/ml). The endotoxin effect on phosphatidylserine liposomes was abolished by EDTA (1 mM) but potentiated by CaCl2 (0.1--2 mM). These results indicate that endotoxin interacts with liposomes both hydrophobically and electrostatically.

Endotoxins↗
PubMed1981

Endotoxin-induced alterations in glucose transport in isolated adipocytes.

2-Deoxyglucose and 3-O-methylglucose were used to assess endotoxin-induced changes in glucose transport in rat adipocytes. 6 h after Escherichia coli endotoxin injection insulin-stimulated 2-deoxyglucose uptake was significantly depressed (V decreased, Km unaltered), phosphorylation of 2-deoxyglucose was seemingly unimpaired; basal 3-methylglucose entry was significantly increased, insulin-stimulated uptake was unaltered. Insulin significantly reduced Km in control and endotoxin-treated cells. Cytochalasin B-insensitive uptake of both 2-deoxy-glucose and 3-methylglucose, a small fraction of total transport, increased significantly in endotoxic cells. Endotoxin reduced spermine- and insulin-stimulated 2-deoxyglucose uptake to a similar extent. Results are consistent with the hypotheses that (1) a site of endotoxin-induced insulin resistance is at the cell membrane level and may reflect a decrease in number of activity of effective carrier units, rather than alterations in affinity, (2) endotoxin does not compromise the hexokinase system, (3) the cell membrane-localized effect of endotoxin on hexose transport is not necessarily mediated by the insulin receptor and (4) the entry of 2-deoxyglucose and 3-methyl-glucose may involve two separate transport systems.

3-O-Methylglucose↗
PubMed1982

Endotoxin and tryptophan-induced hypoglycaemia in rats.

Pretreatment of rats with increasing, but non-lethal, doses of endotoxin was associated with a parallel increase in sensitivity to induction of hypoglycaemia by tryptophan. Acutely streptozotocin-diabetic animals became hypoglycaemic with endotoxin alone, and this was increased further by tryptophan. Variations in tryptophan sensitivity between rat populations cannot be explained by previous history of exposure to endotoxin. Endotoxin abolished the increase in tryptophan dioxygenase activity caused by triamcinolone, but not that caused by tryptophan. Triamcinolone was effective, however, when given together with tryptophan to endotoxin-treated rats. The activity of tryptophan dioxygenase in vivo and in liver cells in vitro is unchanged by exposure to endotoxin at 1 mg/kg body wt. Turnover studies indicated that hypoglycaemia resulted from inhibition of gluconeogenesis. There was no evidence to support a role for insulin in this process and results were consistent with an endotoxin-mediated hepatic insensitivity to glucagon. They also suggested that quinolinate, rather than 5-hydroxytryptamine, may be the intracellular agent responsible for inhibition of gluconeogenesis.

Animals↗
PubMed1985

A new chromogenic endotoxin-specific assay using recombined limulus coagulation enzymes and its clinical applications.

A conventional limulus test is not specific to endotoxin because of the presence in amebocyte lysate of a (1----3)-beta-D-glucan-sensitive factor. By fractionating coagulation enzymes in the lysate and recombining only those factors involved in endotoxin-induced coagulation, we have developed a new test specific to endotoxin. The recombined enzymes reacted only with endotoxin, and not with fungal polysaccharides. Conventional amebocyte lysate, on the other hand, reacted with both of them. A good linearity was obtained with this method between endotoxin concentration and absorbance with a sensitivity of 1 pg/ml of Escherichia coli 0111:B4 endotoxin. The regression lines for different types of endotoxins were parallel to one another. For the correct diagnosis of endotoxemia, this new test has a definite advantage over the one using whole amebocyte lysate.

Arthropod Proteins↗
PubMed1980

Blood levels of 6-oxo-prostaglandin F 1 alpha during endotoxin-induced hypotension in rabbits.

Levels of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), the non-enzymic degradation product of prostacyclin, were measured in arterial blood from anaesthetized rabbits, before and after intravenous (i.v.) administration of endotoxin (Lipopolysaccharine W E. coli 0111:B4, 5 mg/kg). 6-Oxo-PGF1 alpha was assessed by radioimmunoassay after extraction and separation by thin-layer chromatography. The basal concentration of 6-oxo-PGF1 alpha in blood was less than 100 mg/ml in 19 out of 20 rabbits. This indicates that the level of circulating prostacyclin is generally below 100 pg/ml. The administration of endotoxin induced a biphasic hypotension, and increased levels of 6-oxo-PGF1 alpha were found in all endotoxin-treated animals during the secondary hypotension after 60 and 120 min. Pretreatment with indomethacin (2.5 mg/kg) prevented the secondary fall in arterial blood pressure and significantly suppressed the rise in 6-oxo-PGF1 alpha. However, indomethacin failed to alter the endotoxin-induced thrombocytopenia and did not modify the endotoxin-induced platelet aggregation in vitro. It is concluded that prostacyclin contributed to the secondary hypotension which accompanied the i.v. administration of endotoxin. Thromboxane A2 seems not to be of primary importance in the endotoxin-platelet interaction.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Antagonism by E. coli endotoxin of some cardiovascular effects induced in the rat by two alpha 2-adrenoceptor agonists.

E. coli endotoxin (0.01, 0.1 and 1 microgram/kg i.v.) 1 h before alpha 2-adrenoceptor agonists B-HT 933 and clonidine (i.v.) antagonized their bradycardiac and hypotensive effects in intact rats. This antagonism seems not to depend on the presence of the adrenal glands since similar results were obtained in adrenalectomized rats. Endotoxin at higher doses (1 and 10 micrograms/kg) suppressed the hypotensive and reduced the bradycardiac effect of clonidine injected i.c.v. (5 micrograms/kg). In contrast, endotoxin (up to 100 micrograms/kg) did neither increase arterial pressure nor heart rate in the pithed rat. This suggests the participation of a central site of action for endotoxin. However, E. coli endotoxin (1, 10 or 100 micrograms/kg) did not decrease the inhibition by clonidine of the tachycardia induced by stimulation of the cardioacceleratory nerve. This excludes peripheral presynaptic alpha 2-adrenoceptor blockade by endotoxin. Only 100 micrograms/kg decreased the pressor response to clonidine in the pithed rat. These results show that E. coli endotoxin is a potent modificator of the cardiovascular regulation in the rat. It antagonized central alpha 2-adrenoceptor mediated cardiovascular effects at doses lower than those acting on postsynaptic peripheral alpha-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1991

Endotoxin-induced impairment of vasodepressor responses in the pithed rat.

The effects of Eschericia coli endotoxin on vascular responsiveness were compared with those of sodium nitroprusside in pithed rats. Infusion of endotoxin (250 micrograms kg-1 h-1) produced a fall in mean arterial blood pressure (11 mmHg) and impaired vasodepressor responses to endothelin, 5-hydroxytryptamine, acetylcholine, bradykinin, sodium nitroprusside and salbutamol. Prevention of endotoxin-induced hypotension with vasopressin infusion (0.64 i.u. kg-1 h-1 i.v.) restored responsiveness to bradykinin, tended to restore responsiveness to endothelin and sodium nitroprusside but failed to restore responsiveness to acetylcholine, 5-HT or salbutamol. Infusion of sodium nitroprusside at a rate (400 micrograms kg-1 h-1) producing a similar fall in blood pressure to that produced by endotoxin markedly impaired vasodepressor responsiveness to 5-HT. However, this was fully restored when the hypotension was prevented by vasopressin infusion. Vasodepressor responsiveness to either acetylcholine or salbutamol was not impaired by sodium nitroprusside in vasopressin-infused rats. The impairment of vasodepressor responsiveness by endotoxin is not due to endotoxin-induced hypotension and does not fit clearly with an endotoxin-mediated impairment of endothelial function.

Acetylcholine↗
PubMed1992

Endotoxin-induced alterations in rat colonic water and electrolyte transport.

This study examines the effects of endotoxin on intestinal water and electrolyte transport in adult male rats. Endotoxin (1.55 mg/kg, intravenously) reduced in vivo colonic saline absorption 61% in 1 hour. In vitro unidirectional and net 22Na and 36Cl fluxes showed that endotoxin significantly decreased net colonic 22Na absorption compared with control colons (0.3 +/- 1.7 vs. 4.8 +/- 1.1 microEq/h x cm2). Although endotoxin had no significant effect on basal short circuit current (Isc) and conductance, 3H-inulin flux studies suggested an increase in colonic permeability. Isc responses to the 5'-cyclic adenosine monophosphate (cAMP)-dependent secretagogues prostaglandin E2 (1 mumol/L) and vasoactive intestinal peptide (0.1 mumol/L) were diminished by 80% and 50%, respectively. However, cytosolic cAMP-dependent protein kinase activity under basal and stimulated (6 mumol/L 8-bromo-cAMP) conditions was not altered by endotoxin treatment. The Isc responses to 10 mumol/L bethanechol, a Ca(2+)-dependent agonist, were not effected by endotoxin treatment. It was concluded that endotoxin significantly affects colonic transport function and may contribute to the development of diarrhea in inflammatory bowel diseases.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1984

Complement and endotoxin-induced lung injury in sheep.

Intravenous infusions of endotoxin in sheep cause lung injury characterized by edema due to increased microvascular permeability. Similar increases in pulmonary microvascular permeability are seen in septic patients with the adult respiratory distress syndrome. Since endotoxin-induced lung injury may be mediated by interactions between products of complement activation and polymorphonuclear leukocytes, plasma and lung lymph from six unanesthetized sheep infused with Escherichia coli endotoxin (1.0 micrograms/kg over 30 min) were examined for complement-derived chemotactic activity. By 2-3 hr following infusion of endotoxin, all animals had the increased lung lymph fluid and protein flows characteristic of permeability edema. Preinfusion samples of plasma and lung lymph did not contain chemotactic activity for polymorphonuclear leukocytes. Following infusion of endotoxin, however, significant chemotactic activity was detected in plasma at 0.5-3.5 hr (P less than 0.05) and in lymph at 1.5-6.5 hr (P less than 0.025). The chemotactic activity was heat stable (56 degrees C for 30 min) but was abolished by treatment with antibodies to C5. These data indicate that infusions of endotoxin lead to the generation in plasma, and the appearance in lung lymph, of C5-derived peptides with chemotactic activity for polymorphonuclear leukocytes. C5-derived peptides may account for the pulmonary microvascular leukostasis and endothelial injury that lead to increased permeability edema after infusions of endotoxin.

Animals↗
PubMed1991

Attenuation of the pulmonary vascular response to endotoxin by a thromboxane synthesis inhibitor (UK-38485) in unanesthetized sheep.

Previous studies have documented the phasic pulmonary vascular response to infused Escherichia coli endotoxin in unanesthetized sheep. Cyclooxygenase inhibition attenuates the initial vasoconstrictive phase (phase I) but not the late phase of increased microvascular permeability (phase II). We undertook to selectively inhibit thromboxane A2 synthesis and assess the pulmonary microvascular response to endotoxin. Twelve paired studies were carried out in six sheep prepared with chronic lung lymph fistulas and pressure monitoring catheters. Each sheep received E. coli endotoxin (0.5 microgram/kg) at time 0, both alone (control group) and 1 hr after pretreatment with a thromboxane synthetase inhibitor (UK-38485, 2 mg/kg). The animals were monitored for 1-2 hr prior to and 5 hr following endotoxin infusion to ensure a steady-state baseline and a complete late response. The pairs of studies were done in random order. In the presence of UK-38485, endotoxin caused significantly less pulmonary hypertension and shorter duration of leukopenia and lower lung lymph flow and lymph protein clearance rates than did endotoxin alone. The differences in lymph protein clearance were more pronounced in phase II. These data suggest that both the vasoconstrictive and permeability phases of the pulmonary vascular response to endotoxin may be modified on endogenous thromboxane A2.

Animals↗
PubMed1991

Chylomicrons can inhibit endotoxin activity in vitro.

Trauma, thermal injury, and nonlethal doses of endotoxin can promote the translocation of endotoxin across the mucosal barrier of the colon into the mesenteric lymphatics and systemic circulation. Bacterial endotoxemia induces changes in lipid metabolism, including an increase in circulating triglyceride-rich lipoproteins. Because cholesterol-rich lipoproteins can neutralize the toxic activity of endotoxin, both in vitro and in vivo, we asked whether triglyceride-rich chylomicrons can inhibit endotoxin activity in vitro as measured by a chromogenic Limulus assay. We tested the effect of intact versus heat-denatured chylomicrons on the in vitro activity of increasing concentrations of Escherichia coli (055:B5) endotoxin. Intact chylomicrons inhibited up to 12-fold the detection of as much as 1 microgram of endotoxin/mg of chylomicron triglyceride, compared to denatured chylomicrons (P less than 0.001). This study shows that chylomicrons are potent inhibitors of endotoxin activity in vitro. Because translocated endotoxin from the colon associates with gut-derived chylomicrons in the mesenteric lymphatics, this may represent a natural defensive mechanism against endotoxemia of enteric origin.

Chylomicrons↗
PubMed1992

Altered ryanodine receptor of canine cardiac sarcoplasmic reticulum and its underlying mechanism in endotoxin shock.

Effects of endotoxin administration on ryanodine receptor in canine cardiac junctional sarcoplasmic reticulum (SR) were studied. The results show that the Bmax for [3H]ryanodine binding to cardiac junctional SR was decreased by 25% (8 +/- 0.38 vs 6 +/- 0.41 pmole/mg protein for control and endotoxic, respectively; (P less than 0.01) while the kd (13.7 +/- 1 nM for control vs 13.2 +/- 2 nM for endotoxic) was unaffected 4 hr following endotoxin administration. Ca2+ activated [3H]ryanodine binding in both groups sigmoidally but the Vmax for Ca2+ activation was decreased by 24% (P less than 0.05) while the S0.5 and the Hill coefficient values remained unchanged after endotoxin injection. Caffeine, ATP, and AMP-PCP activated while calmodulin, SKF-525A, ruthenium red, and Mg2+ inhibited [3H]ryanodine binding in both groups but the A0.5 (concentration requires for half-maximum activation) and the I50 (concentration requires for half-maximum inhibition) for the above-mentioned activators and inhibitors, respectively, were unaffected during endotoxin shock. Digestion of cardiac SR isolated from control dogs with phospholipase A2 inhibited [3H]ryanodine binding and the inhibition was reversed completely by the addition of phosphatidylserine. Addition of phosphatidylserine to cardiac SR isolated from endotoxic dogs stimulated [3H]ryanodine binding and the stimulation represents a complete reversal of the inhibition caused by endotoxin administration. Based on these findings together with previous observation that phospholipase A2 activity is activated during endotoxin shock, it is concluded that endotoxin administration decreases the number of ryanodine receptor in canine cardiac junctional SR and the decrease in ryanodine receptor is associated with a mechanism involving a modification of membrane lipid microenvironment in response to phospholipase A2 activation.

Adenosine Triphosphate↗
PubMed1991

Serum cortisol changes in heifers induced by lipid X: a monosaccharide precursor in the biosynthesis of Gram-negative endotoxin.

An experiment was conducted to measure the changes in serum cortisol and luteinising hormone (LH) concentrations in heifers during the luteal phase of the oestrous cycle after the administration of lipid X and Gram-negative endotoxin. Nine heifers whose oestrous cycles were synchronised with prostaglandin F2 alpha were assigned at random on day 10 after the second prostaglandin injection to one of the following groups. Group 1 heifers (n = 3) received 5 micrograms kg-1 bodyweight of Escherichia coli endotoxin as an intrauterine infusion and one hour later received an intravenous injection of lipid X (5 micrograms kg-1 bodyweight). The treatment was reversed in group 2 heifers (n = 3), endotoxin was administered one hour after the lipid X treatment. Group 3 heifers (n = 3) received endotoxin infusion and lipid X treatment at the same time. Similar dosages and routes of administration were used in all the groups for lipid X and endotoxin treatments. Blood samples were collected once every 15 minutes for seven hours, beginning once hour before and six hours after the initial treatment. In group 1 heifers there was a fourfold increase in serum cortisol concentrations within 30 minutes after both the treatments (from 6.5 to 24.6 ng ml-1 and from 7.3 to 29.5 ng ml-1 respectively). In group 2 heifers the cortisol concentrations increased from the baseline concentrations of 7.2 to 33.2 ng ml-1 within 30 minutes after lipid X treatment and remained at 22.5 ng ml-1 during endotoxin treatment. There was a further increase in cortisol concentrations (28.9 ng ml-1) after the endotoxin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Role of alveolar macrophages in endotoxin-induced neutrophilic alveolitis in rats.

Although bacterial endotoxins have potent effects on blood monocytes and tissue macrophages, the role of alveolar macrophages in regulating intrapulmonary neutrophil traffic following endotoxemia has not been studied previously. We have previously reported that a single intraperitoneal injection of endotoxin from Escherichia coli serotype 055B5 causes acute lung inflammation by neutrophils (PMN) in rats. The factors which influence the migration of PMN in the lung in this model are unknown. To determine whether macrophage-derived products could play a role in directing migration, we enumerated neutrophils in histologic sections and employed electron microscopy to document the location of neutrophils in the lung in vivo following endotoxin. We also cultured the alveolar macrophages recovered by lung lavage to measure the effect of their culture supernatants on neutrophil migration in vitro. In the first 6 hr following endotoxin, and also 24 hr later, there was an increase in the number of PMN enumerated in the lung parenchyma by light microscopy. Electron microscopy showed the location of the neutrophils to be exclusively intravascular at 6 hr. By contrast, neutrophils were observed in both interstitial and bronchoalveolar spaces at 24 hr, confirming that transvascular migration was active at that time. The pulmonary macrophages which were recovered by lung lavage from groups of rats sacrificed at 4 and at 15 hr following the administration of endotoxin were assayed for the release into culture media of migration-stimulatory activity for neutrophils. Macrophages from animals sacrificed 4 hr following endotoxin released less migration-stimulating activity into media than macrophages from controls. These macrophages could be stimulated to release migration-stimulating activity into culture media at levels comparable to macrophages from controls by the addition of opsonized Zymosan to the culture media. By contrast, macrophages from animals sacrificed 15 hr after endotoxin spontaneously released more migration-stimulating activity for neutrophils than did macrophages from controls. Thus, in this model, a specific increase in the synthesis or release by alveolar macrophages of factors which stimulate the migration of neutrophils in vitro coincided with a transition from intravascular to extravascular alveolar inflammation by neutrophils in vivo. These observations are consistent with the hypothesis that pulmonary alveolar macrophages may contribute to the regulation of alveolar inflammation following endotoxemia by releasing factors which influence the migration of neutrophils.

Animals↗