Biomedical subjects

J C Keith

Publications and source records attributed to J C Keith.

At least 19 recordsLinked to original sources

PubMed2005

Interleukin-11 reduces renal injury and glomerular NF-kappa B activity in murine experimental glomerulonephritis.

BACKGROUND/AIMS: There is now considerable evidence implicating T cells and macrophages in glomerular injury in crescentic glomerulonephritis. Recently, it has been shown that interleukin-11 (IL-11) has an immune modulatory function through its effect on both macrophages and T cells. We, therefore, examined the therapeutic effect of IL-11 in a murine model of experimental glomerulonephritis. METHOD: Accelerated nephrotoxic nephritis was induced in C57BL/6 mice. IL-11 at a dose of 0.5 mg/kg/day (n = 10) in vehicle was given daily subcutaneously from the day of sensitization until day 14 after initiation of glomerulonephritis. Control mice (n = 10) received injection of vehicle alone with the same schedule. RESULTS: IL-11 treatment markedly decreased albuminuria (6.2 +/- 1.9 vs. 18.2 +/- 4.5 mg/day, p < 0.05), the number of glomerular macrophages (1.1 +/- 0.2 vs. 1.7 +/- 0.3 cells/glomerular cross-section, p < 0.05) and glomerular fibrin deposition (fibrin score 0.9 +/- 0.3 vs. 2 +/- 0.3, p < 0.05). There was no difference in the glomerular T cell numbers between the IL-11-treated and the vehicle group. Glomerular NF-kappaB activity was markedly suppressed by 75% in the treated group (p = 0.0015). CONCLUSION: In this study, we provide the first in vivo evidence that IL-11 treatment decreases glomerular NF-kappaB activity and reduces renal injury in experimental glomerulonephritis.

Albuminuria↗

PubMed2002

Differential effects of IL-11 on rat blastocysts and decidua during the peri-implantation period.

PROBLEM: To study effects of interleukin-11 (IL-11) on blastocyst development and decidualization. METHOD OF STUDY: Rats, injected with buffer (C) or IL-11 [1 mg/kg/day = high dose (HD), 60 microg/kg/week = low dose (LD)-1, 30 microg/kg twice a week = low dose (LD)-2] were made pregnant or pseudopregnant to obtain blastocysts or deciduomata. RESULTS: As compared with C, more LD-2 blastocysts hatched in culture, while hatching and attachment of HD blastocysts was decreased. Blastocysts from untreated rats in IL-11 supplemented medium (4 ng/mL) demonstrated increased hatching and attachment. The weight of the decidualized uterus in HD and LD-2 pseudopregnant rats was reduced as compared with C and LD- 1. On deciduomata sections from IL-11 treated rats, the area inside the uterine muscle layer was reduced, and mitotic over pycnotic indices were increased in the anti-mesometrial area and decreased in the mesometrial area. CONCLUSIONS: Low doses of IL-11 improve hatching and attachment of blastocysts, but both high and low doses impair decidualization.

Animals↗

PubMed2002

Pharmacokinetics of recombinant factor IX after intravenous and subcutaneous administration in dogs and cynomolgus monkeys.

Hemophilia B therapy requires intravenous (IV) infusions of large volumes of factor IX due to the low concentration of factor IX in concentrates (approximately 100 IU/mL). High concentration recombinant factor IX (rFIX) could be a significant advance since it would reduce the large volumes necessary for IV dosing and allow for low-volume subcutaneous (SC) administration. To evaluate high concentration factor IX, we produced formulations with either 2,000 or 4,000 IU/mL and studied the SC bioavailability in beagle dogs, cynomolgus monkeys and hemophilia B dogs along with efficacy in hemophilia B dogs. Beagle dog SC bioavailability was 86.4% using a 2000 IU/mL formulation and 77.0% using a 4000 IU/mL formulation. Monkey bioavailability of a 4000 IU/mL formulation of rFIX was 34.8%. A single SC administration of 200 IU/kg (4000 IU/mL) of rFIX to hemophilia B dogs, produced factor IX clotting activity above 5% for 5 days with a bioavailability of 48.6%. High concentration SC rFIX has an acceptable pharmacokinetic profile in monkeys and dogs, and produces a sustained FIX activity in hemophilic dogs.

Animals↗

PubMed2001

Effect of recombinant human interleukin-11 on motilin and substance P release in normal and inflamed rabbits.

Recombinant human interleukin-11 (rhIL-11) normalizes depressed smooth muscle tension generation towards motilin and substance P (SP) in rabbits with colitis. The aim of this paper was to evaluate the effect of rhIL-11 treatment on motilin and SP release which could have an effect on the contractility changes. Rabbits received 4, 40, 72 or 720 microg/kg rhIL-11 s.c. or saline, 1 h later a continuous s.c. administration of rhIL-11 was started with or without the induction of colitis (135 mg/kg TNBS) for 5 days. Motilin and SP levels were measured by RIA, motilin mRNA expression by RT-PCR. TNBS-colitis did not affect plasma motilin levels but increased the motilin content of the duodenal mucosa 1.7-fold. rhIL-11 treatment dose-dependently increased plasma motilin levels (720 microg/kg day: 3.5-fold) and the motilin content of the duodenal mucosa (720 microg/kg day: 3.0-fold). The effects of rhIL-11 were similar in normal rabbits and were accompanied by an increased motilin mRNA expression. TNBS-colitis decreased plasma SP levels 2.7-fold and the SP content in the colonic muscle layer 7.1-fold. The decrease in the muscle layer, but not in the plasma, was normalized by rhIL-11 treatment. In normal rabbits, rhIL-11 caused a decrease in plasma SP levels, but had no effect on the tissue content of SP. In conclusion, treatment of inflamed or normal rabbits with rhIL-11 increases plasma and tissue levels of motilin in the duodenal mucosa via an increased expression of motilin in the endocrine cells and induces the release of SP from extrinsic neurons. These changes do not explain the beneficial effect of rhIL-11 on the lowered contractility in inflamed rabbits although a change in balance of neuropeptides may influence gastro-intestinal inflammation.

Animals↗

PubMed2001

Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia.

Development of placentation and successful pregnancy depend on co-ordinated interactions between the maternal decidua and myometrium, and the invasive properties of the fetal trophoblast. Syncytin, a protein encoded by the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W, is highly expressed in placental tissue. Previously, we have shown that the major site of syncytin expression is the placental syncytiotrophoblast, a fused multinuclear syncytium originating from cytotrophoblast cells. Here we present the first evidence that in pre-eclampsia, syncytin gene expression levels are dramatically reduced. Additionally, immunohistochemical examination of normal placentae and placentae from women with pre-eclampsia reveals that the syncytin protein in placental tissue from women with pre-eclampsia is localized improperly to the apical syncytiotrophoblast microvillous membrane as opposed to its normal location on the basal syncytiotrophoblast cytoplasmic membrane. Our previous results suggest that syncytin may mediate placental cytotrophoblast fusion in vivo and may play an important role in human placental morphogenesis. The present study suggests that altered expression of the syncytin gene, and altered cellular location of its protein product, may contribute to the aetiology of pre-eclampsia.

Female↗

PubMed2001

Evaluation of the safety of recombinant P-selectin glycoprotein ligand-immunoglobulin G fusion protein in experimental models of localized and systemic infection.

P-selectin is a major component in the early interaction between platelets, endothelial cells, and inflammatory cells in the initial phases of the innate immune response. The major ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) and this ligand is expressed on the surface of monocyte, lymphocyte, and neutrophil membranes. A truncated form of recombinant human P-selectin glycoprotein ligand-1 has been covalently linked to immunoglobulin G (rPSGL-Ig) and this fusion peptide functions as a competitive inhibitor of PSGL-1. As an inhibitor of neutrophil-endothelial cell adherence, rPSGL-Ig is in early clinical development for the treatment of ischemia reperfusion injury. To determine the potential for deleterious effects from inhibition in P-selectin-mediated neutrophil attachment in the presence of bacterial infection, the effects of therapeutic doses of rPSGL-Ig were tested in three standard laboratory sepsis models. The experimental models included: the murine systemic Listeria monocytogenes infection model, the Pseudomonas aeruginosa bacteremia model in neutropenic rats, and the cecal ligation and puncture (CLP)-induced peritonitis model in rats. Recombinant human PSGL-Ig had no adverse effects on mortality or immune clearance in systemic bacterial infection in any of the three infection models. The PSGL-1 inhibitor did significantly decrease local neutrophil infiltration and bacterial clearance in the peritoneum following CLP, but this did not increase the systemic levels of proinflammatory cytokines, the quantitative levels of bacteremia, or the overall mortality rate following CLP. The results indicate that rPSGL-Ig did not exacerbate infection in these experimental sepsis models.

Animals↗

PubMed2001

Intratracheal administration of recombinant human factor IX (BeneFix) achieves therapeutic levels in hemophilia B dogs.

The purpose of this paper was to establish proof of concept for administration of human recombinant F.IX (rF.IX) by inhalation for therapy of hemophilia B. The pharmacokinetics of intratracheal (IT) administration of rF.IX was studied in nine hemophilia B dogs randomized into 3 groups that received 200 IU/kg IT, 1,000 IU/kg IT, or 200 IU/kg intravenously (IV). IT rF.IX produced therapeutic levels of F.IX antigen and activity and the pharmacokinetic parameters were consistent with a slow release from a depot site within the lungs. Bioavailability compared to IV administration was 11% for 200 IU/kg IT and 4.9% for 1,000 IU/kg. The whole blood clotting time began to shorten at 2 h but F.IX bioactivity was not detected until 8 h post infusion in both IT groups. In all groups, F.IX activity was detected through 72 h post administration. These data demonstrate that biologically active rF.IX can reach the systemic circulation when given IT. Aerosolization of rF.IX may provide a needle-free therapeutic option for delivery of rF.IX to hemophilia B patients.

Administration, Inhalation↗

PubMed2001

Recombinant human interleukin-11 restores smooth muscle function in the jejunum and colon of human leukocyte antigen-B27 rats with intestinal inflammation.

Recombinant human interleukin (rhIL)-11 has anti-inflammatory and protective effects in models of intestinal mucosal injury. Our aim was to investigate whether oral treatment with rhIL-11 reverses functional abnormalities in intestinal muscle contractility resulting from human leukocyte antigen (HLA)-B27-dependent gut inflammation. Isometric contractions were studied in jejunal and colonic longitudinal muscles. Muscle strips were isolated from HLA-B27 transgenic rats with spontaneous inflammation following treatment with enteric-coated rhIL-11 multiparticulates (500 microg/kg) or placebo multiparticulates given orally every 48 h for 2 weeks. Myeloperoxidase (MPO) activity was measured in intestinal tissue samples and served as an index of inflammation. Colonic damage was also assessed histologically. The HLA-B27 rats receiving placebo had chronic diarrhea, and MPO activity was increased in the jejunum and colon. Intestinal inflammation was associated with a decreased ability of the muscles to generate active tension in response to electrical field stimulation, carbachol, or high KCl. In the jejunum of placebo-treated HLA-B27 rats, concentration-effect curves for carbachol were shifted to lower concentrations yielding a higher EC50. Oral treatment of HLA-B27 rats with rhIL-11 suppressed the symptoms of diarrhea, normalized MPO activity, and improved the colonic damage score. Simultaneously, neurally mediated responses were improved and the maximal tension generated by carbachol or KCl was normalized in the jejunum and colon. The EC50 for carbachol in the jejunum of HLA-B27 rats was also normalized by rhIL-11 treatment. Our data demonstrate that oral administration of enteric-coated rhIL-11 suppresses intestinal inflammation and reverses intestinal smooth muscle dysfunction in HLA-B27 transgenic rats.

Animals↗

PubMed2000

Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.

Many mammalian viruses have acquired genes from their hosts during their evolution. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Here we describe the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that we have called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W. We find that the major sites of syncytin expression are placental syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts. We show that expression of recombinant syncytin in a wide variety of cell types induces the formation of giant syncytia, and that fusion of a human trophoblastic cell line expressing endogenous syncytin can be inhibited by an anti-syncytin antiserum. Our data indicate that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.

Amino Acid Sequence↗

PubMed2000

Effects of interleukin 11 (IL-11) on early post-implantation development of the rat.

The development of embryos, trophoblast and decidua of IL-11-treated rats were examined in vivo, while ectoplacental cones (EPC) were studied in vitro. Female Wistar rats were injected daily with buffer (C), 1 mg/kg IL-11 (HD) daily or 30 microgram/kg (LD) IL-11 twice a week. On day 9 of pregnancy, embryonic tissue volume was reduced in IL-11-treated animals, but EPC volume was elevated, compared to controls. Mitotic indices were reduced in embryos (P<0.05 for LD, P<0.001 for HD) and in EPCs of both groups. Pycnotic indices were elevated in LD (NS) and HD (P<0.05) embryos, but decreased in EPCs of the LD group (P<0.01). Morphological abnormalities were observed in decidua, embryo and trophoblast. In HD, EPC attachment was impaired after 1 day culture but proliferation was stimulated after 5 days. Defective decidualization in IL-11 treated rats may therefore result in abnormal development of embryo and trophoblast.

Animals↗

PubMed2000

Recombinant human interleukin-11 modulates ion transport and mucosal inflammation in the small intestine and colon.

Human recombinant interleukin 11 (rhIL-11) is a cytokine that suppresses the clinical signs of colitis in animal models of inflammatory bowel disease (IBD) and may be an effective therapeutic agent in the treatment of IBD. The objective of the current study was to investigate whether rhIL-11 was capable of reversing abnormalities in secretomotor function associated with gut inflammation. We investigated the effects of rhIL-11 on epithelial electrogenic ion transport in the jejunum and colon. Application of rhIL-11 (10 to 10,000 ng/ml) at either the luminal or serosal side of mucosal sheets isolated from control rats induced a concentration-dependent reduction of transmural potential difference (PD) in the jejunum and decreased the short-circuit current (Isc), representative of active electrogenic transport, in the colon. To investigate the effect of rhIL-11 on an inflamed gut, we isolated jejunal and colonic tissue from HLA-B27 transgenic rats with active inflammation of the bowel that represents an animal model of IBD. In jejunum and colon isolated from HLA-B27 transgenic rats, basal electrogenic ion transport was significantly attenuated and, under these conditions, rhIL-11 caused no changes in either transmural PD or Isc. However, in HLA-B27 rats, pretreatment with subcutaneous doses of rhIL-11 suppressed the symptoms of diarrhea, normalized myeloperoxidase activity in the jejunum and colon and healed mucosal injury. In the jejunum from HLA-B27 rats, healing of the intestinal inflammatory response enhanced basal transmural PD and the rhIL-11-duced changes in mucosal ion transport resembled those seen in uninflamed controls. Conversely, in the colon, healing of the mucosa did not normalize basal active ion transport nor did it reverse the inhibition of rhIL-11-induced changes in colonic Isc. Our results suggest that endogenous IL-11 may act as a modulator of epithelial transport under physiologic conditions and may act as a potent anti-inflammatory cytokine during active intestinal inflammation.

Animals↗

PubMed2000

Recombinant human interleukin-11 has anti-inflammatory actions yet does not exacerbate systemic Listeria infection.

To determine whether recombinant human (rh) interleukin (IL)-11 disrupts the clearance of microbial pathogens, mice were challenged with Listeria monocytogenes after receiving high-dose rhIL-11, anti-tumor necrosis factor (TNF) monoclonal antibody (MAb), anti-IL-11 MAb, or saline control. The LD50 was not affected by rhIL-11 but was 10-fold lower in the anti-TNF MAb group (P<.001). Plasma IL-6, IL-1beta, and TNF-alpha levels were not different between rhIL-11-treated animals and the control group; however, interferon-gamma levels were significantly reduced by IL-11 treatment (2477 vs. 0 pg/mL, P<.01). Compared with the control group, the quantitative level of L. monocytogenes in hepatic and splenic tissue was unchanged by rhIL-11 but was significantly increased by TNF or IL-11 inhibition. The results indicate that IL-11 down-regulates cytokine production but does not exacerbate systemic infection in the murine Listeria infection model.

Animals↗

PubMed2000

Cytotoxic effects of tumour necrosis factor (TNF)-alpha and interferon-gamma on cultured human trophoblast are modulated by fibronectin.

Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, produced by maternal inflammatory cells, may compromise trophoblast survival at the trophoblast-maternal interface and notably in the placental bed which is invaded by trophoblast. Extracellular matrix components, e.g. fibronectin, may enhance trophoblast survival. A possible protective effect of fibronectin against toxic effects of TNF-alpha and IFN-gamma was investigated in cultured trophoblasts isolated from six human term placentas, grown on uncoated and fibronectin-coated plastics. IFN-gamma and increasing doses of TNF-alpha resulted in decreasing viability of trophoblast on uncoated as well as fibronectin-coated dishes, as shown by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays, but for each TNF/IFN treatment condition viability on fibronectin was higher (P < 0.001). Epidermal growth factor (EGF), a growth factor reported to protect against TNF-alpha/IFN-gamma induced toxicity, resulted in further increased viability, but not if IFN-gamma was included in the treatment. EGF caused increased fibronectin secretion into the medium (P < 0.001), and double cytokeratin/fibronectin immunostaining confirmed the trophoblastic nature of fibronectin secreting cells. We conclude that fibronectin increases viability, but does not completely abolish the cytotoxic action of TNF-alpha and IFN-gamma on trophoblast. The protective effect of EGF may be related to stimulation of fibronectin secretion by trophoblast.

Cell Survival↗

PubMed2000

Recombinant human interleukin-11 decreases severity of acute necrotizing pancreatitis in mice.

Interleukin (IL)-11 has anti-inflammatory activity in animal models of gut inflammation, endotoxemia, and radiation-induced thoracic injury. The aim of the present study was to investigate the protective role of IL-11 in a model of acute necrotizing pancreatitis in mice. Acute pancreatitis was induced by administration of seven intraperitoneal injections of cerulein (50 microg/kg) at hourly intervals. Lipopolysaccharide (LPS) was injected 5 hours after the first cerulein injection. Treatment with recombinant human IL-11 (rhIL-11) was started 30 minutes before the first cerulein injection and repeated 4 hours later. Serum levels of amylase, lipase, and tumor necrosis factor (TNF)-alpha were measured at the end of the experiments. The severity of pancreatitis was evaluated by histological scoring using a semiquantitative analysis of hematoxylin and eosin-stained sections of the pancreas. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to quantify the intrapancreatic TNF-alpha mRNA levels. Serum amylase and lipase levels progressively increased with a maximum reached between 8 and 11 hours. Treatment with rhIL-11 significantly decreased amylase and lipase levels at 6 and 8 hours. Serum TNF-alpha peaked at 6 hours and rapidly decreased thereafter. The elevation of serum TNF-alpha was markedly inhibited by treatment with rhIL-11. Histologically, treatment of rhIL-11 reduced the severity of pancreatic injury including edema, inflammatory cell infiltration, and hemorrhage at 6 hours. Intrapancreatic TNF-alpha mRNA levels were reduced by >50% in the rhIL-11-treated group at 6 hours. In conclusion, rhIL-11 decreased the severity of experimental pancreatitis early on but not later and inhibited the intrapancreatic TNF mRNA expression in vivo, suggesting that the protective effect of IL-11 during the early stage of acute pancreatitis may be mediated, at least in part, through modulation of TNF production.

Amylases↗

PubMed2000

Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects.

Recombinant human interleukin-11 (rhIL-11), or Neumega rhIL-11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti-inflammatory and immune-modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL-11-induced volume retention and devise a possible therapeutic intervention to ameliorate this effect. Eighteen healthy volunteers (9 male and 9 female) on a controlled sodium (180 mEq/day) and potassium (120 mEq/day) diet were randomized to one of six treatment sequences in a three-period crossover design. Each subject received 25 micrograms/kg IL-11 s.c. once daily, 25 micrograms/kg IL-11 s.c. once daily + Maxzide-25 twice daily, or placebo for 7 days in a crossover design. There was a 14-day washout period between treatment periods. Renal clearance parameters indicated that mean sodium excretion was decreased compared to placebo within 8 hours after dosing with rhIL-11, with these results reaching statistical significance 8 to 16 hours postdose (p < 0.01). The cumulative sodium excretion (mEq +/- SD) over the 7-day treatment period for each respective treatment group was the following: rhIL-11 = 833 +/- 154, rhIL-11 + Maxzide-25 twice daily = 1114 +/- 178, and placebo = 982 +/- 193 (p < 0.01). Hemoglobin concentration and hematocrit values, used as indicators of hemodilution, decreased in the rhIL-11-treated group as compared to the baseline and placebo groups (p < 0.01). Concurrent dosing with Maxzide-25 twice daily reduced the rhIL-11-associated hemodilution by about 50%.

Adult↗

PubMed2000

Dose-dependent effects of recombinant human interleukin-11 on contractile properties in rabbit 2,4,6-trinitrobenzene sulfonic acid colitis.

We studied the effect of recombinant human interleukin-11 (rhIL-11), a cytokine with protective effects against injury to the intestinal mucosa, on inflammatory changes in the muscle layers of the gut, in rabbits with colitis. A single dose of rhIL-11 (4, 40, or 720 microg/kg) was given 1 h before colitis was induced with 135 mg/kg 2, 4,6-trinitrobenzene sulfonic acid (TNBS), followed by a continuous s. c. administration of 4, 40, or 720 microg/kg. day rhIL-11 or saline for 5 days. Colitis affected mucosal architecture, general mechanical properties (passive tension increased with 12.3 g/mm(2), optimal stretch decreased with 26%), and collagen content (decreased from 366 +/- 25 to 237 +/- 13 microg/mg of protein). Changes in passive tension and collagen content were normalized by the highest and lowest dose of rhIL-11, respectively, but neither dose could normalize the optimal stretch. Colitis also decreased maximal contractile tension in response to acetylcholine (ACh), motilin, substance P (SP), K(+), and prostaglandin E(2) but this was normalized with 40 microg/kg. day (motilin, SP) and 720 microg/kg. day (ACh, K(+)) rhIL-11 but not for prostaglandin E(2). For motilin and SP, receptor density was decreased in colitis and normalized in treated rabbits. Colitis also increased the contractile potency toward ACh, an effect already reversed by rhIL-11, 4 microg/kg. day. In conclusion, rhIL-11 partially normalizes disturbed tension generation in experimental colitis. The use of this cytokine in the treatment of irritable bowel disease may contribute to the restoration of motor dysfunction.

Acetylcholine↗

PubMed1999

Additive effects of human recombinant interleukin-11 and granulocyte colony-stimulating factor in experimental gram-negative sepsis.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to promote granulocyte recovery from a variety of pathologic states. Recombinant human interleukin-11 (rhIL-11) has recently become available clinically as a platelet restorative agent after myelosuppressive chemotherapy. Preclinical data has shown that rhIL-11 limits mucosal injury after chemotherapy and attenuates the proinflammatory cytokine response. The potential efficacy of combination therapy with recombinant human forms of rhIL-11 and rhG-CSF was studied in a neutropenic rat model of Pseudomonas aeruginosa sepsis. At the onset of neutropenia, animals were randomly assigned to receive either rhG-CSF at a dose of 200 micrograms/kg subcutaneously every 24 hours for 7 days; rhIL-11 at 200 micrograms/kg subcutaneously every 24 hours for 7 days; the combination of both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of cyclophosphamide. rhG-CSF resulted in a slight increase in absolute neutrophil counts (ANC), but did not provide a survival advantage (0 of 12, 0% survival) compared with the placebo group (1 of 12, 8% survival). rhIL-11 was partially protective (4 of 10, 40% survival); the combination of rhG-CSF and rhIL-11 resulted in a survival rate of 80% (16 of 20; P <.001). rhIL-11 alone or in combination with rhG-CSF resulted in preservation of gastrointestinal mucosal integrity (P <.001), lower circulating endotoxin levels (P <.01), and reduced quantitative levels of P. aeruginosa in quantitative organ cultures. These results indicate that the combination of rhIL-11 and rhG-CSF is additive as a treatment strategy in the prevention and treatment of experimental Gram-negative sepsis in immunocompromised animals. This combination may prove to be efficacious in the prevention of severe sepsis in neutropenic patients.

Animals↗

PubMed1999

Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model.

BACKGROUND: We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-1 chimera (rPSGL-Ig) in conjunction with thrombolytic therapy would enhance thrombolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall. METHODS AND RESULTS: An occlusive thrombus was formed in an internal iliac artery of Yorkshire pigs by placement of a copper coil in the artery under fluoroscopic guidance. Pigs then received heparin and, 15 minutes later, either vehicle or rPSGL-Ig followed by infusion with 25 mg tissue plasminogen activator according to the 90-minute regimen. Blood flow through the artery was monitored by angiography and scored on a scale of 0 to 3. Lysis of the thrombus was accelerated by 70% in pigs treated with rPSGL-Ig 250 microg/kg compared with control (13.3+/-5.0 versus 44. 4+/-13.3 minutes; n=9 each). Eight of 9 control pigs reoccluded in 13.8+/-16.9 minutes after the end of tissue plasminogen activator infusion, whereas no reocclusion was observed in 8 of 9 pigs in the rPSGL-Ig group. When the dose of rPSGL-Ig was increased to 500 microg/kg, time to lysis was shortened by 61% from control (18.0+/-8. 4 versus 46.0+/-8.9 minutes). Reocclusion occurred in 6.0+/-15.2 minutes in control but not in any rPSGL-Ig-treated pig (n=5 each). In addition, near-normal flow (score 2 or 3) after thrombolysis was achieved 59% and 58% faster in the 2 rPSGL-Ig groups than in their respective controls. CONCLUSIONS: Inhibition of leukocyte accumulation at the site of thrombosis with rPSGL-Ig may represent a safe therapeutic intervention that could be important in accelerating thrombolysis, achieving optimal reperfusion, and reducing incidence of acute reocclusion.

Animals↗