Biomedical subjects

J Shou

Publications and source records attributed to J Shou.

At least 37 records · Page 2Linked to original sources

PubMed1997

Molecular alteration of alpha-induced transformed Syrian hamster embryo cells.

Syrian hamster embryo (SHE) cells are irradiated by alpha particles emitted from Plutonium-238 in vitro. Transfection frequencies of donor DNA derived from passaged cells, including monocloned cells from 20th passage cells, after irradiation are parallel with their tumorigenicity of donor cells. After transformation, expressions of H-ras and c-myc genes are in the state of activation, which might be resulted from occurrence of mutation in H-ras gene and hypomethylation of c-myc gene respectively, even though no alteration was observed on their restriction fragment length polymorphisms (RELP) patterns of both genes. On the other hand, expression of p53 gene is also found to be in the state of activation in transformant, but no heavy staining of p53 protein appeared in the transformant-derived tumor with p53 specific McAb HD 200. This might be result from the partial deletion of p53 cDNA in transformant by reverse transcriptional polymerase chain reaction (RT-PCR). These results imply that activation of H-ras and c-myc genes coupled with inactivation of p53 tumor suppressor gene play important role in alpha particle-induced cell transformation.

Alpha Particles↗

PubMed1996

Colony-forming progenitors from mouse olfactory epithelium: evidence for feedback regulation of neuron production.

The mammalian olfactory epithelium (OE) supports continual neurogenesis throughout life, suggesting that a neuronal stem cell exists in this system. In tissue culture, however, the capacity of the OE for neurogenesis ceases after a few days. In an attempt to identify conditions that support the survival of neuronal stem cells, a population of neuronal progenitors was isolated from embryonic mouse OE and cultured in defined serum-free medium. The vast majority of cells rapidly gave rise to neurons, which died shortly thereafter. However, when purified progenitors were co-cultured with cells derived from the stroma underlying the OE, a small subpopulation (0.07-0.1%) gave rise to proliferative colonies. A morphologically identifiable subset of these colonies generated new neurons as late as 7 days in vitro. Interestingly, development of these neuronal colonies was specifically inhibited when purified progenitors were plated onto stromal feeder cells in the presence of a large excess of differentiated OE neurons. These results indicate that a rare cell type, with the potential to undergo prolonged neurogenesis, can be isolated from mammalian OE and that stroma-derived factors are important in supporting neurogenesis by this cell. The data further suggest that differentiated neurons provide a signal that feeds back to inhibit production of new neurons by their own progenitors.

Animals↗

PubMed1996

Neurogenesis and cell death in olfactory epithelium.

The olfactory epithelium (OE) of the mammal is uniquely suited as a model system for studying how neurogenesis and cell death interact to regulate neuron number during development and regeneration. To identify factors regulating neurogenesis and neuronal death in the OE, and to determine the mechanisms by which these factors act, investigators studied OE using two major experimental paradigms: tissue culture of OE; and ablation of the olfactory bulb or severing the olfactory nerve in adult animals, procedures that induce cell death and a subsequent surge of neurogenesis in the OE in vivo. These studies characterized the cellular stages in the olfactory receptor neuron (ORN) lineage, leading to the realization that at least three distinct stages of proliferating neuronal precursor cells are employed in generating ORNs. The identification of a number of factors that act to regulate proliferation and survival of ORNs and their precursors suggests that these multiple developmental stages may serve as control points at which cell number is regulated by extrinsic factors. In vivo surgical studies, which have shown that all cell types in the neuronal lineage of the OE undergo apoptotic cell death, support this idea. These studies, and the possible coregulation of neuronal birth and apoptosis in the OE, are discussed.

Animals↗

PubMed1996

Oncogenic transformation of Syrian hamster embryo cells by 5.3-MeV alpha particles and a tumor promoter phorbol ester.

The primary Syrian hamster embryo (SHE) cells were used to study the oncogenic transformation by 238pu alpha particles or X-rays alone or in combination with a chemical promoter phorbol ester. Survival curves of SHE cells following exposure to alpha-particles or X-rays were fitted to single-or multi-target models, respectively. Model parameters were: Do = 0.55 Gy, n = 1 for alpha particles; Do = 1.44 Gy, Dq = 3.0 Gy, n = 7.7 for X-rays. Incidence of alpha particles or X-rays induced cell transformation was dose-dependent. alpha particles were more efficient in inducing cell transformation than that of X-rays. The enhancement of SHE cell transformation by phorbol 12-myristate 13-acetate (PMA) following exposure to alpha particles of 0.25-1.00 Gy was observed.

Animals↗

PubMed1996

Partial deletion of p53 gene in alpha particle-induced transformant of Syrian hamster embryo cells.

The mutation of p53 gene was detected in Syrian hamster embryo (SHE) cells neoplastically initiated with alpha particles. The level of the p53 mRNA in transformant was obviously higher than that in non-irradiated counterpart, as measured by Northern blot analysis of total RNA. A pair of primers were designed based on p53 cDNA sequence to produce the whole length of coding sequence about 1.2 kilobase (Kb) by reverse transcription of mRNA followed by the polymerase chain reaction (RT-PCR), but the length of fragment amplified from transformant mRNA was about 0.3 Kb, remarkably shorter than that from normal SHE cells. Immunohistochemical analysis of p53 protein showed that no heavy staining was found on slice of tumor derived from transformant inoculated in nude mice with hamster specific p53 monocloned antibody HD200. The results implied that p53 gene had been mutated by deletion, which might lead to loss of p53 protein expression but the increased expression of p53 remained in alpha particle-induced SHE transformant.

Animals↗

PubMed1996

[DNA damage induced by fotemustine in cultured HL60 cells].

AIM: To detect DNA damage caused by fotemustine (Fot). METHODS: DNA damage in HL60 cells was evaluated by modified alkaline elution technique. DNA interstrand crosslink (ISC) and DNA-protein crosslink (DPC) were determined. Carmustine (Car) was used as control. Drug treatment time was 1 h. RESULTS: After treatment with Fot 300 mumol.L-1, ISC and DPC index were 5.4 and 6.1 at 6 h, 2.7 and 1.2 at 12 h, respectively. ISC reached the maximum at about 6 h. For Fot 100 mumol.L-1, ISC and DPC index at ISC peak time were 2.1 +/- 0.9 and 3.55 +/- 0.23, 5.0 +/- 0.5 and 7.7 +/- 1.1 for Car 100 mumol.L-1, respectively. Single strand break (SSB) was induced by Fot. CONCLUSION: Fot caused HL60 cell DNA ISC, DPC, and SSB. ISC was formed more quickly by Fot than that by Car.

Antineoplastic Agents↗

PubMed1995

Antimicrobial effects of granulocyte-macrophage colony-stimulating factor in protein-energy malnutrition.

OBJECTIVES: To evaluate, in a murine model of protein-energy malnutrition, whether granulocyte-macrophage colony-stimulating factor (GM-CSF) improves the host response to a septic challenge and to determine the potential mechanisms involved. DESIGN: Nonblinded study of GM-CSF in mice with protein-energy malnutrition. SETTING: A university-based surgical laboratory and animal facility. INTERVENTION: In study 1, malnourished mice were randomized to receive either GM-CSF (120 micrograms/kg subcutaneously to receive either GM-CSF (120 micrograms/kg subcutaneously from day 4 to 7 of the protein-free diet) or saline vehicle as a control. On day 7, all mice were given Candida albicans (5 x 10(5) organisms intravenously). In study 2, malnourished mice received the same dose of GM-CSF or saline vehicle for 7 days of the protein-free diet. MAIN OUTCOME MEASURES: In study 1 mice were followed up for survival. In study 2, after 7 days of diets, splenic macrophages were harvested and were assayed for interleukin-6, superoxide anion, and nitric oxide production. Splenocytes were stimulated with concanavalin A (5 micrograms/mL) for interleukin-4, interleukin-10, and interferon-gamma production. RESULTS: Treatment with GM-CSF significantly enhanced survival in malnourished mice infected with C albicans. Treatment with GM-CSF was associated with increased production from splenic macrophages of interleukin-6, superoxide anion, and nitric oxide as well as decreased interleukin-4 production from splenocytes. CONCLUSIONS: This study suggests a beneficial role for GM-CSF in the malnourished host predisposed to infection. The antimicrobial properties of GM-CSF may function through enhanced production of nitric oxide and superoxide anion.

Animals↗

PubMed1995

Antigen presentation in protein-energy malnutrition.

Protein-energy malnutrition is associated with intrinsic defects in macrophage (MO) microbicidal function, but effects on MO-CD4+ cell interaction are unclear. This study examined the effect of protein-energy malnutrition on components of Ag presentation (AP) by peritoneal macrophages (PMO) and splenocyte responses (MLR) in the naive (resident) and infected state (mycobacterium-BCG), and assessed the potential role of prostaglandin (PGE2) and L-arginine-derived nitric oxide (NO) as regulatory mechanisms in these immune interactions. Mice were randomized to receive either a control (24% casein, RD) or low-protein (2.5% casein, LPD) diets for 8 weeks. PMO and splenocytes were harvested and AP function and MLR assessed +/- NG-mono-methyl-L-arginine (NMMA; competitive inhibitor of NO. synthesis) or indomethacin (PGE2 inhibitor). PMO components of AP were evaluated, including phagocytic function, MHC-class II (Ia) expression, and interleukin-1 (IL-1) and interleukin-6 (IL-6) production. PGE2 production and NO. (measured as NO-2) synthesis were also assessed. AP and MLR were preserved in protein-energy malnutrition in both resident and activated states. BCG infection in RD was associated with PMO activation as measured by increased O-2 and NO-2 release, but impaired AP and MLR responses. NMMA and indomethacin enhanced AP and MLR in RD groups only. Individual components of PMO AP (phagocytosis, IL-1 and IL-6 production) were defective during protein-energy malnutrition, as were NO-2 and PGE2 production. Thus, AP and MLR were preserved in LPD groups which may be related to a loss of prostaglandin- and L-arginine-mediated suppressor mechanisms.

Animals↗

PubMed1995

Glucocorticoids mediate macrophage dysfunction in protein calorie malnutrition.

BACKGROUND: In hospitalized patients protein calorie malnutrition substantially increases the incidence of infection and death. Protein calorie malnutrition results in significant macrophage dysfunction. Whether a primary nutrient deficit or elevated glucocorticoids levels mediate this dysfunction is unclear. The aim of this study was to evaluate the neuroendocrine response to protein calorie malnutrition and its effects on macrophage function. METHODS: By use of a murine model of protein calorie malnutrition, mice were randomized to (1) a standard 24% casein diet (control), (2) protein-free diet (PFD), (3) PFD in adrenalectomized mice, (4) PFD plus the glucocorticoid receptor antagonist RU486 (10 mg/kg), or (5) a standard 24% casein diet plus a 50 mg corticosterone pellet implanted subcutaneously for 7 days. Mice were killed after 7 days, and body weight and serum albumin and corticosterone levels were measured. Peritoneal macrophages were obtained, and stimulated superoxide and interleukin-6 productions were measured. RESULTS: Protein calorie malnutrition significantly impaired macrophage function and elevated serum glucocorticoid levels. Blocking the stress corticosterone response with adrenalectomy or using RU486 to block corticosterone receptors prevented the impairment of macrophage function without restoring nutritional indexes (body weight and serum albumin level). Administration of glucocorticoids via a subcutaneous pellet reproduced macrophage impairment without leading to nutritional deficits. CONCLUSIONS: The neuroendocrine systemic response to protein calorie malnutrition with elevated serum corticosterone levels is a major determinant of macrophage dysfunction in protein calorie malnutrition.

Animal Nutritional Physiological Phenomena↗

PubMed1995

Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients.

OBJECTIVE: The objective of this study was to evaluate long-term enteral nutrition support in postoperative cancer patients. BACKGROUND: Multimodality therapy for surgical patients with upper gastrointestinal malignancies may improve survival, but often results in substantial malnutrition, immunosuppression, and morbidity. The benefits of combined inpatient and outpatient enteral feeding with standard diets or diets supplemented with arginine, RNA + omega-3 fatty acids are unclear. METHODS: Sixty adult patients with esophageal (22), gastric (16), and pancreatic (22) lesions were stratified by disease site and percent usual weight and randomized to receive supplemental or standard diet via jejunostomy beginning on the first postoperative day (goal = 25 kcal/kg/day) until hospital discharge. Patients also were randomized to receive (n = 37) or not receive (n = 23) enteral jejunostomy feedings (1000 kcal/day overnight) for the 12- to 16-week recovery and radiation/chemotherapy periods. Plasma and peripheral white blood cells were obtained for fatty acid levels and PGE2 production measurements. RESULTS: Mean plasma and cellular omega 3/omega 6 fatty acid levels (percent composition) increased significantly (p < 0.05) in the arginine + omega-3 fatty acid group by postoperative day 7 (0.30 vs. 0.13) and (0.29 vs. 0.14) and continued to increase over time. Mean PGE2 production decreased significantly (p < 0.05) from 2760 to 1600 ng/10(6) cells/mL at day 7 in the arginine + omega-3 fatty acid group, whereas no significant change over time was noted in the standard group. Infectious/wound complications occurred in 10% of the supplemented group compared with 43% of the standard group (p < 0.05); mean length of hospital stay was 16 vs. 22 (p < 0.05) days, respectively. Of the patients who received postoperative chemoradiation therapy, only 1 (6%) of the 18 patients randomized to receive tube feeding did not continue, whereas 8 (61%) of the 13 patients not randomized to tube feedings required crossover to jejunostomy nutritional support. CONCLUSIONS: Supplemental enteral feeding significantly increased plasma and peripheral white blood cell omega 3/omega 6 ratios and significantly decreased PGE2 production and postoperative infectious/wound complications compared with standard enteral feeding. For outpatients receiving adjuvant therapy, those initially randomized to oral feedings alone required rehospitalization more frequently, and 61% crossed over to supplemental enteral feedings.

Aged↗

PubMed1995

[Clinical value of renal radionuclide imaging for diagnosis of urinary tract tumor].

Combined use of 99mTc-diethylenetriaminepentaacetic acid (DTPA) radionuclide angiography, and 99mTc-gluconate renal venography plus single photo computed tomography (SPECT) were employed for clinical diagnosis of urinary tract tumor. This is what we call serial renal radionuclide imaging (SRI). From Aug, 1989 to May, 1993, 63 patients with urinary tract tumor accepted this examination, including 52 cases with renal space-occupying lesion, 5 cases with retroperitoneal mass outside of kidney, 4 cases with bladder cancer (all 61 cases were confirmed by surgery and pathology) and 2 cases suspected of anastomotic leakage after total cystectomy and Bricker's operation. The results show that 1. The renal space-occupying lesion could be accurately localized by SRI and benign lesions could be differentiated from malignancy. 2. SRI could asertain if a retroperitoneal mass was in or outside of the kidney. 3. Urinary fistula could be demonstrated by SRI, while IVU detection failed.

Adolescent↗

PubMed1994

Inhibition of nitric oxide synthesis is detrimental during endotoxemia.

BACKGROUND: Increased production of nitric oxide has been implicated as a mediator during septic shock and sepsis syndrome. Inhibition of nitric oxide production could be beneficial during endotoxemia to improve the individual's hemodynamic status and possibly outcome. OBJECTIVE: To evaluate the effects of nitric oxide inhibition on macrophage function and survival in a murine sepsis model. DESIGN: Sixty-eight female Swiss-Webster (ND4) mice were injected with a sublethal dose of Escherichia coli lipopolysaccharide (25 mg/kg). INTERVENTION: The treated group (n = 34) received 10 mg/kg of NG-nitro-L-arginine methyl ester at the time of lipopolysaccharide injection. MAIN OUTCOME MEASURES: Blood samples and peritoneal macrophages were obtained at baseline and at 2, 4, and 8 hours after injection. Nitrite levels were measured in 36 mice from plasma and supernatant samples of cultured peritoneal macrophages stimulated with interferon gamma (100 micrograms/mL) for 48 hours. Thirty-two animals were observed for survival. RESULTS: Administration of N-nitro-L-arginine methyl ester after lipopolysaccharide injection caused significant reductions in macrophage mean nitrite production from 13 and 15 mumol/L to 7 and 11 mumol/L (P < .05) and reduced mean plasma nitrite concentrations from 100 and 118 mumol/L to 46 and 108 mumol/L (P < .05) at 2 and 4 hours, respectively. The rate of survival was significantly decreased to 0% in the group receiving N-nitro-L-arginine methyl ester after septic challenge compared with 87.5% in controls (P < .005). CONCLUSIONS: Inhibition of nitric oxide production is detrimental in this murine model of endotoxemia.

Animals↗

PubMed1994

Glucocorticoid receptor blockade reverses postinjury macrophage suppression.

OBJECTIVES: To study the effects of the stress-induced surge of endogenous glucocorticoids on macrophage function and the role of inhibiting glucocorticoids with a receptor antagonist, mifepristone (RU 486). DESIGN: One hundred thirty female Swiss-Webster mice were randomly assigned to either injury by femur fracture or uninjured anesthesia control in this intervention study. SETTING: A university-based surgical laboratory and animal facility. INTERVENTION: Injured mice were randomized to receive either the glucocorticoid receptor antagonist mifepristone (10 mg/kg by oral gavage) or its vehicle. Mifepristone or its vehicle were given either 2 hours before or 2 hours after the injury. MAIN OUTCOME MEASURES: Peritoneal macrophages were harvested 24 hours after the injury. Macrophages were assayed for the stimulated (phorbol myristate acetate, 1 microgram/mL) production of superoxide anion, secretion of interleukin-6, tumor necrosis factor alpha, and prostaglandin E2 in response to endotoxin (lipopolysaccharide at 10 micrograms/mL) and killing of Candida albicans. RESULTS: Pretreatment with mifepristone significantly prevented or reduced suppression of several macrophage functions following injury, including superoxide production and C albicans killing. Treatment after the injury preserved only C albicans. Mifepristone failed to block the increased secretion of prostaglandin E2 after injury. CONCLUSION: Pretreatment with mifepristone before an injury prevented suppression of several macrophage functions. Further studies are required on the effects of glucocorticoid inhibition on other aspects of the immune and metabolic responses to injury to define the potential clinical applications of mifepristone trauma.

Administration, Oral↗

PubMed1994

Total parenteral nutrition, bacterial translocation, and host immune function.

Total parenteral nutrition (TPN) is associated with increased infectious complications in trauma and perioperative patients compared with enteral nutrition support. This study evaluated the effects of TPN on splenocyte and peritoneal macrophage (PM phi) function and intestinal bacterial translocation. Male Wistar rats underwent central vein cannulation and were randomized to isocaloric feeding of a regular chow diet (RD) plus saline infusion or TPN for 7 days. Splenocytes and PM phi were harvested to assess concanavalin A mitogenesis, superoxide production, and Candida albicans phagocytosis. Bacteria-positive mesenteric lymph nodes (MLNs) were found in 77% (10 of 13) of TPN-fed rats compared with 17% (2 of 12) of RD-fed rats (p < 0.05). Splenocyte mitogenesis, PM phi superoxide production, and C. albicans phagocytosis were significantly decreased in the TPN group compared with results in the RD group. In a second study, rats received RD, TPN, and parenteral nutrition (PN) with 10% or 20% of calories given as oral chow (PN and 10% chow and PN and 20% chow) for 7 days. PN and 10% chow reversed the TPN-induced suppression of C. albicans phagocytosis. PN + 20% chow significantly increased splenocyte mitogenesis, PM phi superoxide production, and C. albicans phagocytosis and killing to normal levels and was associated with a decreased incidence of bacteria-positive MLN. Thus, administration of TPN is associated with impaired PM phi microbicidal and splenocyte proliferative function. These defective cellular functions were reversed with a small amount of oral feeding.

Animals↗

PubMed1994

Impairment of pulmonary macrophage function with total parenteral nutrition.

OBJECTIVE: The effects of total parenteral nutrition (TPN) administration on pulmonary macrophage function and host response to gram-negative pulmonary infection were evaluated. SUMMARY BACKGROUND DATA: Administration of TPN resulted in increased infectious complications in traumatized and perioperative patients, but underlying mechanisms are unclear. METHODS: Twenty-six male Wistar rats underwent central vein cannulation and were randomized to isocaloric feeding of a regular chow diet (RD) plus saline infusion or TPN without chow diet for 7 days. Pulmonary alveolar macrophage (PAM phi) superoxide production, Candida albicans phagocytosis and killing, and tumor necrosis factor (TNF) production in response to endotoxin (LPS) were assessed. Mesenteric lymph nodes (MLN) were cultured. A second group of rats (n = 6/group) were inoculated intratracheally with a sublethal dose of 9 x 10(9) live Escherichia coli per animal, and the lungs were cultured quantitatively 72 hours later to assess bacterial clearance. Finally, 11 RD-fed rats and 13 TPN-fed rats received intratracheal inoculation of 1.4 x 10(10) live E. coli and were included in follow-up. RESULTS: Administration of TPN was associated with a significant increase in bacteria positive MLN compared with those in the RD group (p < 0.01). Pulmonary alveolar macrophage superoxide production, Candida albicans phagocytosis and killing, TNF production, and pulmonary clearance of bacteria were decreased significantly in TPN-fed rats compared with those fed a regular chow diet (p < 0.05). These pulmonary macrophage function changes were associated with a significantly higher mortality in TPN-fed rats compared with RD-fed rats after higher dose pulmonary E. coli inoculation. CONCLUSIONS: Defective host pulmonary antimicrobial immune responses during TPN are associated with intestinal bacterial translocation, and may explain increased infectious complications.

Animals↗

PubMed1994

Intestinal microbial translocation: immunologic consequences and effects of interleukin-4.

BACKGROUND: Administration of a chemically defined, liquid, elemental diet (CDD) results in intestinal microbial translocation, but the immunologic consequences of this process are unclear. This study evaluated the effects of CDD feeding and interleukin-4 (IL-4) administration on mesenteric lymphocyte, peritoneal macrophage (PMO), and hepatic Kupffer cell (KC) functions. METHODS: BALB/C mice (n = 60) were randomized to receive a paired feeding of regular diet (RD) or a CDD for 14 days. Mesenteric lymph nodes (MLN) and cecum were cultured for bacteria. Mixed lymphocyte response and cytotoxic T-lymphocyte function of MLN lymphocytes were assayed. PMO and KC were harvested to measure tumor necrosis factor production, macrophage binding of fluorescent-labeled lipopolysaccharide, and Candida albicans phagocytosis (CAP) and killing (CAK); KC-hepatocyte interaction was assessed by hepatocyte protein synthesis. In a second study 75 BALB/c mice received RD, CDD, and CDD+IL-4 (30,000 units/mouse intraperitoneally). MLN lymphocyte and PMO functions were measured and intestinal immunoglobulin A levels were determined. RESULTS: Oral feeding of a CDD resulted in significant impairment of mesenteric lymphocyte mixed lymphocyte response and cytotoxic T-lymphocyte functions and decreased PMO tumor necrosis factor production, fluorescent-labeled lipopolysaccharide binding, CAP, and CAK. KC function was preserved in CDD-fed mice. Administration of IL-4 significantly reduced the incidence of bacteria positive MLN and increased PMO superoxide production, CAP, CAK, and MLN lymphocyte mitogenesis. CONCLUSIONS: Use of IL-4 may be beneficial in situations where intestinal microbial translocation contributes to sepsis.

Animals↗

PubMed1993

Macrophage-dependent candidacidal mechanisms in the murine system. Comparison of murine Kupffer cell and peritoneal macrophage candidacidal mechanisms.

Candida albicans infection is common in immunocompromised patients. The role of fixed tissue macrophages (M phi), including Kupffer cells (KC) and peritoneal macrophages (PM phi), in host defense against C. albicans is unclear. This study examined murine M phi candidacidal mechanisms and evaluated the in vitro role of the macrophage-activating factor IFN-gamma in augmenting these mechanisms. The effect of in vivo administration of IFN-gamma on survival after lethal C. albicans challenge in the murine system was also assessed. Percent PM phi and KC ingestion of C. albicans were similar. Prior opsonization of Candida increased the percentage of M phi ingestion of this pathogen. PM phi and KC phagocytic function was similar for both nonopsonized and opsonized C. albicans, but KC demonstrated markedly decreased ability to kill this pathogen (O2-, Candida killing). IFN-gamma enhanced KC and PM phi candidacidal activity. PM phi and KC Ag presentation was increased in early Candida infection, but diminished in established infection, when the majority of animals died. C. albicans failed to elicit significant amounts of either IL-1 or TNF compared with LPS stimulation of PM phi and KC in vitro. IFN-gamma treatment in vivo was associated with significantly improved survival (p < 0.01).

Animals↗

PubMed1993

Role of bactericidal permeability-increasing protein in the treatment of gram-negative pneumonia.

BACKGROUND: Gram-negative infections are a major cause of morbidity and death. Bactericidal permeability-increasing protein (BPI) is an endotoxin-neutralizing protein that also exhibits potent bactericidal activity. This study compared the efficacy of a 23 kd recombinant N-terminal fragment of BPI (rBPI23) with that of antiendotoxin antibody E5 in a model of gram-negative sepsis. METHODS: Sixty Swiss-Webster mice (Carworth farm) received an intratracheal inoculation of Escherichia coli (7 x 10(6) colony-forming units) and were randomized to three groups (20 per group). Starting immediately after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses), E5 (11 mg/kg intravenously every 24 hours for two doses), or an isotype control antibody B55 (11 mg/kg intravenously every 24 hours for two doses) and were followed up for survival. In a second survival study, 40 mice received the same intratracheal inoculation of E. coli and were randomized to two groups. Starting 2 hours after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses) or E5 (8 mg/kg intravenously every 12 hours for four doses) and were followed up for survival. In a third study, mice received an intratracheal inoculation of 3 x 10(6) colony-forming units E. coli, a sublethal dose, and were killed to determine pulmonary and blood clearance of bacteria. RESULTS: rBPI23 conferred significantly greater protection from death than either E5 or B55 when started immediately (95% survival vs 20% and 10%, respectively; p < 0.001) or 2 hours after inoculation (65% survival vs 25% for E5; p < 0.05). Both pulmonary and vascular clearance of bacteria was enhanced significantly by treatment with rBPI23. CONCLUSIONS: rBPI23 may be a novel therapeutic agent in the management of gram-negative sepsis.

Animals↗