Fumie Ikezawa

National Defense Medical College, Tokorozawa, Saitama-ken, Japan

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Publications (9)24.61 Total impact

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    ABSTRACT: Parenteral nutrition (PN) is indispensable for meeting caloric and substrate needs of patients who cannot receive adequate amounts of enteral nutrition; however, PN impairs hepatic immunity. We examined the effects of ω-3 and -6 polyunsaturated fatty acids, added individually to fat-free PN, on hepatic immunity in a murine model. We focused on serum liver enzymes, cytokine production, histopathology, and the outcomes after intraportal bacterial challenge. Male Institute of Cancer Research mice were randomized into 4 groups; ad libitum chow (CHOW), fat-free PN (FF-PN), PN + fish oil (FO-PN), or PN + safflower oil (SO-PN). After the mice had been fed for 5 days, hepatic mononuclear cells (MNCs) were isolated. The number of MNCs was counted and cytokine production (tumor necrosis factor [TNF]-α and interleukin [IL]-10) by hepatic MNCs in response to lipopolysaccharide (LPS) was measured. Blood samples were analyzed for hepatobiliary biochemical parameters. Moreover, 1.0 × 10(7) pseudomonas aeruginosa were delivered by intraportal injection. Survival and histology were examined. Hepatic MNC numbers were significantly less in the FO-PN and FF-PN than in the CHOW group, whereas the SO-PN group showed moderate recovery of hepatic MNC numbers. The CHOW, FO-PN, and SO-PN groups showed LPS dose-dependent increases in TNF-α levels. These increases were blunted in the FF-PN group. IL-10 levels were increased LPS dose-dependently in the CHOW and FO-PN groups, but no marked changes were observed with LPS stimulation in the SO-PN and FF-PN groups. Plasma levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were significantly greater in the FF-PN than in the FO- and SO-PN and CHOW groups. The FO-PN group showed significantly improved survival compared with the SO-PN and FF-PN groups, showing essentially no morphologic hepatic abnormalities. Addition of fish oil to PN was advantageous in terms of reversing PN-induced deterioration of hepatic immunity, as reflected by altered cytokine production. Fish oil administration was also useful for preventing PN-induced hepatobiliary dysfunction. These changes seem to result in better survival and to protect against severe tissue damage after intraportal bacterial challenge. This therapy may have the potential to ameliorate PN-induced impairment of host immunity and thereby decrease morbidity and mortality.
    Surgery 01/2012; 151(5):745-55. · 3.37 Impact Factor
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    ABSTRACT: Although parenteral nutrition (PN) prevents progressive malnutrition, lack of enteral nutrition (EN) during PN leads to gut associated lymphoid tissue (GALT) atrophy and dysfunction. Administering a small amount of EN with PN reportedly prevents increases in intestinal permeability. However, its effects on GALT remain unclear. We analyzed the minimum amount of EN required to preserve gut immunity during PN. Male Institute of Cancer Research mice underwent jugular vein catheter insertion and tube gastrostomy. They were randomized into four groups to receive isocaloric and isonitrogenous nutritional support with variable EN to PN ratios (EN 0, EN 33, EN 66, and EN 100). EN was provided with a complex enteral diet. After 5 days of feeding, the mice were killed and whole small intestines were harvested. GALT lymphocytes were isolated and counted. Their phenotypes were analyzed by flow cytometry. IgA levels of small intestinal washings were analyzed with enzyme-linked immunosorbent assay. Body weight changes did not differ between any two of the groups. Peyer's patch lymphocyte numbers increased in proportion to EN amount, whereas lamina propria lymphocyte numbers were significantly higher in the EN 100 than in the EN 0 group, with no marked increases in the EN 33 and EN 66 groups. Small intestinal IgA levels increased EN amount-dependently and reached a plateau at EN 66. A small amount of EN partially reverses PN-induced GALT changes, suggesting beneficial but limited effects on gut mucosal immunity.
    The Journal of trauma 09/2008; 65(2):360-5; discussion 366. · 2.35 Impact Factor
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    ABSTRACT: To clarify the influence of nutritional route on hepatic immunity in a murine model. Parenteral nutrition is disadvantageous for preventing infectious complications in critically ill and/or severely injured patients as compared with enteral nutrition. To date, lack of enteral nutrition has been demonstrated to impair mucosal immunity, gut barrier function, and the peritoneal defense system. However, influences of nutritional route on hepatic immunity, another important defense system against infection, have not been well studied. Male ICR mice were randomized to 3 groups: ad libitum chow (chow), intravenous (IV)-TPN and intragastric (IG)-TPN groups. The TPN groups were given isocaloric and isonitrogenous TPN solutions. After the mice had been fed for 5 days, hepatic mononuclear cells (MNCs) were isolated. Hepatic MNC numbers and functions (cytokine production, intracellular signaling, and LPS receptor expression) were determined. Moreover, 1.0 x 10 Pseudomonas aeruginosa were delivered by intraportal injection. Survival and histology were examined. Hepatic MNC numbers were significantly lower in the IV-TPN group than in the chow and IG-TPN groups, without subpopulation changes. As compared with enterally fed mice, cytokine production (TNF-alpha, IFN-gamma, and IL-10) by hepatic MNCs in response to LPS was impaired in parenterally fed mice in association with blunted phosphorylation of ERK1/2, a MAPK. Hepatic MNCs from IV-TPN mice showed decreased expressions of CD14 and TLR4/MD2, as compared with enterally fed mice. Survival times were reduced in the IV-TPN group as compared with the chow and IG-TPN groups. Preservation of hepatic immunity with enteral feeding is important for prevention of infectious complications in severely injured and/or critically ill patients.
    Annals of Surgery 05/2007; 245(4):642-50. · 6.33 Impact Factor
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    ABSTRACT: Our recent study clarified that gut ischemia-reperfusion (I/R) causes gut-associated lymphoid tissue (GALT) mass atrophy, a possible mechanism for increased morbidity of infectious complications after severe surgical insults. Because albumin administration reportedly reduces hemorrhagic shock-induced lung injury, we hypothesized that albumin treatment prevents GALT atrophy due to gut I/R. Male mice (n = 37) were randomized to albumin, normal saline, and sham groups. All groups underwent jugular vein catheter insertion. The albumin and normal saline groups underwent 75-minute occlusion of the superior mesenteric artery. During gut ischemia, all mice received normal saline infusions at 1.0 mL/h. The albumin group was given 5% bovine serum albumin in normal saline at 1.0 mL/h for 60 minutes after reperfusion, whereas the normal saline group received 0.9% sodium chloride at 1.0 mL/h. The sham group underwent laparotomy only. Mice were killed on day 1 or 7, and the entire small intestine was harvested. GALT lymphocytes were isolated and counted. Their phenotypes (alphabetaTCR, gammadeltaTCR, CD4, CD8, B220) were determined by flow cytometry. On day 1, the gut I/R groups showed significantly lower total lymphocyte and B cell numbers in Peyer's patches and the lamina propria than the sham group. However, the albumin infusion partially but significantly restored these cell numbers. On day 7, there were no significant differences in any of the parameters measured among the 3 groups. Albumin infusion after a gut ischemic insult may maintain gut immunity by preventing GALT atrophy.
    Journal of Parenteral and Enteral Nutrition 01/2006; 30(5):380-6; discussion 386-7. · 2.49 Impact Factor
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    ABSTRACT: In the absence of enteral nutrient delivery, gut-associated lymphoid tissue (GALT) mass and function are reduced. The purpose of this study was to examine whether exogenous interleukin (IL)-7 treatment reverses intravenous (IV)-total parenteral nutrition (TPN)-induced changes in GALT, immunoglobulin (Ig) A levels, and gut barrier function. Eighty-nine mice were randomized to chow, TPN, or TPN + IL-7 (1 microg/kg, administered IV twice a day) and treated for 5 days. The entire small intestine was harvested and lymphocytes were isolated from Peyer's patches (PPs), intraepithelial (IE) spaces, and the lamina propria (LP). Small intestinal and bronchoalveolar IgA levels were measured. Proximal and distal small intestinal levels of IgA-stimulating (IL-10) and IgA-inhibiting (IFNgamma) cytokines were determined with enzyme-linked immunoabsorbant assay. Moreover, 1 x 10 live Pseudomonas aeruginosa were delivered by gavage and survival was observed. TPN decreased total cell yields from PPs, IE spaces, and the LP compared with the chow group. IL-7 treatment restored cell numbers. PP CD4+, PP CD8+, IE gammadeltaTCR+, and LP CD4+ cell numbers were higher in the TPN + IL-7 group than in the TPN group. Secretory IgA levels were lower in the TPN and TPN + IL-7 than in the chow group. In the distal small intestine, IFNgamma levels were similar in the three groups, whereas IL-10 levels were reduced in the TPN and TPN + IL-7 groups relative to the chow group. Survival times were reduced in the TPN compared with the chow group, but IL-7 treatment significantly improved survival. Thus, exogenous IL-7 does not improve secretory IgA levels, nor are there any remarkable effects on levels of gut IgA-mediating cytokines. However, IL-7 treatment during TPN reverses TPN-induced GALT atrophy and improves survival in a gut-derived sepsis model.
    Shock 01/2006; 24(6):541-6. · 2.61 Impact Factor
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    ABSTRACT: Long-term antibiotic administration is sometimes necessary to control bacterial infections during the perioperative period. However, antibiotic administration may alter gut bacterial flora, possibly impairing gut mucosal immunity. We hypothesized that 1 week of subcutaneous (SC) antibiotic injections would affect Peyer's patch (PP) lymphocyte numbers and phenotypes, as well as mucosal immunoglobulin A (IgA) levels. Sixty-one male Institute of Cancer Research mice were randomized to CMZ (cefmetazole 100 mg/kg, administered SC twice a day), IPM (imipenem/cilastatin 50 mg/kg x 2), and control (saline 0.1 mL x 2) groups. After 7 days of treatment, the mice were killed and their small intestines removed. Bacterial numbers in the small intestine were determined using sheep blood agar plates under aerobic conditions (n = 21). PP lymphocytes were isolated to determine cell numbers and phenotypes (CD4, CD8, alphabetaTCR, gammadeltaTCR, B220; n = 40). IgA levels in the small intestinal and bronchoalveolar washings were also measured with ELISA. Antibiotic administration decreased both bacterial number and the PP cell yield compared with the control group. There were no significant differences in either phenotype percentages or IgA levels at any mucosal sites among the 3 groups. Long-term antibiotic treatment reduces PP cell numbers while decreasing bacterial numbers in the small intestine. It may be important to recognize changes in gut mucosal immunity during long-term antibiotic administration.
    Journal of Parenteral and Enteral Nutrition 01/2006; 30(5):395-8; discussion 399. · 2.49 Impact Factor
  • Journal of Parenteral and Enteral Nutrition - J PARENT ENTER NUTR. 01/2006; 30(5):388-394.
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    ABSTRACT: Without enteral nutrition, the mass and function of gut-associated lymphoid tissue (GALT), a center of systemic mucosal immunity, are reduced. Therefore, new therapeutic methods, designed to preserve mucosal immunity during parenteral nutrition (PN), are needed. Our recent study revealed that exogenous interleukin-7 (IL-7; 1 microg/kg twice a day) restores the GALT cell mass lost during intravenous (IV) PN but does not improve secretory immunoglobulin A (IgA) levels. Herein, we studied the IL-7 dose response to determine the optimal IL-7 dose for recovery of GALT mass and function during IV PN. We hypothesized that a high dose of IL-7 would increase intestinal IgA levels, as well as GALT cell numbers. Male mice (n = 42) were randomized to chow, IL-7-0, IL-7-0.1, IL-7-0.33, IL-7-1 and IL-7-3.3 groups and underwent jugular vein catheter insertion. The IL-7 groups were fed a standard PN solution and received IV injections of normal saline (IL-7-0), 0.1, 0.33, 1, or 3.3 microg/kg of IL-7 twice a day. The chow group was fed chow ad libitum. After 5 days of treatment, the entire small intestine was harvested and lymphocytes were isolated from Peyer's patches (PPs), intraepithelial (IE) spaces, and the lamina propria (LP). The lymphocytes were counted and phenotypes determined by flow cytometry (alphabetaTCR, gammadeltaTCR, CD4, CD8, B cell). IgA levels of small intestinal washings were also examined using ELISA (enzyme-linked immunoabsorbent assay). IL-7 dose-dependently increased total lymphocyte numbers in PPs and the LP. The number of lymphocytes harvested from IE spaces reached a plateau at 1 microg/kg of IL-7. There were no significant differences in any phenotype percentages at any GALT sites among the groups. IgA levels of intestinal washings were significantly higher in the chow group than in any of the IL-7 groups, with similar levels in all IL-7 groups. Exogenous IL-7 dose-dependently reverses PN-induced GALT cell loss, with no major changes in small intestinal IgA levels. IL-7 treatment during PN appears to have beneficial effects on gut immunity, but other therapeutic methods are needed to restore secretory IgA levels.
    Journal of Parenteral and Enteral Nutrition 30(5):388-93; discussion 393-4. · 2.49 Impact Factor
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    ABSTRACT: Lack of enteral nutrition reduces gut-associated lymphoid tissue (GALT) mass and function, a mechanism underlying the increased morbidity of infectious complications in severely injured or critically ill patients. Strategies to restore parenteral nutrition (PN)-induced changes of GALT mass and function have been pursued. However, the influences of adding fish oil to PN on gut immunity remain to be clarified. Male Institute of Cancer Research (ICR) mice (n = 50) were randomized to 4 groups: ad libitum chow (chow), fat free PN (fat (-)-PN), PN + fish oil (FO-PN), and PN + safflower oil (SO-PN). The PN groups were given isocaloric and isonitrogenous PN solutions. The FO- and SO-PN groups received 20% of total calories from fat emulsions. After 5 days of feeding, lymphocytes from Peyer's patches (PPs), the intraepithelial space (IE), and the lamina propria (LP) of the entire small intestine were isolated. GALT lymphocyte numbers and phenotypes (CD4+, CD8+, alphabetaTCR+, gammadeltaTCR+, B220+ cells) were determined. Immunoglobulin A (IgA) levels of small intestinal washings were also measured by enzyme-linked immunosorbent assay. Another set of mice (n = 24) was used to determine plasma fatty acid compositions after feeding. Lymphocyte numbers from PPs and the LP and intestinal IgA levels were significantly lower in the PN groups than in the chow group, with no significant differences between any 2 PN groups. The FO- and SO-PN groups showed moderate recovery of IE cell numbers compared with the fat (-)-PN group. Omega-3 and omega-6 fatty acid levels were increased with fish and safflower oil additions, respectively, compared with the fat (-)-PN group. Adding fish oil to PN does not exacerbate PN-induced GALT changes but rather partially reverses these changes, with increased plasma omega-3 fatty acid levels.
    Journal of Parenteral and Enteral Nutrition 31(5):416-22. · 2.49 Impact Factor