Impact of Sarcopenic Obesity on Severe Postoperative Complications in Patients with Gastric Cancer Undergoing Gastrectomy.

INTRODUCTION: Several studies have indicated that sarcopenia affects the short- and long-term outcomes of cancer patients, including those with gastric cancer. In recent years, sarcopenic obesity and its effects have been reported in cancer patients. This study aimed to evaluate the impact of sarcopenic obesity on postoperative complications in patients with gastric cancer undergoing gastrectomy. METHODS: This single-center, retrospective study included 155 patients who underwent curative gastrectomy for gastric cancer from January 2015 to July 2021. Sarcopenia was defined by the psoas muscle index (<6.36 cm2/m2 in men and <3.92 cm2/m2 in women), which measures the iliopsoas muscle area at the lumbar L3 level using computed tomography. Obesity was defined by body mass index (≥25). Patients with both sarcopenia and obesity were defined as the sarcopenic obesity group and others as the non-sarcopenic obesity group. Severe postoperative complications were defined as Clavien-Dindo classification grade IIIa or higher. RESULTS: Of the 155 patients, 26 (16.8%) had sarcopenic obesity. The incidence of severe postoperative complications was significantly higher in the sarcopenic obesity group (30.8% vs. 10.9%; p = 0.014). Multivariate analysis indicated that sarcopenic obesity was an independent risk factor for severe postoperative complications (odds ratio, 3.950; 95% confidence interval, 1.390-11.200; p = 0.010). CONCLUSION: Sarcopenic obesity is an independent risk factor for severe postoperative complications.

Laparoscopic-assisted modified Kugel herniorrhaphy for obturator hernia: a case report.

Obturator hernia (OH) is a relatively rare disease and there are various surgical procedures for treating it. We report the case of a patient with an OH who underwent laparoscopic-assisted modified Kugel herniorrhaphy. The patient was a 74-year-old woman admitted to our hospital with nausea and abdominal distension. A diagnosis of intestinal obstruction was made because abdominal computed tomography revealed incarcerated right OH. No apparent strangulation findings were observed, and reduction was performed under ultrasound guidance. Laparoscopic-assisted modified Kugel herniorrhaphy for OH was performed. There were no signs of the bowel necrosis. Pneumoperitoneum was temporarily discontinued, and the OH was repaired by the modified Kugel herniorrhaphy. Laparoscopy confirmed that the direct Kugel patch was placed at the appropriate position. Laparoscopic-assisted modified Kugel herniorrhaphy is considered to be safe and useful for patients with OH and is considered as one of the treatment options.

[Surgical Resection of Solitary Brain Metastasis from Breast Cancer].

BACKGROUND: Brain metastasis from breast cancer has a poor prognosis. For solitary cerebral metastases, surgical resection may contribute to the improvement of survival and QOL. We studied the prognosis and characteristics of solitary brain metastasis from breast cancer in patients undergoing surgical resection. METHODS: Seventeen patients had tumors metastatic to the brain at Kasukabe Municipal Hospital between June 2009 and May 2016, and 7 of them underwent craniotomy. Their treatment outcomes were analyzed retrospectively. RESULTS: The median age at diagnosis of brain metastasis was 56 years. The median survival duration was 19.6 months. With regard to radiation therapy after surgery, 3 patients received whole brain irradiation, 2 patients received stereotactic brain irradiation, and 2 patients received both. The site of brain metastasis was the cerebellum in 6 patients, and the occipital lobe in 1 patient. The number of HER2-positive breast cancer patients was 5, and lapatinib and capecitabine were administered to 4 out of these 5 patients. CONCLUSION: For solitary brain metastasis, the improvement in symptoms and the extension of the survival can be achieved using multidisciplinary treatment with surgery, radiation, and molecular targeting drugs.

Expression of peroxiredoxin I regulated by gonadotropins in the rat ovary.

OBJECTIVE: Peroxiredoxins (Prxs) play an important role in regulating cellular differentiation and proliferation in several types of mammalian cells. This report examined the expression of Prx isotype I in the rat ovary after hormone treatment. METHODS: Immature rats were injected with 10 IU of pregnant mare's serum gonadotropin (PMSG) to induce the growth of multiple preovulatory follicles and 10 IU of human chorionic gonadotropin (hCG) to induce ovulation. Immature rats were also treated with diethylstilbestrol (DES), an estrogen analogue, to induce the growth of multiple immature follicles. Northern blot analysis was performed to detect gene expression. Cell-type specific localization of Prx I mRNA were detected by in situ hybridization analysis. RESULTS: During follicle development, ovarian Prx I gene expression was detected in 3-day-old rats and had increased in 21-day-old rats. The levels of Prx I mRNA slightly declined one to two days following treatment with DES. A gradual increase in Prx I gene expression was observed in ovaries obtained from PMSG-treated immature rats. Furthermore, hCG treatment of PMSG-primed rats resulted in a gradual stimulation of Prx I mRNA levels by 24 hours (2.1-fold increase) following treatment, which remained high until 72 hours following treatment. In situ hybridization analysis revealed the expression of the Prx I gene in the granulosa cells of PMSG-primed ovaries and in the corpora lutea of ovaries stimulated with hCG for 72 hours. CONCLUSION: These results demonstrate the gonadotropin and granulosa cell-specific stimulation of Prx I gene expression, suggesting its role as a local regulator of follicle development.

Parenteral feeding depletes pulmonary lymphocyte populations.

BACKGROUND: The effect of parenteral nutrition (PN) on lymphocyte mass in the lung is unknown, but reduced mucosal lymphocytes are hypothesized to play a role in the reduced immunoglobulin A-mediated immunity in both gut and lung. The ability to transfer and track cells between mice may allow study of diet-induced mucosal immune function. The objectives of this study are to characterize lung T-cell populations following parenteral feeding and to study distribution patterns of transferred donor lung T cells in recipient mice. METHODS: In experiment 1, cannulated male Balb/c mice are randomized to receive chow or PN for 5 days. Lung lymphocytes are obtained via collagenase digestion, and flow cytometric analysis is used to identify total T (CD3+) and B (CD45/B220+) cells. In experiment 2, isolated lung T cells from chow-fed male Balb/c mice are pooled and labeled in vitro with a fluorescent dye (carboxyfluorescein diacetate succinimidyl ester [CFSE]), and 1.1 x 10(8) CFSE+ cells (3.1 x 10(6) T cells) are transferred to chow-fed Balb/c recipients. Cells recovered from recipient lungs and intestinal lamina propria (LP) are analyzed by flow cytometry to determine CFSE/CD3+ T cells at 1, 2, and 7 days. In experiment 3, cells are transferred to PN-fed recipients. RESULTS: In experiment 1, PN significantly decreases lung T- and B-cell populations compared with chow feeding. In experiment 2, CFSE+ T-cell retention is highest on day 1 in lung and LP, and decreases on day 2. Cells are gone by day 7; 98.1% of retained donor lung T cells migrate to recipient lungs and 1.9% to the intestine on day 1. Similar results are seen in experiment 3 after transfer of cells to PN-fed recipients. CONCLUSIONS: PN reduces pulmonary lymphocyte populations consistent with impaired respiratory immunity. Transferred lung T cells preferentially localize to recipient lungs rather than intestine with maximal accumulation at 24 hours. Limited cross-talk of transferred lung T cells to the intestine indicates that mucosal lymphocyte traffic might be programmed to localize to specific effector sites.

Parenteral nutrition maintains pulmonary IgA antibody transport capacity, but not active transport, following injury.

BACKGROUND: Parenteral nutrition (PN) increases post-trauma pneumonia versus enteral feeding. PN impairs murine immunoglobulin A (IgA) airway defenses and abrogates a normal IgA increase following injury. This work investigates the effect of type/route of nutrition on lung IgA and its transport protein, polymeric immunoglobulin receptor (pIgR), after injury. METHODS: Catheterized mice were randomized to Chow or PN for 5 days and sacrificed without injury (Chow: n = 12; PN n = 11), or 8 hours after laparotomy + neck incisions (Chow-injury: n = 11, PN-injury: n = 13). Bronchoalveolar lavage (BAL) and lung IgA levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and lung pIgR by Western blot. RESULTS: BAL IgA levels increased in Chow-injury versus PN-injury (P <.01) with no differences in pIgR. PN-injury tissue IgA levels decreased versus Chow (P <.01), Chow-injury (P <.01), and PN (P <.05). CONCLUSIONS: PN impairs the airway IgA response to injury but not due to impaired IgA transport capacity/pIgR level.

Parenteral nutrition induces organ specific alterations in polymeric immunoglobulin receptor levels.

BACKGROUND: Secretory immunoglobulin A (IgA) prevents pathogen adherence at mucosal surfaces to prevent infection. Polymeric immunoglobulin receptor (pIgR), located on the basolateral surface of mucosal cells, binds dimeric IgA produced by B cells with the cooperation of T cells in the lamina propria. This IgA-pIgR complex is transported apically, where it is exocytosed as secretory IgA to the mucosal surface. Our prior work shows that parenteral nutrition (PN) impairs both airway and small intestine mucosal immunity by reducing T and B cells and IgA levels. This work examines intestinal and respiratory tissue-specific pIgR responses to PN. METHODS: Cannulated male Institute of Cancer Research mice were randomized to Chow (n = 10) or PN (n = 10). After 5 days, animals were sacrificed and lavages obtained from the small intestine, lung (BAL = bronchoalveolar lavage), and nasal airways (NAL). Small intestine, lung, and nasal passage tissues were also collected. Lavage and tissue homogenate IgA levels were quantified by enzyme-linked immunosorbent assay and pIgR by Western blot. RESULTS: PN group SIL and NAL IgA levels dropped significantly compared with Chow. PN significantly reduced pIgR levels in the SI while no pIgR change was noted in nasal passages and lung pIgR actually increased with PN. Tissue homogenate IgA levels did not change with PN in the SI while levels in the nasal passage and lung decreased. CONCLUSIONS: PN impairs airway mucosal immunity by reduction in IgA available for transport rather than via a reduction in pIgR levels. In the small intestine, diminished pIgR is implicated in the deterioration of antibody-mediated mucosal immunity.

Parenteral nutrition inhibits tumor necrosis factor-alpha-mediated IgA response to injury.

BACKGROUND: Parenteral nutrition (PN) increases the incidence of pneumonia in severely injured patients compared with enteral feeding (ENT). Injury induces an innate airway IgA response in severely injured patients; similar responses occur in mice. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) stimulate the production of polymeric immunoglobulin receptor (pIgR), the protein required to transport immunoglobulin A (IgA) to mucosal surfaces. We have shown that PN alters levels of lung and nasal passage IgA and several IgA-stimulating cytokines. We hypothesized that TNF-alpha and IL-1beta blockade, as well as PN, would blunt the airway IgA response to injury. METHODS: Male Institute of Cancer Research (ICR) mice were randomized to uninjured controls (n = 10) or to intra-peritoneal phosphate-buffered saline (PBS) (n = 9), antagonistic TNF-alpha antibody (100 mcg, n = 7), or antagonistic IL-1beta antibody (50 mcg, n = 8) 30 min prior to surgical stress with laparotomy and neck incisions. Mice were sacrificed at 8 h for nasal and bronchoalveolar lavage (NAL, BAL) to measure IgA by enzyme-linked immunosorbent assay. In a separate experiment, 12 mice underwent intravenous cannulation followed by chow (n = 5) or PN (n = 7) feeding for 5 days prior to the same stress and IgA measurement. RESULTS: Injury significantly increased NAL and BAL IgA (225 +/- 104 ng) compared with baseline (145 +/- 38 ng; p = 0.01). Blockade of TNF-alpha eliminated the innate airway IgA response to injury (130 +/- 47 ng; p = 0.01), whereas IL-1beta blockade blunted and PN eliminated it completely. CONCLUSIONS: Tumor necrosis factor-alpha is involved in the respiratory IgA immune response to injury. Both TNF-alpha blockade and PN impair this innate response, and blockade of IL-1beta impairs it to a degree. We hypothesize that these cytokines blunt this response via their known effects on the polymeric immunoglobulin receptor (pIgR), whereas the PN-induced deficit likely is multifactorial.

Decreased enteral stimulation alters mucosal immune chemokines.

BACKGROUND: Migration of lymphocytes into and through the mucosal immune system depends upon adhesion molecules to attract circulating cells and chemokines to stimulate diapedesis into tissues. Decreased enteral stimulation significantly reduces mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) levels, an adhesion molecule critical for homing of T and B cells to Peyer's patches (PP), which reduces PP and intestinal T and B cells. We studied the effect of type and route of nutrition on tissue specific chemokines in PP (CXCL-12, -13 and CCL-19, -20 and -21), small intestine (SI; CCL-20, -25 and -28) and lung (CXCL-12, CCL-28). METHODS: Intravenously cannulated male Institute of Cancer Research (ICR) mice were randomized to chow or parenteral nutrition (PN) for 5 days. PP, SI, and lung chemokine mRNA levels were measured using real-time qRT-polymerase chain reaction, and analyzed semiquantitatively by the DeltaDeltaCt method. Protein levels were quantified using enzyme-linked immunosorbent assay (ELISA) techniques, and groups compared using Student's t-test. RESULTS: PP CXCL13 protein significantly decreased, whereas CCL21 protein increased significantly in the parenterally fed group. Parenteral feeding significantly decreased SI CCL20 and CCL 25 protein levels. CCL28 decreased significantly in the SI and lung of intravenously fed animals. mRNA levels changed in the opposite direction (compared with protein) for all chemokines except CCL28. CONCLUSIONS: Decreased enteral stimulation significantly alters key mucosal immune chemokine protein levels at multiple sites. In general, PN (and concomitant lack of enteral stimulation) results in decreased levels of chemokines that control lymphocyte migration within the mucosal immune system.

Enteral feeding of a chemically defined diet preserves pulmonary immunity but not intestinal immunity: the role of lymphotoxin beta receptor.

BACKGROUND: Compared with chow or a complex enteral diet (CED), IV administration of a parenteral nutrition solution (IV-PN) impairs intestinal and respiratory mucosal immunity, resulting in cellular and immunoglobulin A (IgA) defects in the intestine and impaired respiratory antiviral and antibacterial defenses. PN given intragastrically (IG-PN) impairs intestinal immunity similar to IV-PN but preserves antiviral defences and partially preserves antibacterial defenses. Lymphotoxin beta receptor (LTbetaR) is a molecule essential for development and organization of lymphoid tissue. It controls many molecules important in mucosal immune integrity. This study examines effects of route (IV or enteral) and type (PN, CED, or chow) on murine intestine and lung LTbetaR expression. METHODS: Forty-three mice randomly received IV-PN (n = 12), IG-PN (n = 11), IV saline + chow (chow; n = 11), or a CED (n = 9). After 5 days of feeding, intestinal and lung samples were obtained and processed for levels of LTbetaR by Western blot. RESULTS: IV-PN significantly reduced intestinal and lung LTbetaR compared with CED and chow. IG-PN reduced LTbetaR levels only in the intestine but preserved lung levels. CONCLUSIONS: Route and type of nutrition differentially influence molecular events in the intestinal and respiratory mucosal immune systems. Enteral feeding with any diet (complex or chemically defined) maintains lung LTbetaR expression, whereas intestinal LTbetaR levels are maintained only with CEDs (chow and CED). We hypothesize that LTbetaR is responsible for the observed preservation of respiratory tract immunity with administration of a noncomplex, chemically defined enteral diet, whereas intestinal immunity is compromised with this diet.

Effects of lymphotoxin beta receptor blockade on intestinal mucosal immunity.

BACKGROUND: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) directs lymphocyte migration into gut-associated lymphoid tissue (GALT) through Peyer's patches (PPs). Parenteral nutrition (PN) impairs mucosal immunity by reducing PPs MAdCAM-1 expression, T and B cells in GALT, and intestinal and respiratory immunoglobulin (Ig) A levels. We previously showed that PN reduces lymphotoxin beta receptor blockade (LTbetaR) in PPs and intestine, and that stimulation with LTbetaR agonist antibodies reverses these defects. To confirm that LTbetaR regulates transcription of MAdCAM-1 message and more fully understand the effects of LTbetaR on MAdCAM-1 function within the mucosal immune system, we studied the effect of LTbetaR blockade with a chimeric LTbetaR Ig-fusion protein on MAdCAM-1 mRNA levels, PP lymphocyte mass and IgA levels in the intestinal and respiratory tracts. METHODS: Mice were cannulated and killed 3 days after receiving chow + control Ig, chow + LTbetaR-Ig fusion protein (100 microg IV), or PN + control Ig. The PPs of half of the animals were processed for lymphocyte count, and the other half were processed for complementary DNA and subsequent polymerase chain reaction (PCR). mRNA levels of MAdCAM-1 were determined by real-time PCR; intestinal and respiratory IgA levels were measured by ELISA. RESULTS: PN significantly reduced PP lymphocyte mass, MAdCAM-1 mRNA, and intestinal IgA. As anticipated, LTbetaR blockade significantly decreased PP cells and MAdCAM-1 mRNA, but not intestinal IgA because chow feeding was maintained. Both LTbetaR blockade and PN decreased nasal IgA, but not significantly. CONCLUSIONS: LTbetaR blockade in chow animals significantly reduces transcription of MAdCAM-1 gene and PPs lymphocyte mass. These data implicate inadequate LTbetaR signaling as a major mechanism for decreased GALT cells with lack of enteral stimulation, and further establish the role of LTbetaR in the mucosal immune system.

Intestinal polymeric immunoglobulin receptor is affected by type and route of nutrition.

BACKGROUND: Secretory immunoglobulin A (SIgA) prevents adherence of pathogens at mucosal surfaces to prevent invasive infection. Polymeric immunoglobulin receptor (pIgR) is located on the basolateral surface of epithelial cells and binds dimeric immunoglobulin A (IgA) produced by plasma cells in the lamina propria. This IgA-pIgR complex is transported apically, where IgA is exocytosed as SIgA to the mucosal surface. Our prior work shows that mice fed intragastric (IG, an elemental diet model) and IV parenteral nutrition (PN) solution have reduced intestinal T and B cells, SIgA, and interleukin-4 (IL-4) compared with mice fed chow or a complex enteral diet (CED). Prior work also demonstrates a reduction in IgA transport to mucosal surfaces in IV PN-fed mice. Because IL-4 up-regulates pIgR production, this work studies the effects of these diets on intestinal pIgR. METHODS: Male Institute of Cancer Research (ICR) mice were randomized to chow (n = 11) with IV catheter, CED (n = 10) or IG PN (n = 11) via gastrostomy and IV PN (n = 12) for 5 days. CED and PN were isocaloric and isonitrogenous. Small intestine was harvested for pIgR and IL-4 assays after mucosal washing for IgA. IgA and IL-4 levels were analyzed by enzyme-linked immunosorbent assay and pIgR by Western blot. RESULTS: Small intestinal pIgR expression, IgA levels, and IL-4 levels decreased significantly in IV PN and IG PN groups. CONCLUSIONS: Lack of enteral stimulation affects multiple mechanisms responsible for decreased intestinal SIgA levels, including reduced T and B cells in the lamina propria, reduced Th-2 IgA-stimulating cytokines, and impaired expression of the IgA transport protein, pIgR.

Nutritional route affects ERK phosphorylation and cytokine production in hepatic mononuclear cells.

OBJECTIVE: To clarify the influence of nutritional route on hepatic immunity in a murine model. SUMMARY BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Preservation of hepatic immunity with enteral feeding is important for prevention of infectious complications in severely injured and/or critically ill patients.

Is there evidence that the gut contributes to mucosal immunity in humans?

BACKGROUND: Our understanding of the common mucosal immune system derives from animal studies. Antigen-sensitized lymphocytes in the gut-associated lymphoid tissue (GALT) migrate via the blood to mucosal tissues to generate the mucosal-associated lymphoid tissue (MALT). In these sites, B cells differentiate into plasma cells and produce antigen-specific secretory IgA, the principal specific immune antiviral and antibacterial defense of moist mucosal surfaces. Responses to oral intake seem necessary to actively maintain this system in health. Experimentally, lack of enteral stimulation with parenteral feeding alters GALT and MALT size and function. These alterations disturb intestinal and extraintestinal mucosal immunity. METHODS: This review is an overview of current and classical studies demonstrating the human mucosal immune system and interactions with nutrition. RESULTS: Human evidence of the mucosal immune system exists, although most data are indirect. Gut stimulation after oral intake induces a generalized immune response in the human MALT through a mucosal-immune network. Examples include neonatal development of GALT influenced by enteral feeding, the presence of antigen-specific IgA and antigen-specific IgA-secreting plasma cells in distant mucosal effector sites such as the breast after gut luminal antigen exposure, and isolation of IgA-producing cells from circulating blood. CONCLUSIONS: It is unlikely that clinical studies will ever completely define the effect of route of feeding in all patient populations. This may be possible, however, if investigators understand, define and characterize nutrition-dependent immunologic mechanisms, allowing clinicians to examine clinical responses to nutrition in specific patient populations. This might allow generation of new approaches to protect mucosal immunity.

Lack of enteral nutrition blunts extracellular-regulated kinase phosphorylation in gut-associated lymphoid tissue.

The mitogen-activated protein kinase (MAPK) family (extracellular-regulated kinase [ERK], p38, etc.) of signal transduction proteins includes important intracellular mediators of inflammation, playing critical roles in host defense. Phosphorylations of ERK and p38 are responsible for cell proliferation, cell differentiation, and cell death. We hypothesized that impaired gut-associated lymphoid tissue (GALT) function in the absence of enteral nutrition is associated with reduced MAPK phosphorylation in GALT cells. Fifty-three male Institute of Cancer Research mice were randomized into 3 groups; ad libitum chow, intragastric (i.g.)-TPN, and intravenous (i.v.)-TPN. TPN groups were administered a standard TPN solution. After 5 days of feeding, lymphocytes from Peyer patches (PPs), the lamina propria (LP) cells, and intraepithelial (IE) spaces in the small intestine were isolated. GALT lymphocyte numbers were determined. The lymphocytes were incubated with or without 50 ng/mL of phorbol myristate acetate (PMA) for 15 min, and phosphorylated ERK (p-ERK) and p38 (p-p38) levels were determined using laser scanning cytometry. In PP (GALT inductive site) lymphocytes, p-ERK was increased after PMA in all three groups. However, ERK phosphorylation in GALT effector sites (IE and LP) was enhanced only in the enteral groups. p38 phosphorylation was not increased in any GALT sites, in any of the three groups, in response to PMA. In another set of mice (n = 33), in vitro LP lymphocyte proliferation was assessed with BrdU with or without PMA. Cell proliferation was increased or maintained at high level with PMA in the i.g.-TPN and chow group, but remained low in the i.v.-TPN group. In conclusion, lack of enteral feeding blunts ERK activation and cell proliferation in response to PMA stimulation in GALT effector sites, which may be an important mechanism underlying reduced GALT function. The influence of nutrition on GALT p38 phosphorylation must be assessed with other types and dosages of stimulants.

Parenteral nutrition and fasting reduces mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) mRNA in Peyer's patches of mice.

BACKGROUND: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) in Peyer's patches (PP) is the gateway molecule for cellular migration into the mucosal immune system. Lack of enteral feeding during parenteral nutrition (PN) rapidly decreases PP MAdCAM-1, leading to drops in mucosal T and B cells and intestinal and respiratory IgA. We determined the molecular events associated with MAdCAM-1 mRNA and protein during PN (short and long term) and fasting (1 and 2 days). METHODS: Experiment 1: Cannulated mice received PN for 8 hours (short-term PN, n = 6) or chow + saline (chow, n = 6). Experiment 2: Cannulated mice received PN (long-term PN, n = 4) or chow (n = 3) for 5 days. Experiment 3: Noncannulated chow mice were fasted for 1 and 2 days (n = 2/time). Total cellular RNA from the PP was quantified for MAdCAM-1 mRNA by real-time polymerase chain reaction (PCR). MAdCAM-1 protein was measured by Western blot. RESULTS: PN rapidly down-regulated MAdCAM-1 gene expression. After 8 hours of PN with lack of enteral feeding, MAdCAM-1 mRNA levels dropped 20% (0.8-fold vs chow, p > .05); 5 days of PN reduced MAd-CAM-1 levels 64% (0.34-fold vs chow, p < .05). PN reduced MAdCAM-1 protein levels by 30% (chow: 329 +/- 14 vs PN: 230 +/- 35, p < .05) after 5 days. Fasting of uncannulated mice decreased MAdCAM-1 mRNA levels by 16% (0.84-fold, p < .05) at day 1 and 30% (0.7-fold, p < .05) by day 2 compared with chow. CONCLUSIONS: Both PN with lack of enteral feeding and fasting down-regulate MAdCAM-1 mRNA and protein levels in PP. The MAdCAM-1 changes are due to lack of enteral stimulation rather than toxic effects of PN.

Parenteral nutrition impairs gut-associated lymphoid tissue and mucosal immunity by reducing lymphotoxin Beta receptor expression.

OBJECTIVE: To determine the effects of parenteral nutrition (PN) on LTbetaR in gut-associated lymphoid tissue (GALT), particularly the intestine and Peyer's patches (PP). SUMMARY BACKGROUND DATA: Lack of enteral stimulation with PN impairs mucosal immunity and reduces IgA levels through depression of GALT cytokines (IL-4 and IL-10) and GALT specific adhesion molecules. We have shown that each is critical to intact mucosal immunity through effects on lymphocyte homing, IgA production, and resistance to antibacterial and antiviral immunity. IgA is the principal specific immunologic mucosal defense. LTbetaR stimulation controls production of IL-4, the adhesion molecule MAdCAM-1, and other key components of GALT, all of which are important in increasing IgA levels and maintaining mucosal defenses. METHODS: Experiment 1: LTbetaR expression in intestine and PP was analyzed by Western blot after 5 days of chow, a complex enteral diet (CED), or PN. Diets were isocaloric and isonitrogenous except for chow. Experiment 2: After completing pilot experiments to determine the appropriate dose of the LTbetaR agonistic antibody, mice received chow, PN + 5 mug of anti-LTbetaR mAb (2 times/d, i.v.) or PN + isotype control antibody. PP lymphocytes and intestinal IgA levels were measured after 2 days. RESULTS: Lack of enteral stimulation with PN significantly decreased LTbetaR expression in intestine and PP compared with chow and CED. LTbetaR stimulation with an agonistic anti-LTbetaR mAb significantly increased PP lymphocyte counts and intestinal IgA in PN fed-mice. CONCLUSIONS: LTbetaR expression is critical for GALT control mechanisms and intact mucosal immunity. PN reduces LTbetaR expression, PP lymphocytes, and intestinal IgA production. Exogenous LTbetaR stimulation reverses PN-induced depression of gut mucosal immunity.

Lack of enteral nutrition delays nuclear factor kappa B activation in peritoneal exudative cells in a murine glycogen-induced peritonitis model.

BACKGROUND: Early enteral nutrition is associated with a lower incidence of intraabdominal abscess in severely injured patients than parenteral nutrition (PN). We explored the underlying mechanisms by examining the influence of nutrition route on nuclear factor kappaB (NFkappaB) activation in peritoneal exudative cells (PECs) and peritoneal cytokine levels. METHODS: Thirty male Institute Cancer Research mice were randomized to chow (n = 10), IV PN (n = 10), or intragastric (IG) PN (n = 10) and fed for 5 days. PECs were harvested at 2 or 4 hours after intraperitoneal injection of 2 mL of 1% glycogen. Intranuclear NFkappaB activity in PECs was examined by laser scanning cytometry. Cytokine (tumor necrosis factor-alpha [TNF-alpha], macrophage inflammatory protein-2 [MIP-2], interleukin-10 [IL-10]) levels in peritoneal lavaged fluid were determined by enzyme-linked immunosorbent assay. RESULTS: Intranuclear NFkappaB at 2 hours was significantly higher in the chow and IG-PN groups than in the IV-PN group. TNF-alpha and IL-10 levels of the chow group were significantly higher than those of IV-PN mice at 2 hours, whereas those of IG-PN mice were midway between those of the chow and IV-PN groups. MIP-2 was significantly higher in the chow group than in the IG-PN and IV-PN mice at 2 hours. TNF-alpha levels correlated positively with intranuclear NFkappaB activity in PECs. CONCLUSIONS: Enteral nutrition may improve peritoneal defense by preserving early NFkappaB activation in PECs and cytokine responses.

Route and type of nutrition influence nuclear factor kappaB activation in peritoneal resident cells.

Morbidity of intra-abdominal abscess is increased when severely injured patients are fed parenterally. Lack of enteral nutrition appears to impair peritoneal cavity host defense. Because the transcription factor nuclear factor kappaB (NFkappaB) regulates various genes involved in inflammatory responses and its activation is important for host defense, we hypothesized that enteral nutrition would preserve appropriate NFkappaB activation in peritoneal resident cells (PRCs), the first defense line against peritoneal contamination. Mice (n = 105) were randomized to chow (n = 38), intravenous (IV)-total parenteral nutrition (TPN) (n = 34), or intragastric (IG)-TPN (n = 33) for 5 days' feeding. In experiment 1, PRCs were harvested for measurement of intranuclear NFkappaB activity with or without in vitro lipopolysaccharide (LPS) stimulation using laser scanning cytometry and enzyme-linked immunoabsorbant assay. PRC numbers tended to be higher in enterally fed mice than in IV-TPN mice. The main PRC subpopulation was macrophages in all groups. NFkappaB activation was increased in response to LPS in chow mice, whereas there was no increase in the IV-TPN group. IG-TPN mice demonstrated moderate NFkappaB activation. In experiment 2, mice underwent cecal ligation and puncture (CLP). Survival was observed up to 5 days. In another set of mice, tumor necrosis factor (TNF) alpha levels of peritoneal lavaged fluid were measured 4 h after CLP. Survival times after CLP improved in the chow and IG-TPN groups compared with the IV-TPN group. TNFalpha levels were significantly higher in the chow than in the IV-TPN group. In conclusion, parenteral nutrition decreases PRC number and blunts NFkappaB activation in PRCs. These changes may impair host defense in the peritoneal cavity.

Brief refeeding rapidly reverses dietary restriction-induced nuclear factor-kappaB downregulation in peritoneal resident cells.

BACKGROUND: Malnutrition impairs host immunity, resulting in high mortality and morbidity, secondary to infections. Nuclear factor kappaB (NFkappaB) plays a critical role in host defense, but how quickly refeeding normalizes the impaired NFkappaB activity in peritoneal resident cells (PRCs) is unknown. Our aim was to investigate the effects of 1-day ad libitum refeeding on severe diet restriction-induced NFkappaB activity in PRCs. METHODS: Mice received chow, 146 g/kg per day (ad libitum) or 36.5 g/kg per day (severe diet restriction), for 7 days. One-half the mice in the diet-restricted group were then fed ad libitum for 1 day (refeeding). PRCs were harvested by peritoneal lavage. After incubation with tumor necrosis factor-alpha (TNF-alpha), nuclear translocation of NFkappaB in PRCs was investigated using laser scanning cytometry. RESULTS: The main subpopulation of PRCs was macrophages in all groups. Mean fluorescence intensity over the nuclear area at 0 or 100 ng/mL of TNF-alpha was 16 +/- 2 or 31 +/- 8* in the ad libitum, 20 +/- 4 or 19 +/- 3 in the severe diet-restricted, and 20 +/- 4 or 30 +/- 5* in the refeeding group, respectively (*p < .05 versus 0 ng/mL of TNF-alpha in each group versus 100 ng/mL of TNF-alpha in diet-restricted group). Cytoplasmic accumulation of NFkappaB was significantly increased after TNF-alpha stimulation in the refed group but not in the ad libitum group. CONCLUSIONS: The blunted NFkappaB activity in PRCs, after exposure to inflammatory stimuli, was restored after 1 day of refeeding, with increased accumulation of NFkappaB in the cytoplasm. Even brief nutritional replenishment in malnutrition may improve host defense by restoring NFkappaB activity and thereby improving macrophage functions.